Novel stereocontrolled approach to syn- and anti-oxepene-cyclogeranyl trans-fused polycyclic systems: Asymmetric total synthesis of (-)-Aplysistatin, (+)-Palisadin A, (+)-Palisadin B, (+)-12-hydroxy-Palisadin B, and the AB ring system of adociasulfate-2 a

Article abstract of DOI:10.1002/chem.200400407

A new stereocontrolled method for the formation of trans-anti cyclogeranyl-oxepene systems is described. The demanding stereochemistry is secured by stereoselective coupling of a cyclogeranyl tertiary alcohol with a 1,2-unsymmetrically substituted epoxide

Full text of DOI:10.1002/chem.200400407

FULL PAPER
Novel Stereocontrolled Approach to syn- and anti-Oxepene Cyclogeranyl
trans-Fused Polycyclic Systems: Asymmetric Total Synthesis of
(ꢀ)-Aplysistatin, (+)-Palisadin A, (+)-Palisadin B, (+)-12-Hydroxy-
Palisadin B, and the AB Ring System of Adociasulfate-2 and Toxicol A
Elias A. Couladouros*[a, b] and Veroniki P. Vidali[a, b]
Abstract:
A
new stereocontrolled
Since the stereochemistry of the trans-
fused 6,7-ring system is determined by
the epoxide, the method also allows
the construction of trans syn 6,7-ring
systems. This approach leads to the
synthesis of the AB fragment of Ado-
ciasulfate-2 and Toxicol A, for the first
time. The flexibility and efficiency of
the presented strategy is demonstrated
by the total asymmetric synthesis of
(ꢀ)-Aplysistatin, (+)-Palisadin A, (+)-
12-hydroxy-Palisadin B, and (+)-Palisa-
din B, employing two similar key inter-
mediates.
method for the formation of trans-anti
cyclogeranyl oxepene systems is de-
scribed. The demanding stereochemis-
try is secured by stereoselective cou-
pling of a cyclogeranyl tertiary alcohol
with a 1,2-unsymmetrically substituted
epoxide, while the formation of the
highly strained oxepene is achieved
employing ring-closing metathesis.
Keywords: epoxide opening reac-
tion ¥ natural products ¥ oxepenes ¥
ring-closing metathesis
synthesis
¥
total
Introduction
sistatin, he succeeded in cyclising olefin I in 62% yield
(Scheme 1a). However, key intermediate I was prepared in
low stereoselectivity, while in the following syntheses of re-
Polycyclic compounds possessing a trans-fused oxepane ring
abound in nature (Figure 1). They are classified as trans syn
systems, such as Brevetoxin B and related Dinoflagellate
metabolites,[1] and trans anti systems, including the selective
kinesin inhibitor Adociasulfate-2,[2] Toxicol A,[3], cytotoxic
Aplysistatin, and related bioactive halosesquiterpenoids,[4]
for example, Palisadin A, Palisadin B, and 12-hydroxy-Pali-
sadin B.
Regarding the first class, a large number of efficient meth-
odologies for the stereoselective construction of the cyclic
ether linkages has been developed,[5] mainly designed and
applied for this particular stereochemistry.[6] On the other
hand, only limited reports investigate the construction of
trans anti systems.[7] Besides the impressive pioneer ap-
proaches of Hoye, established more than twenty years
ago,[7a] no significant progress has been accomplished since.
In his methodology towards the total synthesis of (ꢁ)-Aply-
[a] Prof. Dr. E. A. Couladouros, V. P. Vidali
Chemistry Laboratories
Agricultural University of Athens
Iera Odos 75, Athens 118 55 (Greece)
Fax : (+30)210-677-7849
E-mail: ecoula@chem.demokritos.gr
[b] Prof. Dr. E. A. Couladouros, V. P. Vidali
Organic and Bioorganic Chemistry Laboratory
NCSR ™Demokritos∫, 153 10 Ag. Paraskevi, Athens (Greece)
Figure 1. Naturally occurring oxepane-containing fused polycyclic sys-
tems.
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200400407
Chem. Eur. J. 2004, 10, 3822 3835

3822 3835
Results and Discussion
Synthetic strategy: In an effort to circumvent the problems
encountered by previous approaches, which involved con-
comitant ether and ring formation (see above), we opted to
explore an alternative route, based on a cyclization reaction
with only one possible reaction pathway, by securing the
sterically demanding stereochemistry of the ether linkages
prior to oxepane ring formation. This short and highly con-
vergent strategy (Figure 2) involves two straightforward dis-
Scheme 1. Previous approaches to Aplysistatin and related halosesquiter-
penoids.
lated compounds, based on polyene cyclizations, the stereo-
selectivities and/or the chemical yields were even lower
f]
(Scheme 1b).[7b Evidently the formation of these oxepanes
was thermodynamically unfavorable due to the severe repul-
sion between the 1,3-alkyl substituents adjacent to the ring
oxygen atom. Regarding Adociasulfates, Overman et al.
have already disclosed a method for the construction of the
steroid skeleton in their synthesis of Adociasulfate-1
(Figure 1);[8] however, the problem of the oxepane ring
system of Adociasulfate-2 remains to be solved.
Herein, we describe a new stereocontrolled method for
the formation of trans-fused oxepene cyclogeranyl systems,
as well as its application to the synthesis of the AB fragment
of Adociasulfate-2 and Toxicol A, and the synthesis of the
title sesquiterpenoids. Some interesting synthetic methods
for the construction of commonly used geranyl and cycloger-
anyl derivatives are also disclosed.
Figure 2. Retrosynthetic analysis of trans anti fused bicyclic key inter-
mediates 1 and 2.
connections, which, however, in terms of the synthesis, re-
quires two challenging bond formations: the demanding
stereoselective coupling of a tertiary alcohol with a 1,2-un-
symmetrically disubstituted epoxide,[9] and the formation of
a sterically crowded oxepene with increased strain, due to
the unfavorable 1,3-interaction of alkyl substituents adjacent
to the ring oxygen atom.[10] Nonetheless, should this strategy
be proved successful, it would be endowed with great flexi-
bility, since it has been designed to allocate most of the re-
maining functional group modifications on the linear epox-
ide fragment, allowing the construction of diversified poly-
cyclic systems. In addition, the resulting relative stereochem-
istry is dictated by the epoxide, allowing the synthesis of
both trans anti and trans syn systems in a stereocontrolled
fashion.
Abstract in Greek:
Enantioselective synthesis of tertiary alcohols 3 and 4: For
the synthesis of cyclogeranyl tertiary alcohol 3,[11] lactone 7,
prepared from the easily accessible (S)-(+)-Wieland
Miescher ketone analogue 6 (Scheme 2),[12] was subjected to
transesterification and silylation to afford methyl ester 8.
The latter was converted to its olefinic analogue 9 employ-
ing the diphenyldiselenide protocol. Ozonolysis coupling of
the resulting aldehyde 10 with methylylide and TBAF-medi-
ated (TBAF=tetrabutylammonium fluoride) desilylation af-
forded key intermediate 3, in optically pure form and in
good overall yield.
On the other hand, for the synthesis of bromocyclogeranyl
alcohol 4, lactone 18 was envisioned as an ideal precursor
(Scheme 3). Surprisingly, despite the use of the latter as key
intermediate and the amount of chemistry developed
Chem. Eur. J. 2004, 10, 3822 3835
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E. A. Couladouros and V. P. Vidali
FULL PAPER
anyl nitrile 11[15] to geometrically pure (E)-homogeranic
acid 12, employing diisobutylaluminum hydride (DIBAL-H)
reduction with concomitant mild acidic hydrolysis and sub-
sequent ™Jones∫ oxidation of the resulting aldehyde. The
above approach was found to be more convenient and scal-
able than the previously reported ones.[16] Anticipating an
acidic hydrolysis at a later step, acid 12 was esterified with
tert-butanol,[16a] and the appropriate asymmetry was effi-
ciently introduced by applying Sharpless asymmetric dihy-
droxylation conditions,[17] to afford diol 13 in 61% yield
(75% based on recovered material, 97% ee). Subsequent se-
lective tosylation furnished optically active monotosylate 14.
Direct bromination of 14 afforded optically active bromohy-
drine 17 in low yield (~40%, enantiomeric ratio (S)/(R) 8:2)
together with a substantial amount of allylic alcohol 15
(~15%). The observed partial retention of stereochemistry,
proved at a later step of the synthesis,[18] was attributed to
the formation of an epoxide intermediate. Thus, in a second
approach, we opted for a two-step double-inversion proto-
col, involving a base-mediated epoxide formation and subse-
quent regio- and diastereoselective bromide-induced open-
ing under acidic conditions.[19] To this end, epoxide 16 was
prepared in 87% yield upon treatment of tosylate 14 with
Scheme 2. Asymmetric synthesis of tertiary alcohol 3. Reagents and con-
ditions: a) K2CO3, MeOH, 258C, 1.5 h, 96%; b) TMS imidazole, 258C,
93%; c) LDA, HMPA, THF, ꢀ788C, 1.5 h; then PhSeSePh, THF, ꢀ788C,
30 min, 89%; d) H2O2 (30%), CH2Cl2/H2O (15:1), 258C, 20 min, 95%;
e) O3, CH2Cl2, ꢀ788C; then PPh3, ꢀ788C!258C, 93%; f) PPh3CH3+Brꢀ,
NaHMDS, THF, 258C, 45 min; then 10 in THF, 08C, 30 min, 95%;
g) TBAF, THF, 258C, 3 h, 96%. TMS=trimethylsilyl, LDA=lithium di-
isopropylamide, HMPA=hexamethyl phosphoramide, THF=tetrahydro-
furan, NaHMDS=sodium bis(trimethylsilyl)amide, TBAF=tetra-n-butyl
ammonium fluoride.
1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU).
Subsequent
treatment with LiBr in hexamethylphosphoramide (HMPA),
employing camphorosulfonic acid (CSA) led to the regiose-
lective formation of bromohydrin 17 (53%) together with
the dehydrated byproduct 15 (18%). After considerable ex-
perimentation, the formation of the latter was suppressed to
less than 5% by the use of milder acidic conditions (pyridi-
nium p-toluenesulfonate (PPTS) in 1-methyl-2-pyrrolidinone
(NMP)), leading to bromohydrin 17 in high yield and excel-
lent optical purity.
Gratifyingly, by applying modified Gosselin×s condi-
tions[14b] on tert-butylate 17, one-pot deprotection cycliza-
tion was achieved in 60% yield. Thus, lactone 18 was syn-
thesized in six steps from (E)-homogeranic acid 12 in 25%
overall yield and in optically pure form. Target alcohol 4
was finally reached upon reduction of lactone 18 to the cor-
responding lactol,[7a] followed by one-carbon homologation,
in 54% overall yield for two steps.
Scheme 3. Asymmetric synthesis of tertiary alcohol 4. Reagents and con-
ditions: a) DIBAL, CH2Cl2, ꢀ788C, 30 min; then aq. NH4Cl, 10% HCl,
258C, 20 min; b) Jones reagent, acetone, ꢀ208C, 60% from 11; c)
(TFA)2O, tBuOH, 258C, 15 min, 95%, see ref. [16a]; d) K3Fe(CN)6,
K2CO3, (DHQ)2PHAL, K2OsO2(OH)4, CH3SO2NH2, tBuOH/H2O (2:1),
12 h, 08C, 61%, (75% based on recovered material), >97% ee; e) Ts2O,
pyridine, 08C, 1 h, 86%; f) LiBr, HMPA, 608C, 20 min, 17: 40%, 15:
15%; g) DBU, DMF, 258C, 15 min, 87%; h) LiBr, PPTS, NMP, 208C, 1 h,
85%; i) SnCl4, CH3NO2, 08C, 30 min, 60%; k) DIBAL, CH2Cl2, ꢀ788C,
30 min, 90%, see ref. [7a]; l) PPh3CH3+Brꢀ, NaHMDS, THF, 258C, 1 h;
then dropwise addition to lactol in THF during 12 h, 60% (90% based
on recovered lactol). DIBAL=diisobutylaluminum hydride, (TFA)2O=
trifluoroacetic anhydride, (DHQ)2PHAL=hydroquinine 1,4-phthalazine-
diyl diether, Ts2O=p-toluenesulfonic anhydride, DBU=1,8-diazabicy-
clo[5.4.0]undec-7-ene, DMF=N,N-dimethylformamide, PPTS=pyridini-
um p-toluenesulfonate, NMP=1-methyl-2-pyrrolidinone.
Synthesis of coupling ™partners∫, epoxides 22a d: The re-
quired coupling ™partners∫ for model studies, as well as for
the preparation of the title compounds were designed to be
allylic epoxides 22a d. Their synthesis relied on Sharpless
asymmetric epoxidation of the corresponding allylic alcohols
21a c (Scheme 4).[20]
Thus, while epoxidation precursors 21b and 21c were
known,[21] allylic alcohol 21a was prepared by means of a
short synthetic route, involving Stille coupling of vinyl stan-
nane 19[22] and vinyl bromide 20 in the presence of
[Pd2(dba)3] (dba=dibenzylideneacetone). Each alcohol was
then epoxidized regio- and enantioselectively in the pres-
ence of l-(+)-diisopropyltartrate to afford, after silylation
with tert-butyldimethylsilyl chloride (TBSCl) or tert-butyldi-
phenylsilyl chloride (TPSCl), allylic epoxides 22a d. The
enantiomeric form of 22a, ent-22a (Scheme 5), was similarly
prepared as an indicative entry to trans syn 6,7-ring systems.
around similar compounds,[13] to the best of our knowledge
there is no reported method for the preparation of its opti-
cally pure form.[14] Thus, its synthesis commenced with a
straightforward conversion of the easily accessible (E)-ger-
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Oxepene Cyclogeranyl Systems
3822 3835
Table 1. Yields of dienes and oxepenes prepared according to Scheme 5.
Coupled pair
alcohol+epoxide
Diene
Yields
[%][a]
Oxepene
Yield
[%]
1
2
3
4
5
6
7
3
3
3
3
4
4
4
22a
22b
22c
22d
22a
23a
23b
23c
23d
24a
56 (80)
55 (83)
50 (78)
60
25a
25b
25c
25d
26a
(78)
(93)
(88)
(88)[c]
(80)[d]
(90)
50 (80)[b]
54 (82)
48 (75)[b]
22b
24b
26b
ent-22a
epi-24a
epi-26a
(76)[d]
[a] Yields are based on epoxide. Yields in parentheses are based on alco-
hol, after four cycles. [b] Yield for coupling and desilylation. [c] Olefin
metathesis of this less substituted diene was successfully performed at
room temperature, with a first-generation Grubbs catalyst. [d] RCM was
performed after desilylation.
Scheme 4. Synthesis of allylic epoxide coupling ™partners∫. Reagents and
general conditions: a) [Pd2(dba)3], CH2Cl2, 258C, 3 h, 60%; b) l-(+)-
DIPT, Ti(O-iPr)4, MS 4 ä, tBuOOH, ꢀ208C; c) TPSCl or TBSCl, imida-
zole, cat. 4-DMAP, DMF, 258C, 22a: 76%, 22b: 72%, 22c: 75%, 22d:
60% (yields over 2 steps). PMB=p-methoxybenzyl, dba=dibenzylide-
neacetone,
DIPT=diisopropyltartrate,
TPS=tert-butyldiphenylsilyl,
cohol 3 (Table 1, entry 4). More substituted epoxides re-
quired practically solvent-free conditions along with excess
of alcohol. Thus, each of the substituted ethers 23a c (en-
tries 1 3) and 24a,b (entries 5, 6) was isolated in 50 60%
yield, based on the epoxide. It should be noted, that despite
the moderate coupling yields, valuable alcohols 3 or 4 could
be recovered and recycled to achieve, after three more
cycles, a final yield of approximately 80%, based on the al-
TBS=tert-butyldimethylsilyl, 4-DMAP=4-dimethylaminopyridine.
Coupling and oxepene ring formation: The stage was now
set for the crucial coupling between tertiary alcohols 3 or 4
and allylic epoxides 22a d (Scheme 5, Table 1). Initial at-
ꢀ
cohol. In this impressive reaction, a new C O bond was
formed between a tertiary alcohol and a 1,2-unsymmetrical-
ly disubstituted epoxide in a completely diastereo- and re-
gioselective fashion, providing direct access to ring-closing
metathesis precursors.
To complete the construction of the designed oxepene
systems, olefin metathesis was initially attempted with the
first-generation Grubbs catalyst (A)[23] affording poor yields
of the desired products, with the exception of the less-substi-
tuted model diene 23d (Table 1, entry 4). To our delight, the
use of second-generation Grubbs catalyst (B)[24] converted
dienes 23a c into the functionalized trans anti cyclogeran-
yl oxepene systems 25a c (entries 1 3), potential precursors
of Adociasulfate-2 and Toxicol A, in high yields. Similarly,
bromocyclogeranyl analogues 24a,b were converted to the
corresponding trans anti oxepenes 26a,b (entries 5, 6), key
intermediates for the title halosesquiterpenoids.
As anticipated, the above reaction sequence constitutes a
stereocontrolled method for the construction of either
trans anti or trans syn 6,7-ring systems. Indeed, by employ-
ing the antipode of the highly substituted epoxide 22a, that
is, (R,R)-epoxide ent-22a, the formation of a trans syn bicy-
clic system, epi-26a, (Scheme 5) was accomplished in equal-
ly high chemical yield and stereospecificity (Table 1,
entry 7).
Scheme 5. Synthesis of anti and syn trans-fused cyclogeranyl oxepenes.
Reagents and general conditions: a) 3 or
4 (2 2.5 equiv), 22a d
(1.0 equiv, 10m in CH2Cl2), BF3¥OEt2 (0.1 equiv), 08C, 20 30 min;
b) 23a d: first- (A) or second-generation (B) Grubbs catalyst (0.1
0.15 equiv), 358C, 1 h; c) 24a,b, epi-24a: 1) TBAF (1m solution in THF,
1.0 equiv), THF, 258C, 2 h; 2) Second-generation Grubbs catalyst (B;
0.1 0.15 equiv), 358C, 1 h. [The b),c) reaction sequence was inverted in
the case of 24b.]
tempts, involving alcohol 3, the unsubstituted model epoxide
22d, and Lewis acids SnCl4, AlCl3, Sc(OTf)3, or [Pd(PPh3)4]
proved completely unsuccessful as they resulted only in de-
composition of the epoxide and/or the alcohol. Utilization
of BF3¥OEt2 in a 1m solution of stoichiometric amounts of
the coupling ™partners∫, as reported for related substrates,[9a]
resulted in slow decomposition of the epoxide, yet at a
slower rate, while a small amount of of the desired diene
23d was observed (10 15%). The yield of diene 23d was
dramatically increased (60%) by using twofold excess of al-
Synthesis of sesquiterpenoids 28, 30, 32 and 34: The general-
ity of the originally designed disconnection and the flexibili-
ty of intermediates 26a and 26b allowed the synthesis of the
title sesquiterpenoids in three or four steps for each com-
pound (Scheme 6). Thus, one-pot periodate cleavage and re-
duction of diol 26b to alcohol 27b, followed by a tosylation
bromination sequence furnished (+)-Palisadin B (28). On
the other hand, oxidative removal of the p-methoxybenzyl
group of bromide 29, similarly prepared from diol 26a, af-
forded (+)-12-hydroxy-Palisadin B (30). Moreover, con-
Chem. Eur. J. 2004, 10, 3822 3835
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E. A. Couladouros and V. P. Vidali
FULL PAPER
Scheme 6. Synthesis of (ꢀ)-Aplysistatin, (+)-Palisadin A, (+)-Palisadin B, and (+)-12-hydroxy-Palisadin B. Reagents and conditions: a) NaIO4
(5.8 equiv), MeOH/H2O (2:1), 258C, 20 min; then NaBH4, 08C, 1 h, 27a: 75%, 27b: 90%; b) TsCl, pyridine, CH2Cl2, 258C, 12 h, 85% from 27a, 90%
from 27b; c) 28: LiBr, HMPA, 408C, 16 h, 75%, 29: LiBr, HMPA, 508C, 20 h, 80%; d) DDQ, CH2Cl2/H2O (10:1), 258C, 30: 30 min, 78%, 31: 30 min,
80%, 33: 3 h, 76%; e) K2CO3 (10% in MeOH), 30 min, 95%; f) MnO2, CH2Cl2, 258C, 2 h, 93%; g) PCC, benzene, 258C, 48 h, 50% (90% based on re-
covered 32); h) SeO2, EtOH/H2O (8:2), 808C, 2 h; then NaBH4, 08C, 30 min, 24%. DDQ=2,3-dicloro-5,6-dicyano-1,4-benzoquinone, TsCl=p-toluene-
sulfonyl chloride, PCC=pyridinium chlorochromate.
struction of the 6,7,5-tricyclic system of (+)-Palisadin A (32)
was achieved by a Williamson-type intramolecular etherifi-
cation of hydroxytosylate 31. Finally, deprotection of alcohol
27a to diol 33 and subsequent one-pot oxidative lactoniza-
tion provided (ꢀ)-Aplysistatin (34) in 93% yield. In this in-
teresting cascade of transformations, a selective oxidation of
the allylic hydroxyl group of diol 33 occurred, followed by
spontaneous formation of a five-membered lactol and fur-
ther oxidation to the corresponding lactone. Spectroscopical
data and optical rotation of synthetic (ꢀ)-Aplysistatin (34)
was identical, in all respects, to those reported.[4a] Although
1H and 13C NMR spectra of compounds 28, 30, and 32 were
slightly different from those originally reported by Fenical
for the isolated natural products,[4b] they were all successful-
ly converted to 34 by following his protocol for the conver-
sion of natural 30 to 32 and eventually to 34. Synthetic (+)-
Palisadin B was also converted to 30 upon allylic hydroxyla-
tion. Furthermore, failing to obtain authentic samples from
preparation procedures for the commonly used (E)-homoge-
ranic acid 12, optically active lactone 18, and tertiary alco-
hols 3 and 4 were also developed.
Completion of the synthesis of Adociasulfate-2 as well as
other sesquiterpenoids, elaborating the above strategy, is
currently underway.
Experimental Section
General: All reactions were carried out under anhydrous conditions and
argon atmosphere using dry, freshly distilled solvents, unless otherwise
noted. Tetrahydrofuran (THF) and diethyl ether (ether) were distilled
from sodium/benzophenone, dichloromethane (CH2Cl2) from CaH2 and
toluene from sodium. Yields refer to chromatographically and spectro-
scopically (1H NMR) homogeneous materials, unless otherwise stated.
All reagents were purchased at highest commercial quality and used
without further purification, unless otherwise stated. All reactions were
monitored by thin-layer chromatography (TLC) carried out on 0.25 mm
Merck silica gel plates (60 F254) by using UV light as visualizing agent
and ethanolic phosphomolybdic acid or p-anisaldehyde solution and heat
as developing agents. Merck silica gel (60, particle size 0.040 0.063 mm)
was used for flash column chromatography. NMR spectra were recorded
on Bruker AMX-500 or AC-250 instruments, at 258C. The following ab-
breviations were used to explain NMR signal multiplicities: s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet, brs=broad singlet,
dd=doublet of doublets, ddd=doublet of doublets of doublets, dddd=
doublet of doublets of doublets of doublets. IR spectra were recorded on
a Perkin Elmer 1600 series FT-IR or Nicolet Magna system 550 FT-IR
instruments. Optical rotations were recorded on a Perkin Elmer 241 po-
larimeter. High-resolution mass spectra (HRMS) were recorded on a VG
ZAB-ZSE mass spectrometer under fast atom bombardment (FAB) con-
ditions, while matrix-assisted (MALDI-FTMS) mass spectra were record-
ed on a PerSeptive Biosystems Voyager IonSpect mass spectrometer.
Melting points (m.p.) were recorded on a Gallenkamp melting point ap-
paratus and are uncorrected.
1
any source, we compared H and 13C NMR spectra of the
title natural products, kindly provided by Prof. T. Higa and
Prof. M. Kuniyoshi, with the corresponding synthetic ones
and found them identical. Full spectroscopic data of the syn-
thesized natural products are given in the Experimental Sec-
tion.
Conclusion
In conclusion, we have demonstrated a general stereocon-
trolled strategy for the construction of either syn or anti
trans-fused cyclogeranyl oxepenes, by employing epoxide
opening by a tertiary alcohol and subsequent ring-closing
metathesis. Besides the first total synthesis of (+)-Palisa-
din B, three related natural products were also synthesized
from the same key intermediate 4. En route, convenient
Preparation of methyl ester
8 from lactone 7: Lactone 7 (272 mg,
1.3 mmol) was dissolved in dry methanol (10 mL) and K2CO3 (180 mg,
1.3 mmol) was added at ice-bath temperature. The reaction mixture was
stirred under argon for 1.5 h at 258C, poured in water (30 mL), and ex-
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Chem. Eur. J. 2004, 10, 3822 3835

Oxepene Cyclogeranyl Systems
3822 3835
tracted with ethyl acetate (EtOAc) (2î20 mL). The combined organic
extracts were washed with water and brine, dried over sodium sulphate,
and concentrated in vacuo. The crude mixture was subjected to flash
chromatography (silica gel, hexanes/EtOAc 9:1) to afford the corre-
sponding hydroxymethyl ester (302 mg, 96%), as a colorless liquid. Rf =
0.16 (hexanes/EtOAc 9:1); [a]2D0 =+4.6 (c=5.0 in CHCl3); 1H NMR
(250 MHz, CDCl3): d=3.63 (s, 3H; CH3O-), 2.31 (t, 3J(H,H)=7.4 Hz,
2H; -CH2COOCH3), 1.84 1.05 (m, 11H; -(CH2)3-C(CH3)2-CH-, -(CH2)2-
CH2COOCH3), 1.12 (s, 3H; -(CH3)C-OH), 0.90 (s, 3H; -C(CH3)a(CH3)b),
0.75 ppm (s, 3H; -C(CH3)a(CH3)b); 13C NMR (62.5 MHz, CDCl3): d=
174.5, 74.1, 57.1, 51.4, 43.3, 41.5, 35.4, 34.5, 32.7, 27.8, 25.7, 23.3, 21.2,
20.4 ppm; IR (neat): n˜ =3488, 2950, 2929, 2868, 1742, 1464, 1440, 1367,
1254, 1198, 1167, 1104, 915, 888 cmꢀ1; HRMS (MALDI-FTMS): m/z
calcd for C14H26O3 [M+Na]+: 265.1774; found: 265.1777.
n˜ =2950, 2874, 1729, 1656, 1459, 1435, 1252, 1164, 1112, 1073, 1055, 846,
757 cmꢀ1; MS (ESI): m/z calcd for C17H32O3Si [M+Na]+: 335; found: 335.
Preparation of aldehyde 10: a,b-Unsaturated methyl ester
9 (2.4 g,
7.68 mmol) was dissolved in dichloromethane (50 mL) and the solution
was cooled at ꢀ788C. A stream of ozone was passed through the solu-
tion. Immediately after consumption of 9 (monitored by TLC), triphenyl-
phosphine (3 g, 11.5 mmol) was added with stirring. The reaction mixture
was brought to room temperature with stirring, concentrated in vacuo,
and subjected to flash column chromatography (silica gel, hexanes/
EtOAc 9:1) to afford pure aldehyde 10 (1.8 g, 93%) as a pale yellow oil.
1
Rf =0.74 (hexanes/EtOAc 7:3); [a]2D0 =+47.0 (c=1.3 in CHCl3); H NMR
(250 MHz, CDCl3): d=9.58 (dd, 3J(H,H)=1.1 Hz, 3J(H,H)=4.8 Hz, 1H;
-CH=O), 2.39 (ddd, 3J(H,H)=4.8 Hz, 2J(H,H)=15.6 Hz, 3J(H,H)=
10.1 Hz, 1H; -CHaHb CHO), 2.25 (ddd, 2J(H,H)=15.6 Hz, 3J(H,H)=
ꢀ
3
3
ꢀ
1.2 Hz, J(H,H)=3.7 Hz, 1H; -CHaHb CHO), 1.94 (dd, J(H,H)=3.7 Hz,
Trimethylsilylimidazole (80 mL, 0.42 mmol) was added to the above alco-
hol (51 mg, 0.21 mmol) under argon, at 258C. After 30 min of stirring,
the reaction was quenched with methanol. The mixture was concentrated
in vacuo and subjected to flash chromatography (silica gel, hexanes/
EtOAc 95:5) to afford the silylated methyl ester 8 (61.2 mg, 93%) as a
colorless liquid. Rf =0.48 (hexanes/EtOAc 9:1); [a]2D0 =+8.7 (c=7.0 in
CHCl3); 1H NMR (250 MHz, CDCl3): d=3.66 (s, 3H; CH3O-), 2.31 (m,
3
ꢀ
ꢀ
J(H,H)=9.7 Hz, 1H; -C(CH3)2 CH-), 1.86 (m, 6H; -(CH2)3 C(CH3)2-),
ꢀ
1.20 (s, 3H; -(CH3)C OSi(CH3)3), 0.95 (s, 3H; -C(CH3)a(CH3)b), 0.81 (s,
3H; -C(CH3)a(CH3)b), 0.08 ppm (s, 9H; -OSi(CH3)3); 13C NMR
(62.5 MHz, CDCl3): d=202.8, 76.8, 53.5, 42.9, 41.1, 40.9, 34.6, 33.1, 23.9,
21.3, 20.4, 2.6 ppm; IR (neat): n˜ =2961, 2936, 1726, 1252, 1161, 1108,
1074, 1021, 843, 757 cmꢀ1
; HRMS (MALDI-FTMS): m/z calcd for
C14H28O2Si [M+H]+: 257.1931; found: 257.1942.
ꢀ
ꢀ
2H; -CH2COOCH3), 1.91 1.13 (m, 11H; -(CH2)3 C(CH3)2 CH-,
Synthesis of tertiary alcohol 3 from aldehyde 10: Sodium bis(trimethylsi-
lyl)amide (1m solution in THF, 9.1 mL, 9.1 mmol) was added to a solu-
tion of triphenylphosphonium bromide (3.75 g, 10.5 mmol) in dry THF
(15 mL) at 08C stirring under argon. After 45 min of stirring at 258C, a
solution of aldehyde 10 in dry THF (25 mL) was added at 08C. The reac-
tion mixture was stirred for 30 min at this temperature, poured to a satu-
rated solution of NH4Cl (40 mL), and extracted with Et2O (2î40 mL).
The combined organic extracts were washed with water and brine, dried
over Na2SO4, and concentrated in vacuo. Subjection of the crude mixture
to flash chromatography (silica gel, hexanes/EtOAc 98:2) yielded the
pure silylated alkene (1.69 g, 95%) as a colorless liquid. Rf =0.81 (hex-
anes/EtOAc 95:5); [a]2D0 =+4.5 (c=0.44 in CHCl3); 1H NMR (250 MHz,
CDCl3): d=5.94 (m, 1H; -CH=CH2), 4.94 (ddd, 3J(H,H)=17.1 Hz,
4J(H,H)=2.2 Hz, 2J(H,H)=3.7 Hz, 1H; -CH=CHtransHcis), 4.83 (ddd,
3J(H,H)=10.1 Hz, 4J(H,H)=1.5 Hz, 2J(H,H)=3.7 Hz, 1H; -CH=
ꢀ
-(CH2)2CH2COOCH3), 1.17 (s, 3H; -(CH3)C OSi(CH3)3), 0.91 (s, 3H;
-C(CH3)a(CH3)b), 0.78 (s, 3H; -C(CH3)a(CH3)b), 0.08 ppm (s, 9H;
-OSi(CH3)3); 13C NMR (62.5 MHz, CDCl3): d=174.5, 77.7, 57.0, 51.3,
43.3, 41.4, 35.2, 34.9, 33.0, 27.9, 26.2, 23.9, 21.4, 20.5, 2.8, 1.0 ppm; IR
(neat): n˜ =2950, 2867, 1748, 1462, 1436, 1380, 1253, 1164, 1108, 1081,
1052, 1032, 1007, 841, 754 cmꢀ1; MS (ESI): m/z calcd for C17H34O3Si
[M+Na]+: 337; found: 337.
Preparation of a,b-unsaturated methyl ester 9 from ester 8: Methyl ester
8 (113.5 mg, 0.361 mmol) was dissolved in dry THF (1 mL) and hexa-
methylphosphoramide (HMPA) (82 mL, 0.469 mmol) was added at 258C
under argon. The reaction mixture was cooled to ꢀ788C and a solution
of freshly prepared lithium diisopropylamide (LDA) in THF (0.73m,
634 mL, 0.469 mmol) was added dropwise. After 1.5 h of stirring at
ꢀ788C, a solution of diphenyl diselenide (147 mg, 0.469 mmol) in THF
(1 mL) was added; the reaction mixture was stirred for 30 min at ꢀ788C
and poured in a mixture of a saturated aqueous solution of ammonium
chloride (5 mL) and Et2O (5 mL). The organic phase was separated and
the aqueous phase was washed with Et2O (2î5 mL). The combined or-
ganic extracts were washed with water and brine, dried over sodium sul-
phate, and concentrated in vacuo. Flash chromatography of the crude
mixture (silica gel, hexanes/EtOAc 98:2) afforded the a-phenylselenyl
ester (151 mg, 89%), as a yellow oil. Rf =0.7 (hexanes/EtOAc 95:5);
1H NMR (250 MHz, CDCl3) (mixture of isomers): d=7.56 (m, 4H;
ꢀ
ꢀ
CHtransHcis), 2.34 (m, 1H; -CHaHb CH=CH2), 2.04 (m, 1H; -CHaHb CH=
ꢀ
ꢀ
CH2), 1.84 1.20 (m, 7H; -(CH2)3 C(CH3)2 CH-), 1.19 (s, 3H; -(CH3)C-
OSi(CH3)3), 0.94 (s, 3H; -C(CH3)a(CH3)b), 0.84 (s, 3H; -C(CH3)a(CH3)b),
0.10 ppm (s, 9H; -OSi(CH3)3); 13C NMR (62.5 MHz, CDCl3): d=142.9,
112.4, 77.5, 57.5, 43.4, 41.8, 35.5, 33.4, 31.1, 24.1, 21.6, 20.6, 2.9 ppm; IR
(neat): n˜ =2958, 2937, 2873, 1638, 1616, 1465, 1380, 1251, 1114, 1073,
1054, 1010, 873, 840, 757 cmꢀ1; HRMS (EI): m/z calcd for C15H30OSi
[M+H]+: 255.2139; found: 255.2137.
The above alkene (295 mg, 1.16 mmol) was dissolved in THF (2.3 mL)
and TBAF (1m solution in THF, 1.74 mL, 1.74 mmol) was added at 08C.
The reaction mixture was stirred at 258C for 3 h, poured in a saturated
solution of NH4Cl (10 mL), and extracted with Et2O (2î10 mL). The or-
ganic extracts were washed with water and brine, dried over Na2SO4, and
concentrated in vacuo. Flash column chromatography of the crude mix-
ture (silica gel, hexanes/EtOAc 9:1) afforded pure tertiary alcohol 3
(203 mg, 96%) as a colorless liquid. Rf =0.16 (hexanes/EtOAc 9:1);
[a]2D0 =+11.4 (c=1.4 in CHCl3); 1H NMR (250 MHz, CDCl3): d=6.02
(m, 1H; -CH=CH2), 5.09 (ddd, 4J(H,H)=3.4 Hz, 3J(H,H)=17.1 Hz,
2J(H,H)=1.9 Hz, 1H; -CH=CHtransHcis), 4,97 (ddd, 4J(H,H)=3.0 Hz,
ꢀ
-SeAr-H), 7.25 (m, 6H; -SeAr-H), 3.72 3.60 (m, 2H; -CH SePh), 3.60
ꢀ
(2s, 6H; CH3O-), 2.32 1.15 (m, 22H; -(CH2)3 C(CH3)2-CH-,
ꢀ
-(CH2)2CH(SePh)COOCH3), 1.13 (s, 6H; -(CH3)C OSi(CH3)3), 0.87
0.81 (2s, 6H; -C(CH3)a(CH3)b), 0.76 0.70 (2s, 6H; -C(CH3)a(CH3)b-),
0.05 ppm (s, 18H; -OSi(CH3)3); IR (neat): n˜ =2953, 2870, 1740, 1480,
1464, 1439, 1256, 1169, 1113, 1072, 1025, 845, 748, 695 cmꢀ1
.
The above a-selenyl ester (380 mg, 0.81 mmol) was dissolved in dichloro-
methane (9 mL), and water (0.61 mL) and a 30% aqueous solution of hy-
droperoxide (1.84 mL, 16.2 mmol) were added, at 258C. After 20 min of
stirring, the reaction mixture was poured in a 20% aqueous solution of
sodium carbonate (10 mL) and extracted with Et2O (30 mL). The organic
phase was separated and the aqueous phase was washed with Et2O (2î
10 mL). The combined organic extracts were sequentially washed with
water, saturated aqueous NH4Cl, water, and brine, dried over Na2SO4,
and concentrated in vacuo. Flash column chromatography of the crude
mixture (silica gel, hexanes/EtOAc 98:2) afforded pure ester 9 (240 mg,
95%) as a pale yellow oil. Rf =0.7 (hexanes/EtOAc 95:5); [a]2D0 =ꢀ5.1
(c=0.6 in CHCl3); 1H NMR (250 MHz, CDCl3): d=7.12 (dt, 3J(H,H)=
7.4 Hz, 3J(H,H)=15.6 Hz, 1H; -CH=CHCOOCH3), 5.75 (dt, 3J(H,H)=
15.6 Hz, 4J(H,H)=1.5 Hz, 1H, -CH=CHCOOCH3), 3.71 (s, 3H;
3J(H,H)=10.1 Hz, 2J(H,H)=1.9 Hz, 1H; -CH=CHtransHcis), 2.26 (t,
3
ꢀ
J(H,H)=7.1 Hz, 2H; -CH2 CH=CH2), 1.84 (brs, -OH), 1.78 1.20 (m,
ꢀ
ꢀ
ꢀ
7H; -(CH2)3 C(CH3)2 CH-), 1.22 (s, 3H; -(CH3)C OH), 0.96 (s, 3H;
-C(CH3)a(CH3)b), 0.83 ppm (s, 3H; -C(CH3)a(CH3)b); 13C NMR
(62.5 MHz, CDCl3): d=142.2, 114.5, 74.4, 56.5, 42.6, 41.8, 33.0, 31.1, 23.9,
21.2, 20.1 ppm; IR (neat): n˜ =3412, 2934, 2869, 1637, 1463, 1391, 1382,
1372, 1102, 914 cmꢀ1; HRMS (EI): m/z calcd for C12H22O [M+H]+:
183.1743; found: 183.1740.
Preparation of pure (E)-Homogeranic acid (12): Geranyl nitrile 11
(4.3 gr, 26.3 mmol) was dissolved in dichloromethane (110 mL) and the
mixture was cooled at ꢀ788C under argon. A solution of DIBAL-H
(1.0m in CH2Cl2, 34.2 mL, 34.2 mmol) was added. After 30 min at ꢀ788C,
the reaction mixture was quenched with MeOH and poured in a mixture
of EtOAc/NH4Cl(aq) 1:1 (50 mL). A solution of 10% HCl was then added
at room temperature with stirring until the pH of the aqueous phase was
ꢀ
-COOCH3), 2.43 (m, 1H; -CHaHb CH=CH-), 1.87 1.22 (m, 7H;
ꢀ
ꢀ
-(CH2)3 C(CH3)2 CH-), 1.19 (s, 3H; -(CH3)C-OSi(CH3)3), 0.92 (s, 3H;
-C(CH3)a(CH3)b), 0.82 (s, 3H; -C(CH3)a(CH3)b-), 0.08 ppm (s, 9H;
-OSi(CH3)3); 13C NMR (62.5 MHz, CDCl3): d=167.5, 154.0, 118.8, 77.1,
57.4, 51.2, 43.2, 41.5, 35.2, 33.3, 29.6, 23.9, 21.4, 20.4, 2.8 ppm; IR (neat):
Chem. Eur. J. 2004, 10, 3822 3835
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3827

E. A. Couladouros and V. P. Vidali
FULL PAPER
~3 4. Stirring was continued for 20 min at room temperature. Potassium
sodium tartrate was then added until the pH of the aqueous phase was
~7 8 and stirring was continued until there was a sufficient separation of
the two phases (~1 h). The organic phase was separated and the aqueous
phase was washed with EtOAc (2î50 mL). The combined organic ex-
tracts were washed with water and brine, dried over sodium sulphate,
and concentrated in vacuo at 25 308C. The crude aldehyde was immedi-
ately dissolved in acetone (150 mL) and cooled at ꢀ208C. A solution of
Jones reagent (8m) was added portionwise until no aldehyde was traced
by TLC (~7 mL). The reaction was then quenched with isopropanol, fil-
tered through Celite, and poured in EtOAc/H2O 1:1 (200 mL). The or-
ganic phase was separated, the aqueous phase was washed with EtOAc
(2î50 mL), and the combined organic extracts were washed successively
with water and brine, dried over Na2SO4, and concentrated in vacuo. The
crude mixture was subjected to flash column chromatography (silica gel,
hexanes/EtOAc 9:1) to afford pure (E)-homogeranic acid (2.9 g, 60%) as
(neat): n˜ =3530, 2978, 2934, 1730, 1367, 1189, 177, 1150, 904, 670,
559 cmꢀ1; HRMS (MALDI-FTMS): m/z calcd for C22H34O6S [M+Na]+:
449.1968; found: 449.1964.
Synthesis of bromohydrin 17:
Method A–by direct bromination of monotosylate 14: Monotosylate 14
(223 mg, 0.52 mmol) was dissolved in HMPA (0.7 mL) and LiBr (226 mg,
2.6 mmol) was added at 258C. The reaction was stirred at 508C under
argon for 30 min and saturated aqueous NH4Cl was added. The reaction
mixture was extracted with EtOAc (2î20 mL) and the combined organic
extracts were washed successively with water and brine, dried over
Na2SO4, and concentrated in vacuo. The crude mixture was subjected to
flash column chromatography to afford an inseparable mixture of bromo-
hydrin 17 with allylic alcohol 15 (122 mg, 17/15 3:1 detected by 1H NMR
spectroscopy). Bromohydrin 17 obtained this way was separated from the
allylic alcohol 15 after acetylation of the latter. The enantiomeric excess
of 17 was calculated from the diastereomeric excess of oxepene 26b (syn/
1
a yellow oil. Rf =0.44 (hexanes/EtOAc 7:3); H NMR (250 MHz, CDCl3):
1
anti 2:8, detected by H NMR spectroscopy) prepared after converting 17
d=5.32 (t, 3J(H,H)=6.9 Hz, 1H; -CH=C(CH3)-), 5.09 (m, 1H;
to bromoalcohol 4 (17!18!4), subsequent coupling with epoxide 22b
3
ꢀ
(CH3)2C=CH-), 3.09 (d, J(H,H)=6.9 Hz, 2H; -CH2 COOH), 2.07 (m,
and ring-closing metathesis of the corresponding diene 24b.
4H; -CH2CH2-), 1.68 (s, 3H; (CH3)trans(CH3)cis C=CH-), 1.64 (s, 3H;
-(CH3)C=CH-), 1.60 ppm (s, 3H; (CH3)trans(CH3)cisC=CH-); 13C NMR
(62.5 MHz, CDCl3): d=178.8, 131.7, 123.9, 114.9, 39.5, 33.5, 26.4, 25.6,
18.7, 17.7, 16.3 ppm; IR (neat): n˜ =3300, 2973, 2926, 2859, 1712, 1443,
Data for the acetylated form of allylic alcohol 15: 1H NMR (250 MHz,
CDCl3): d=5.32 (t, 3J(H,H)=7.0 Hz, 1H; -C(CH3)=CH-), 5.13 (t,
3J(H,H)=6.4 Hz, 1H; -CH(OAc)-), 4.94 (s, 1H; -(CH3)C=CHaHb), 4.89
(s, 1H; -(CH3)C=CHaHb), 2.94 (d, 3J(H,H)=7.0 Hz, 2H; -CH2-
1418, 1383, 1301, 1235 cmꢀ1
.
ꢀ
COO(CH3)3), 2.06 (s, 3H; -CH(OOCCH3)-), 2.01 (m, 2H; -CH2
Synthesis of diol 13: (E)-Homogeranic tert-butylate (1.0 g, 4.2 mmol),
prepared from (E)-homogeranic acid 12 according to Gosselin,[16a] was
dissolved in a mixture of tBuOH/H2O 2:1 (45 mL). After cooling at 08C,
K2CO3 (2.32 g, 16.8 mmol), K3Fe(CN)6 (5.5 g, 16.8 mmol), hydroquinine
1,4-phthalazinediyl diether ((DHQ)2PHAL; 549 mg, 0.168 mmol),
K2OsO2(OH)4 (61.9 mg, 0.168 mmol), and CH3SO2NH2 (520 mg,
5.46 mmol) were added successively. After 12 h at 08C, Na2SO3 (2.1 g,
16.8 mmol) was added and stirring was continued for 1 h at this tempera-
ture. The reaction mixture was then partitioned between EtOAc
(100 mL) and water (100 mL). The organic phase was separated, the
aqueous phase was washed with EtOAc (2î50 mL), and the combined
organic extracts were washed successively with water and brine, dried
over Na2SO4, and concentrated in vacuo. The crude mixture was subject-
ed in flash column chromatography (silica gel, hexanes/EtOAc 6:4) to
afford pure diol 13 (699 mg, 61%, 97% ee, detected by 1H NMR spec-
trum of the Mosher ester) as a pale yellow oil and recovered (E)-homo-
geranic tert-butylate (293 mg, 75%). Rf =0.22 (hexanes/EtOAc 6:4);
[a]2D0 =ꢀ22.0 (c=1.3 in CHCl3); 1H NMR (250 MHz, CDCl3): d=5.35 (t,
ꢀ
C(CH3)=CH-), 1.75 (m, 2H; -(OAc)CH CH2-), 1.72 (brs, 3H; -(CH3)C=
CH2), 1.62 (brs, 3H; -(CH3)C=CH-), 1.44 ppm (brs, 9H; -C(CH3)3).
Method B–by means of epoxide ring opening: DBU (393 mg,
2.58 mmol) was added at 258C to a solution of monotosylate 14 (220 mg,
0.516 mmol) in DMF (0.4 mL) under argon. After 15 min of stirring, satu-
rated aqueous solution of NH4Cl was added. The reaction mixture was
extracted with EtOAc (2î20 mL) and the combined organic extracts
were washed successively with water and brine, dried over Na2SO4, and
concentrated in vacuo. The crude mixture was subjected to flash column
chromatography (silica gel, hexanes/EtOAc 95:5) to afford pure epoxide
16 (114 mg, 87%), as a pale yellow oil. Rf =0.8 (hexanes/EtOAc 8:2);
[a]2D0 =+3.0 (c=1.2 in CHCl3); 1H NMR (500 MHz, CDCl3): d=5.35 (t,
3J(H,H)=7.1 Hz, 1H; -C(CH3)=CH-), 2.96 (d, 3J(H,H)=7.1 Hz, 2H;
3
ꢀ
ꢀ
-CH2 COOC(CH3)3), 2.71 (t, J(H,H)=6.3 Hz, 1H; (CH3)2C CH-), 2.17
ꢀ
ꢀ
ꢀ
(m, 2H; -CH2 C(CH3)=CH-), 1.78 1.60 (m, br s, 6H; -CH2 CH2
C(CH3)=CH-), 1.44 (brs, 9H; -C(CH3)3), 1.30 (s, 3H; -C(CH3)a(CH3)b),
1.26 ppm (s, 3H; -C(CH3)a(CH3)b); 13C NMR (62.5 MHz, CDCl3): d=
172.0, 138.0, 117.4, 80.8, 64.4, 58.7, 36.6, 35.4, 28.5, 27.7, 25.3, 19.1,
16.8 ppm; HRMS (MALDI-FTMS): m/z calcd for C15H26O3 [M+H]+:
255.1954; found: 255.1960.
3J(H,H)=6.9 Hz, 1H; -(CH3)C=CH-), 3.34 (d, 3J(H,H)=10.2 Hz, 1H;
3
ꢀ
ꢀ
-CH OH), 2.95 (d, J(H,H)=6.9 Hz, 2H; -CH2 COO(CH3)3), 2.43 2.00
(m, 4H; -CH2CH2-), 1.63 (s, 3H; -(CH3)C=CH-), 1.43 (s, 3H; C(CH3)3),
ꢀ
LiBr (89 mg, 1.02 mmol) and PPTS (199 mg, 0.79 mmol) were added at
258C to a solution of epoxide 16 (200 mg, 0.79 mmol), in NMP (0.22 mL)
under argon. After 1 h of stirring, a saturated aqueous solution of
NaHCO3 was added, the reaction mixture was extracted with EtOAc (2î
10 mL), and the combined organic extracts were washed successively
with water and brine, dried over Na2SO4, and concentrated in vacuo.
Flash column chromatography of the crude mixture (silica gel, hexanes/
EtOAc 9:1) yielded bromohydrin 17 (225 mg, 85%, 95% ee according to
the procedure described above) as an inseparable mixture with allylic al-
cohol 15 (<5%, detected by 1H NMR spectroscopy). Rf =0.3 (hexanes/
EtOAc 8:2); 1H NMR (500 MHz, CDCl3): d=5.40 (t, 3J(H,H)=7.1 Hz,
1.18 (s, 3H; -(CH3)a(CH3)bC OH), 1.14 ppm (s, 3H; -(CH3)a(CH3)bC-
OH); 13C NMR (62.5 MHz, CDCl3): d=172.0, 138.9, 116.8, 80.6, 78.1,
72.9, 36.9, 34.7, 29.5, 28.1, 26.3, 23.2, 16.2 ppm; IR (neat): n˜ =3447, 2979,
2932, 2874, 1732, 1455, 1368, 1143, 1078, 951, 836, 766 cmꢀ1; HRMS
(MALDI-FTMS): m/z calcd for C15H28O4 [M+Na]+: 295.1880; found:
295.1883.
Synthesis of monotosylate 14: p-Toluenesulfonyl anhydride (1.6 g,
4.77 mmol) was added at 08C to a solution of diol 13 (1.0 g, 3.67 mmol)
in pyridine (4.6 mL) under argon. The reaction mixture was stirred for
1 h and then it was partitioned between saturated aqueous solution of
NH4Cl (40 mL) and EtOAc (40 mL). The organic phase was separated
and the aqueous phase was washed with EtOAc (2î20 mL). The com-
bined organic extracts were washed successively with water and brine,
dried over Na2SO4, and concentrated in vacuo. Flash column chromatog-
raphy (silica gel, hexanes/EtOAc 8:2) of the crude mixture yielded pure
monotosylate 14 (4.94 g, 86%) as a pale yellow oil. Rf =0.65 (hexanes/
EtOAc 6:4); [a]2D0 =ꢀ18.0 (c=0.4 in CHCl3); 1H NMR (250 MHz,
CDCl3): d=7.82 (d, 3J(H,H)=8.7 Hz, 2H; ArH), 7.34 (d, 3J(H,H)=
8.7 Hz, 2H; ArH), 5.25 (t, 3J(H,H)=7.0 Hz, 1H; -CH=C(CH3)-), 4.56
1H; -C(CH3)=CH-), 3.99 (dd, 3J(H,H)=1.9 Hz, 3J(H,H)=11.0 Hz, 1H;
3
ꢀ
-(Br)CH-), 2.97 (d, J(H,H)=7.1 Hz, 2H; -CH2 COOC(CH3)3), 2.36 (m,
1H; -CHaHbC(CH3)-), 2.17 (m, 1H; -CHaHbC(CH3)-), 2.10 1.95 (m, 1H;
ꢀ
ꢀ
-(Br)CH CHaHb-), 1.92 1.73 (m, 2H; -(Br)CH CHaHb-), 1.63 (brs, 3H;
-(CH3)C=CH-), 1.45 (brs, 9H; -C(CH3)3), 1.36 1.33 ppm (2s, 6H;
-C(OH)(CH3)2); 13C NMR (62.5 MHz, CDCl3): d=171.6, 136.8, 117.9,
80.5, 72.4, 70.3, 38.0, 35.0, 31.9, 28.1, 26.5, 26.0, 16.3 ppm; IR (neat): n˜ =
3469, 2977, 2934, 1733, 1369, 1144, 954, 842, 459 cmꢀ1; HRMS (EI): m/z
calcd for C15H27BrO3 ([M+H]+): 335.1222; found: 335.1229.
(dd, 3J(H,H)=3.0 Hz, 3J(H,H)=8.9 Hz, 1H; -CHOTs), 2.92 (d,
3
ꢀ
J(H,H)=7.0 Hz, 2H; -CH2 COOC(CH3)3), 2.44 (s, 3H; CH3Ar), 2.01
Synthesis of optically active bromolactone 18: A solution of bromohydrin
17 (640 mg, 1.91 mmol) in dry CH3NO2 (8 mL) was added portionwise to
a solution of SnCl4 (1.24 g, 4.75 mmol) in dry CH3NO2 (16 mL) at 08C
under argon. After 30 min of stirring, the reaction mixture was poured in
an ice-cold solution of Et2O/H2O 1:1 (40 mL). The organic phase was
separated, the aqueous phase was washed with diethyl ether (2î20 mL),
ꢀ
(m, 2H; -CH2 C(CH3)=CH-), 1.85 1.61 (m, 2H; -CH(OTs)CH2-), 1.54
(s, 3H; -C(CH3)=CH-), 1.44 (s, 9H; -OC(CH3)3), 1.19 (s, 3H;
-(CH3)a(CH3)bC(OH)-), 1.18 ppm (s, 3H; (CH3)a(CH3)bC(OH)-);
13C NMR (62.5 MHz, CDCl3): d=171.6, 144.7, 137.4, 134.5, 129.7, 127.7,
117.1, 90.3, 80.4, 72.2, 35.8, 34.8, 29.1, 28.1, 26.2, 24.6, 21.6, 16.4 ppm; IR
3828
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3822 3835

Oxepene Cyclogeranyl Systems
3822 3835
and the combined organic extracts were washed successively with water
and brine, dried over Na2SO4, and concentrated in vacuo. Flash column
chromatography of the crude mixture (silica gel, hexanes/EtOAc 9:1)
yielded pure bromolactone 5 (299 mg, 60%), as a pale yellow oil with
spectroscopical data identical to the reported ones.[4a] Rf =0.64 (hexanes/
EtOAc 5:5); [a]2D0 =ꢀ24.0 (c=0.8 in CHCl3); 1H NMR (250 MHz,
CDCl3): d=3.93 (dd, 3J(H,H)=4.8 Hz, 3J(H,H)=12.0 Hz, 1H; -CH(Br)-),
2.53 (dd, 3J(H,H)=13.5 Hz, 2J(H,H)=15.8 Hz, 1H; -CHaHbCO), 2.38
(dd, 3J(H,H)=6.9 Hz, 2J(H,H)=15.8 Hz, 1H; -CHaHbCO), 2.20 1.92 (m,
Preparation of the allylic epoxide coupling partners 22a d: Each of the
allylic alcohols 21a c was epoxidized and subsequently silylated, as it is
described below:
Compound 22a: Ti(O-iPr)4 (336 mg, 1.18 mmol) was added to a mixture
of l-(+)-diisopropyltartrate (330 mg, 1.40 mmol) and molecular sieves
(MS) 4 ä (250 mg) in dry CH2Cl2 (4 mL) at ꢀ208C under argon. After
20 min of stirring,
a solution of the allylic alcohol 21a (513 mg,
2.19 mmol) in dry CH2Cl2 (4 mL) was added. The mixture was stirred for
20 min and then an anhydrous solution of tBuOOH (5.5m in decane,
0.8 mL, 4.38 mmol) was added. The reaction was stirred at ꢀ208C for
12 h. Water (13 mL) was added at 08C and the resulting mixture was
brought to 258C over a period of 30 min. A 30% solution of NaOH in
brine was then added and the mixture was vigorously stirred for 1 h at
08C. After separation of the dichloromethane phase, the aqueous phase
was washed with CH2Cl2 (4î30 mL) and the combined organic extracts
were washed successively with water and brine, dried over Na2SO4, and
concentrated in vacuo. Flash column chromatography of the crude mix-
ture (silica gel, hexanes/EtOAc 7:3) yielded the pure epoxy alcohol
(438 mg, 80%, 95% ee determined by the 1H NMR spectrum of Mosher
ester) and recovered hydroxydiene 21a (93 mg, 90%). Rf =0.3 (hexanes/
EtOAc 7:3); [a]2D0 =+2.0 (c=0.54 in CHCl3); 1H NMR (250 MHz,
CDCl3): d=7.25 (d, 3J(H,H)=8.5 Hz, 2H; ArH), 6.88 (d, 3J(H,H)=
8.5 Hz, 2H; ArH), 5.36 (brs, 1H; -C=CHaHb), 5.29 (brs, 1H; -C=
ꢀ
ꢀ
ꢀ
3H; -C(CH3)2 CH-, -CH2 CH(Br)-), 1.50 1.90 (m, 2H; -CH2 C(CH3)-
O-), 1.37 (s, 3H; -C(CH3)O-), 1.07 (s, 3H; -C(CH3)a(CH3)b), 1.02 ppm (s,
3H; -C(CH3)a(CH3)b); 13C NMR (62.5 MHz, CDCl3): d=175.3, 84.6, 62.7,
54.4, 38.5, 38.4, 32.3, 30.2, 30.0, 20.4, 17.0 ppm.
Synthesis of optically active tertiary alcohol 4: NaHMDS (1m solution in
THF, 3.3 mL, 3.3 mmol) was added to a solution of PPh3CH3+Brꢀ (1.57 g,
4.40 mmol) in dry THF (5.3 mL) at 08C under argon. After stirring at
258C for 1 h, the solution of the ylide was added to a solution of
(3aS,5S,7aS)-5-bromo-octahydro-4,4,7a-trimethylbenzofuran-2-ol
(580 mg, 2.20 mmol), prepared from lactone 18 according to Hoye,[7a] in
dry THF (4 mL) over a period of 12 h. After addition was completed, the
reaction mixture was poured in an aqueous saturated NH4Cl solution; it
was then extracted with EtOAc (2î40 mL). The combined organic ex-
tracts were washed successively with water and brine, dried over Na2SO4,
and concentrated in vacuo. The crude mixture was subjected to flash
column chromatography (silica gel, hexanes/EtOAc 9:1) to afford pure
alcohol 4 (345 mg, 60%) as a colorless liquid and recovered lactol
(208 mg, 90%). Rf =0.5 (hexanes/EtOAc 7:3); [a]2D0 =+13.0 (c=3.7 in
CHCl3); 1H NMR (250 MHz, CDCl3): d=5.97 (m, 1H; -CH=CH2), 5.11
(ddd, 2J(H,H)=1.5 Hz, 3J(H,H)=17.2 Hz, 4J(H,H)=3.4 Hz, 1H; -CH=
CHtransHcis), 5.00 (ddd, 2J(H,H)=1.5 Hz, 3J(H,H)=10.3 Hz, 4J(H,H)=
2.9 Hz, 1H; -CH=CHtransHcis), 4.00 (dd, 3J(H,H)=4.2 Hz, 3J(H,H)=
CHaHb), 4.46 (d, 2J(H,H)=11.1 Hz, 1H; Ar CHaHbO-), 4.40 (d,
ꢀ
2
ꢀ
ꢀ
J(H,H)=11.1 Hz, 1H; Ar CHaHbO-), 3.96 (brs, 2H; ArCH2O CH2-),
3.93 (dd, 2J(H,H)=12.8 Hz, 3J(H,H)=2.0 Hz, 1H; -CHaHbOH), 3.81 (s,
3H; CH3OAr-), 3.67 (dd, 2J(H,H)=12.8 Hz, 3J(H,H)=4.2 Hz, 1H;
-CHaHbOH), 3.48 (d, 3J(H,H)=1.9 Hz, 1H; CH2=C CH-(OCH)-),
ꢀ
3.17 ppm (m, 1H; -(-CHO-) CH CH2OH); 13C NMR (62.5 MHz,
CDCl3): d=159.3, 141.2, 130.0, 129.4, 116.4, 113.8, 71.8, 69.2, 61.4, 59.6,
55.5, 55.3 ppm; IR (neat): n˜ =3442, 2995, 2958, 2936, 2855, 2840, 1614,
1516, 1465, 1251, 1087, 1037, 823 cmꢀ1; HRMS (MALDI-FTMS): m/z
calcd for C14H18O4 [M+Na]+: 273.1097; found: 273.1090.
ꢀ
ꢀ
ꢀ
11.9 Hz, 1H; -CH(Br)-), 2.35 (m, 2H; -CH2 CH=CH2), 2.23 1.91 (m,
2H; -CH2 CH(Br)-), 1.75 (ddd, 2J(H,H)=13.4 Hz, 3J(H,H)=3.2 Hz,
ꢀ
Imidazole (120 mg, 1.76 mmol), tert-butyldiphenylchlorosilane (352 mg,
3J(H,H)=3.2 Hz, 1H; -CHaxHeqC(OH)-), 1.65 1.46 (m, 2H; -CHaxHeq
-
1.28 mmol), and
a catalytic amount of 4-dimethylaminopyridine (4-
ꢀ
C(OH), -C(CH3)2 CH-), 1.25 (s, 3H; -C(OH)CH3), 1.14 (s, 3H;
-C(CH3)a(CH3)b), 0.96 ppm (s, 3H; -C(CH3)a(CH3)b); 13C NMR
(62.5 MHz, CDCl3): d=141.2, 115.1, 73.4, 67.0, 56.5, 43.0, 40.8, 32.1, 32.0,
30.6, 23.7, 17.3 ppm; IR (neat): n˜ =3444, 2976, 2953, 2928, 2873, 1637,
1466, 1393, 1372, 1154, 1078, 1004, 985, 915, 708, 582 cmꢀ1; HRMS (EI):
m/z calcd for C12H21BrO [M+H]+: 261.0848; found: 261.0854.
DMAP) were successively added to a solution of the above-mentioned
epoxy alcohol (246.8 mg, 0.99 mmol) in anhydrous DMF (0.4 mL) at 08C
under argon. After 30 min of stirring, the reaction mixture was quenched
with saturated ammonium chloride solution. EtOAc (25 mL) was added
and the organic phase was separated. The aqueous phase was washed
with EtOAc (2î20 mL) and the combined organic extracts were washed
successively with water and brine, dried over Na2SO4, and concentrated
in vacuo. The crude mixture was subjected to flash column chromatogra-
phy (silica gel, hexanes/EtOAc 9:1) to afford pure allylic epoxide 22a
(455 mg, 95%). Rf =0.64 (hexanes/EtOAc 8:2); [a]2D0 =+0.8 (c=3.2 in
Preparation of vinyl bromide 20: Vinyl bromide 20, was prepared from
p-methoxybenzyl alcohol and 2,3-dibromobut-1-ene according to refer-
ence [20a]. Yellow oil; Rf =0.5 (hexanes/EtOAc 8:2); 1H NMR
(250 MHz, CDCl3): d=7.29 (d, 3J(H,H)=8.2 Hz, 2H; ArH), 6.90 (d,
3J(H,H)=8.2 Hz, 2H; ArH), 5.95 (brs, 1H; -C=CHaHb), 5.64 (brs, 1H;
1
CHCl3); H NMR (250 MHz, CDCl3): d=7.71 (m, 4H; -SiArH), 7.40 (m,
6H; -SiArH), 7.25 (d, 3J(H,H)=8.6 Hz, 2H; CH3OArH), 6.87 (d,
ꢀ
ꢀ
-C=CHaHb), 4.50 (s, 2H; ArCH2-), 4.11 (s, 2H; -O CH2 C=C-),
3.81 ppm (s, 3H; CH3O-Ar); 13C NMR (62.5 MHz, CDCl3): d=159.4,
129.6, 129.5, 117.7, 113.9, 73.7, 71.7, 55.3 ppm; IR (neat): n˜ =3001, 2958,
2935, 2909, 2859, 2835, 1642, 1614, 1589, 1514, 1465, 1303, 1251, 1177,
1085, 1035, 900, 823, 668, 575, 532, 516 cmꢀ1; HRMS (MALDI-FTMS):
m/z calcd for C11H13BrO2 [M+Na]+: 278.9991; found: 278.9992.
3J(H,H)=8.6 Hz, 2H; CH3OArH), 5.33 (brs, 1H; -C=CHaHb), 5.28 (brs,
2
ꢀ
1H; -C=CHaHb), 4.46 (d, J(H,H)=11.2 Hz, 1H; Ar CHaHbO-), 4.40 (d,
2
ꢀ
ꢀ
J (H,H)=11.2 Hz, 1H; Ar CHaHbO-), 3.95 (brs, 2H; ArCH2O CH2-),
3.88 (dd, 2J(H,H)=12.4 Hz, 3J(H,H)=3.2 Hz, 1H; -CHaHbOSi-), 3.80 (s,
3H; CH3OAr-), 3.75 (dd, 2J(H,H)=12.4 Hz, 3J(H,H)=3.9 Hz, 1H;
3
ꢀ
ꢀ
CHaHbOSi-), 3.39 (d, J(H,H)=2.0 Hz, 1H; CH2=C CH (OCH)-), 3.17
Synthesis of allylic alcohol 21a: A mixture of vinyl bromide 20 (225 mg,
0.88 mmol) and 3-tributylstannylprop-2-en-1-ol (608 mg, 1.75 mmol)[22] in
dry CH2Cl2 (1.7 mL) was stirred at 258C under argon and [Pd2(dba)3]
(81 mg, 0.088 mmol) was added. After stirring for 3 h, the reaction mix-
ture was concentrated in vacuo and immediately subjected to flash
column chromatography (silica gel, hexanes/EtOAc 7:3) to yield pure al-
lylic alcohol 21a (124 mg, 60%) as a pale yellow oil. Rf =0.31 (hexanes/
EtOAc 6:4); 1H NMR (250 MHz, CDCl3): d=7.27 (d, 3J(H,H)=8.5 Hz,
2H; ArH), 6.88 (d, 3J(H,H)=8.5 Hz, 2H; ArH), 6.30 (d, 3J (H,H)=
ꢀ
ꢀ
(m, 1H; -(-CHO-) CH CH2OSi), 1.08 ppm (brs, 9H, -C(CH3)3);
13C NMR (62.5 MHz, CDCl3): d=159.2, 141.7, 135.6, 135.5, 134.8, 130.1,
129.7, 129.6, 129.3, 127.7, 115.8, 113.8, 71.7, 69.2, 63.7, 59.8, 55.7, 55.2,
26.7, 26.5, 19.2 ppm; HRMS (MALDI-FTMS): m/z calcd for C30H36O4Si
[M+Na]+: 511.2275; found: 511.2264.
By using d-(ꢀ)-diisopropyltartrate, the same procedure was followed to
prepare the antipode of 22a, ent-22a.
Compounds 22b,c: Epoxidation of allylic alcohol 21b (300 mg,
3.06 mmol), was performed as described for 21a, in this case by using l-
(+)-diisopropyltartrate (459 mg, 1.96 mmol), Ti(OiPr)4 (470 mg,
1.65 mmol), tBuOOH (5.5m in decane, 1.1 mL, 6.12 mmol) and MS 4 ä
(150 mg) in dry CH2Cl2 (5 mL). Epoxy alcohol obtained this way was iso-
lated in pure form, as a pale yellow oil (280 mg, 80%, 95% ee). Rf =0.38
(hexanes/EtOAc 6:4); [a]2D0 =ꢀ13.0 (c=1.1 in CHCl3); 1H NMR
(250 MHz, CDCl3): d=5.15 (brs, 1H; -C=CHaHb), 5.04 (m, 1H; -C=
16.2 Hz, 1H; -CH=CH CH2OH), 5.95 (dt, 3J(H,H)=5.6 Hz, 3J(H,H)=
ꢀ
ꢀ
16.2 Hz, 1H; -CH=CH CH2OH), 5.26 (brs, 1H; -C=CHaHb), 5.20 (brs,
1H; -C=CHaHb), 4.46 (s, 2H; ArCH2), 4.20 (d, 3J(H,H)=5.6 Hz, 2H;
-CH2OH), 4.15 (s, 2H; -OCH2-), 3.81 ppm (s, 3H; CH3O); 13C NMR
(62.5 MHz, CDCl3): d=159.2, 141.6, 130.6, 130.2, 129.4, 129.1, 117.5,
113.8, 71.7, 70.0, 63.6, 55.2 ppm; IR (neat): n˜ =3405, 2954, 2931, 2856,
1613, 1585, 1514, 1464, 1372, 1302, 1249, 1174, 1091, 1035, 970, 820 cmꢀ1
;
CHaHb), 3.97 (d, 2J(H,H)=12.8 Hz, 1H; -CHaHbOH), 3.69 (d, 2J(H,H)=
HRMS (MALDI-FTMS): m/z calcd for C14H18O3 [M+Na]+: 257.1148;
3
ꢀ
ꢀ
12.8 Hz, 1H;-CHaHbOH), 3.42 (d, J(H,H)=1.9 Hz, 1H; CH2=C CH
ꢀ
ꢀ
found: 257.1150.
(OCH)-), 3.15 (m, 1H; -(-CHO-) CH CH2OH), 1.66 ppm (brs, 3H;
Chem. Eur. J. 2004, 10, 3822 3835
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3829

E. A. Couladouros and V. P. Vidali
FULL PAPER
-(CH3)C=CH2); 13C NMR (62.5 MHz, CDCl3): d=140.5, 114.9, 61.5, 57.8,
57.7, 16.7 ppm; IR (neat): n˜ =3415, 2924, 2855, 1462, 1376, 1084, 906,
1H; CH2=C CHaHb O-), 3.79 (s, 3H; CH3O Ar CH2-), 3.63 (m, 3H;
ꢀ
ꢀ
ꢀ ꢀ
3
ꢀ
ꢀ
ꢀ
ꢀ
-CH(OH) CH2O Si-), 2.86 (d, J(H,H)=3.7 Hz, 1H; -CH(OH) CH2O
878 cmꢀ1
.
ꢀ
Si-), 2.31 1.90 (m, 2H; -CH2 CH=CH2), 1.80 1.11 (m, 7H; -(CH2)3-,
-C(CH3)2 CH-), 1.57 (brs, 3H; -(CH3)C O-), 1.07 (brs, 9H;
-Si C(CH3)3), 0.90 (s, 3H; -C(CH3)a(CH3)b), 0.81 ppm (s, 3H;
ꢀ
ꢀ
For the silylation of the above epoxy alcohol (132 mg, 1.16 mmol) the
same procedure as for the synthesis of 22b was followed, in this case by
using imidazole (142 mg, 2.09 mmol), tert-butyldiphenylchlorosilane
(412 mg, 1.5 mmol) or tert-butyldimethylchlorosilane (233 mg, 1.5 mmol),
and a catalytic amount of 4-DMAP in anhydrous DMF (0.2 mL) to iso-
late 22b (368 mg, 90%) or 22c (250 mg, 94%), respectively.
ꢀ
-C(CH3)a(CH3)b); 13C NMR (62.5 MHz, CDCl3): d=159.2, 145.9, 143.1,
133.4, 135.6, 134.8, 130.3, 129.6, 129.3, 127.7, 127.6, 115.1, 113.7, 112.3,
80.3, 74.2, 72.5, 72.3, 67.8, 64.5, 55.7, 55.2, 41.6, 38.9, 35.4, 33.3, 30.9, 26.7,
26.5, 21.4, 20.0, 18.6 ppm; IR (neat): n˜ =3423, 2960, 2933, 2857, 1619,
1516, 1472, 1432, 1392, 1382, 1253, 1115, 825, 759, 742, 702 cmꢀ1; HRMS
(MALDI-FTMS): m/z calcd for C42H58O5Si [M+Na]+: 693.3946; found:
693.3951.
Data for 22b: Colorless liquid; Rf =0.54 (hexanes/EtOAc 8:2); [a]D20
=
+1.9 (c=1.6 in CHCl3); 1H NMR (250 MHz, CDCl3): d=7.70 (m, 4H;
-SiArH), 7.40 (m, 6H; -SiArH), 5.12 (brs, 1H; -C=CHaHb), 5.01 (m,
1H; -C=CHaHb), 3.87 (dd, 2J(H,H)=11.9 Hz, 3J(H,H)=4.2 Hz, 1H;
Compound 23b: Coupling of alcohol 3 (400 mg, 2.19 mmol) with allylic
epoxide 22b (309 mg, 0.88 mmol) was performed as described above, by
using BF3¥OEt2 (8.6 mL, 0.07 mmol) in dry CH2Cl2 (88 mL) to afford, after
purification, diene 23b (259 mg, 55%) as a colorless liquid and recovered
alcohol 3 (295 mg, 95%). Rf =0.6 (hexanes/EtOAc 9:1); [a]2D0 =+1.2 (c=
1.1 in CHCl3); 1H NMR (250 MHz, CDCl3): d=7.66 (m, 4H; -SiAr-H),
7.39 (m, 6H; -SiAr-H), 5.84 (m, 1H; -CH=CH2), 4.90 (brs, 2H;
-CHaHbOSi), 3.78 (dd, 2J(H,H)=11.9 Hz, 3J(H,H)=5.2 Hz, 1H;
3
ꢀ
-CHaHbOSi-), 3.29 (d, J(H,H)=1.9 Hz, 1H; CH2=C -CH-(OCH)-), 3.12
ꢀ
ꢀ
(m, 1H; -(-CHO-) CH CH2OSi-), 1.64 (brs, 3H, CH2=C(CH3)-),
1.07 ppm (brs, 9H, -C(CH3)3); 13C NMR (62.5 MHz, CDCl3): d=141.0,
135.6, 135.5, 133.3, 133.2, 130.0, 129.8, 127.7, 114.5, 63.9, 58.2, 58.0, 29.7,
26.8, 19.3, 16.8 ppm; IR (neat): n˜ =3075, 2963, 2931, 2859, 1477, 1468,
3
-C(CH3)=CH2), 4.86 (d, J(H,H)=16.2 Hz, 1H; -CH=CHtransHcis), 4.76 (d,
1431, 1116, 891, 742, 701, 510 cmꢀ1
; HRMS (EI): m/z calcd for
3J(H,H)=10.0 Hz, 1H; -CH=CHtransHcis), 4.05 (d, 3J(H,H)=6.3 Hz, 1H;
C22H28O2Si [M+Na]+: 375.1751; found: 375.1759.
ꢀ
ꢀ
-O CH CH(OH)-), 3.80 3.54 (m, 3H; -CH(OH)-CH2OSi-), 2.37 (d,
J(H,H)=3.3 Hz, 1H; -CH(OH)-), 2.18 (m, 1H; -CHaHb CH=CH2), 1.98
(m, 1H; -CHaHb CH=CH2), 1.74 (brs, 3H; -(CH3)C=CH2)), 1.64 1.11
Data for 22c: Colorless liquid; Rf =0.81 (hexanes/EtOAc 6:4); [a]D20
=
3
ꢀ
+0.5 (c=1.2 in CHCl3); 1H NMR (250 MHz, CDCl3): d=5.13 (s, 1H;
-C=CHaHb), 5.00 (brs, 1H; -C=CHaHb), 3.87 (dd, 2J(H,H)=11.9 Hz,
3J(H,H)=3.0 Hz, 1H; -CHaHbOSi-), 3.70 (dd, 2J(H,H)=11.9 Hz,
ꢀ
(m, 7H; -(CH2)3-, -C(CH3)2-CH-), 1.07 (brs, 9H; -SiC(CH3)3), 1.04 (s,
3H; -(CH3)C-O-), 0.90 (s, 3H; -C(CH3)a(CH3)b), 0.81 ppm (s, 3H;
-C(CH3)a(CH3)b); 13C NMR (62.5 MHz, CDCl3): d=146.2 , 143.0, 135.6,
133.4, 133.3, 129.6, 127.7, 112.3, 80.1, 74.1, 73.2, 64.7, 55.7, 41.7, 38.8, 35.4,
33.3, 30.9, 26.9, 21.4, 20.0, 19.2, 18.5 ppm; IR (neat): n˜ =3576, 3078, 2939,
3
3J(H,H)=4.8 Hz, 1H; -CHaHbOSi-), 3.29 (d, J(H,H)=2.2 Hz, 1H; CH2=
ꢀ
ꢀ
ꢀ
ꢀ
C(CH3) CH (OCH)-), 3.06 (m, 1H; -(-CHO-) CH CH2OSi-), 1.64
(brs, 3H; -(CH3)C=CH2), 0.90 (brs, 9H; -SiC(CH3)3), 0.08 ppm (2s, 6H;
-Si(CH3)2); 13C NMR (62.5 MHz, CDCl3): d=141.0, 114.0, 63.3, 58.2,
58.1, 25.9, 18.4, 16.8, 3.7 ppm; IR (neat): n˜ =2960, 2930, 2861, 1766, 1481,
2863, 1476, 1461, 1429, 1115, 1067, 1052, 906, 761, 701, 507, 439 cmꢀ1
;
HRMS (MALDI-FTMS): m/z calcd for C34H50O3Si [M+Na]+: 557.3421;
1463, 1259, 1147, 1116, 847, 785 cmꢀ1
C12H24O2Si [M+Na]+: 251.1438; found: 251.1444.
Compound 22d:
; HRMS (EI): m/z calcd for
found: 557.3438.
Compound 23c: Coupling of alcohol 3 (40 mg, 0.22 mmol) with allylic ep-
oxide 22c (20 mg, 0.09 mmol) was performed as described above, by
using BF3¥OEt2 (0.9 mL, 0.008 mmol) in dry CH2Cl2 (10 mL) to afford,
after purification, diene 23c (19 mg, 50%) as a colorless liquid and recov-
ered alcohol 3 (29 mg, 92%). Rf =0.32 (hexanes/EtOAc 9:1); 1H NMR
(250 MHz, CDCl3): d=5.92 (m, 1H; -CH=CH2), 4.95 (d, 3J(H,H)=
19.0 Hz, 1H; -CH=CHtransHcis), 4.84 (d, 3J(H,H)=10.0 Hz, 1H; -CH=
CHtransHcis), 4.92 (brs, 1H; -C(CH3)=CHaHb), 4.90 (brs, 1H; -C(CH3)=
CHaHb), 4.00 (d, 3J(H,H)=6.3 Hz, 1H; -O-CH-CH(OH)-), 3.69 (dd,
(ꢀ)-(2S,3S)-2,3-Epoxypent-4-en-1-ol
(100 mg,
1.0 mmol)[20c] was silylated, as described above in this case by using imi-
dazole (122 mg, 1.8 mmol), tert-butyldimethylchlorosilane (196 mg,
1.3 mmol), and a catalytic amount of 4-DMAP in anhydrous DMF
(0.2 mL) to isolate pure vinyl epoxide 22d (204 mg, 60% for two steps)
as a colorless liquid. Rf =0.42 (hexanes/EtOAc 95:5); [a]2D0 =ꢀ12.0 (c=
1
4.5 in CHCl3); H NMR (250 MHz, CDCl3): d=5.57 (m, 1H; CH2=CH-),
5.47 (dd, 2J(H,H)=1.9 Hz, 3J(H,H)=17.1 Hz, 1H; CHcisHtrans=CH-), 5.27
2
3
3J(H,H)=4.4 Hz, 2J(H,H)=10.0 Hz, 1H; -CHaHb O Si-), 3.60 (dd,
( dd, J(H,H)=1.9 Hz, J(H,H)=10.1 Hz, 1H; CHcisHtrans=CH-), 3.86 (dd,
3J(H,H)=3.0 Hz, 2J(H,H)=11.9 Hz, 1H; -CHaHbOSi-), 3.70 (dd,
3J(H,H)=4.5 Hz, 2J(H,H)=11.9 Hz, 1H; -CHaHbOSi-), 3.28 (dd,
ꢀ
ꢀ
2
3J(H,H)=5.6 Hz, J(H,H)=10.0 Hz, 1H; -CHaHb O Si-), 3.53 (m, 1H;
ꢀ
ꢀ
ꢀ
ꢀ
-CH(OH)-CH2 OSi-), 2.32 (m, 1H; -CHaHb CH=CH2), 2.06 (m, 1H;
-CHaHb CH=CH2), 1.77 (brs, 3H; -(CH3)C=CH2), 1.51 1.08 (m, 7H;
-(CH2)3-, -C(CH3)2 CH-), 1.13 (s, 3H; -(CH3)C O-), 0.92 (s, 3H;
-C(CH3)a(CH3)b), 0.90 (brs, 9H; -SiC(CH3)3), 0.84 (s, 3H;
-C(CH3)a(CH3)b), 0.06 ppm (s, 6H; -Si(CH3)2); HRMS (MALDI-FTMS):
calcd for C24H46O3Si [M+Na]+: 433.3109; found: 433.3130.
3
3
ꢀ
J(H,H)=1.9 Hz, J(H,H)=7.1 Hz, 1H; CH2=CH CH-(OCH)-), 3.00 (m,
ꢀ
ꢀ
ꢀ
1H; -(-CHO-) CH CH2OSi), 0.90 (brs, 9H; -SiC(CH3)3), 0.07 ppm (s,
6H; -Si(CH3)2); 13C NMR (62.5 MHz, CDCl3): d=135.2, 119.5, 62.9, 60.2,
56.1, 25.8, 18.3, 3.7 ppm; IR (neat): n˜ =2958, 2930, 2861, 1644, 1474, 1460,
ꢀ
ꢀ
1261, 1145, 1110, 839, 778, 665 cmꢀ1
; HRMS (EI): m/z calcd for
C12H24O2Si [M+Na]+: 237.1282; found: 237.1278.
Compound 23d: Coupling of alcohol 3 (40 mg, 0.22 mmol) with allylic
epoxide 22d (23.5 mg, 0.11 mmol) was performed as described above, by
using BF3¥OEt2 (1.1 mL, 0.009 mmol) in dry CH2Cl2 (11 mL) to afford,
after purification, diene 23d (26 mg, 60%) as a colorless liquid and re-
Representative procedure for coupling of tertiary alcohols 3 or 4 with al-
lylic epoxides 22a d: A solution of redistilled BF3¥OEt2 (0.08 0.15 mmol)
in dry dichloromethane (0.01 1 mL) was added to a mixture of alcohol
(2.0 2.5 mmol) and epoxide (1 mmol) at 08C under argon. The reaction
was monitored by TLC. After 15 30 min at 08C, the reaction was
quenched with 5% solution of Et3N in diethyl ether. The mixture was
concentrated in vacuo and fitered through a short silica gel column to
afford the corresponding diene and recovered alcohol.
covered alcohol
3 (26 mg, 93%). Rf =0.32 (hexanes/EtOAc 9:1);
1
ꢀ
ꢀ
ꢀ
H NMR (250 MHz, CDCl3): d=5.84 (m, 2H; -CH2 CH=CH2, -O CH
3
ꢀ
CH=CH2), 5.22 (d, J(H,H)=17.5 Hz, 1H; -CH2 CH=CHtransHcis), 5.16
3
(d, J(H,H)=10.0 Hz, 1H, -O CH CH=CHtransHcis), 5.00 (d, 3J(H,H)=
ꢀ
ꢀ
19.2 Hz, 1H; -O CH CH=CHtransHcis), 4.93 (d, 3J(H,H)=10.0 Hz, 1H;
ꢀ
ꢀ
-CH2 CH=CHtransHcis), 4.11 (dd, 3J(H,H)=4.5 Hz, 3J(H,H)=6.7 Hz, 1H;
ꢀ
Compound 23a: Coupling of alcohol 3 (40 mg, 0.22 mmol) with allylic ep-
oxide 22a (43 mg, 0.088 mmol) was performed as described above, by
using BF3¥OEt2 (1.5 mL, 0.012 mmol) in dry CH2Cl2 (9 mL), to afford after
purification diene 23a (34 mg, 56%) as pale yellow oil and recovered al-
cohol 3 (30 mg, 93%). Rf =0.33 (hexanes/EtOAc 8:2); [a]2D0 =+1.6 (c=
-O-CH-CH(OH)-), 3.65 3.54 (m, 3H; -CH(OH)-CH2O-Si-), 2.04 (m, 2H;
-CH2-CH=CH2), 1.81 1.20 (m, 7H; -(CH2)3-, -C(CH3)2 CH-), 1.25 (s,
3H; -(CH3)C O-), 1.13 (s, 3H; -C(CH3)a(CH3)b), 0.90 (brs, 9H;
-SiC(CH3)3), 0.81 (s, 3H; -C(CH3)a(CH3)b), 0.07 ppm (s, 6H; -Si(CH3)2);
13C NMR (62.5 MHz, CDCl3): d=157.3, 139.0, 116.2, 114.2, 80.5, 74.8,
71.8, 63.5, 56.2, 41.3, 39.5, 35.3, 33.1, 32.5, 29.7, 26.2, 25.9, 21.5, 20.1, 18.7,
3.7, 1.0 ppm; HRMS (MALDI-FTMS): m/z calcd for C23H44O3Si
[M+Na]+: 419.2952; found: 419.2964.
ꢀ
ꢀ
0.4 in CHCl3); 1H NMR (250 MHz, CDCl3): d=7.69 (m, 4H; -SiArH),
3
ꢀ
7.40 (m, 6H; -SiArH), 7.26 (d, J(H,H)=8.2 Hz, 2H; CH3OAr H), 6.87
3
ꢀ
(d, J(H,H)=8.2 Hz, 2H; CH3OAr H), 5.81 (m, 1H; -CH=CH2), 5.26
(brs, 1H; -C=CHaHb), 5.16 (brs, 1H; -C=CHaHb), 4.88 (dd, 3J(H,H)=
17.0 Hz, 2J(H,H)=1.5 Hz, 1H; -CH=CHcisHtrans), 4.76 (dd, 3J(H,H)=
10.0 Hz, 2J(H,H)=1.5 Hz, 1H; -CH=CHcisHtrans), 4.45 (brs, 2H; Ar-CH2-
Compound 24a: Coupling of alcohol 4 (431 mg, 1.65 mmol) with allylic
epoxide 22a (323 mg, 0.66 mmol) was performed as described above, by
using BF3¥OEt2 (12 mL, 0.093 mmol) in dry CH2Cl2 (67 mL) to afford,
after purification, a mixture of diene 24a with the starting bromoalcohol
O-), 4.30 (d, 3J(H,H)=4.8 Hz, 1H; -O CH CH(OH)-), 4.10 (d,
ꢀ
ꢀ
J(H,H)=13.0 Hz, 1H; CH2=C CHaHb O-), 3.97 (d, 2J(H,H)=13.0 Hz,
2
ꢀ
ꢀ
3830
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3822 3835

Oxepene Cyclogeranyl Systems
3822 3835
ꢀ
ꢀ
ꢀ
4. Since complete separation of 24a and 4 was impossible, the mixture of
the two compounds was used in the next step, without futher purification.
Thus, it was dissolved in THF (1 mL), cooled at 08C, and TBAF (1m sol-
ution in THF, 660 mL, 0.66 mmol) was added. Stirring was continued for
3 h. The reaction mixture was partitioned between a saturated ammoni-
um chloride solution and ethyl acetate. After separation of the organic
phase, the aqueous phase was washed with EtOAc (2î20 mL) and the
combined organic extracts were washed successively with water and
brine, dried over Na2SO4, and concentrated in vacuo. The crude mixture
was subjected to flash column chromatography (silica gel, hexanes/
EtOAc 6:4) to afford the pure desilylated form of diene 24a (169 mg,
50% over two steps), as a yellow oil and recovered alcohol 4 (246 mg,
95%). Rf =0.25 (hexanes/EtOAc 6:4); [a]2D0 =ꢀ1.4 (c=0.9 in CHCl3);
1H NMR (250 MHz, CDCl3): d=7.26 (d, 3J(H,H)=8.6 Hz, 2H; ArH),
6.89 (d, 3J(H,H)=8.6 Hz, 2H; ArH), 5.84 (m, 1H; -CH=CH2), 5.32
(brs,1H; -C=CHaHb), 5.24 (brs, 1H; -C=CHaHb), 4.99 (dd, 2J(H,H)=
1.5 Hz, 3J(H,H)=17.4 Hz, 1H; -CH=CHtransHcis), 4.89 (dd, 2J(H,H)=
1.5 Hz, 3J(H,H)=10.2 Hz, 1H; -CH=CHtransHcis), 4.52 (d, 2J(H,H)=
C CH2 O-, -CH(OH)-), 3.87 3.72 (m, brs, 4H; CH3OAr CH2-,
-CHaHbO Si-), 3.65 (dd, 3J(H,H)=7.4 Hz, 2J(H,H)=11.2 Hz, 1H;
ꢀ
-CHaHbO-Si-), 2.63 (d, 3J(H,H)=7.6 Hz, 1H; -CH(OH)-), 2.23 (m, 1H;
-CHaHb CH=C-), 2.01 (m, 1H; -CHaHb CH=C-), 1.71 (d, 3J(H,H)=
ꢀ
ꢀ
ꢀ
10.0 Hz, 1H; -C(CH3)2 CH-), 1.14 1.16 (m, 6H; -(CH2)3-), 1.12 (s, 3H;
-(CH3)C O-), 1.04 (brs, 9H; -SiC(CH3)3), 0.91 (s, 3H; -C(CH3)eq(CH3)ax),
0.76 ppm (s, 3H; -C(CH3)eq(CH3)ax); IR (neat): n˜ =2963, 2931, 2859,
1517, 1465, 1431, 1263, 1249, 1111, 1075, 1039, 821, 806, 705 cmꢀ1; HRMS
(MALDI-FTMS): m/z calcd for C40H54O5Si [M+Na]+: 665.3633; found:
665.3640.
ꢀ
Compound 25b: Ring-closing metathesis of diene 23b (400 mg,
0.75 mmol) was performed as described above, in this case by using
second-generation Grubbs catalyst (B in Scheme 5; 64 mg, 0.075 mmol)
in CH2Cl2 (115 mL) to afford, after purification, oxepene 25b (354 mg,
93%) as a colorless oil. Rf =0.5 (hexanes/EtOAc 9:1); [a]2D0 =ꢀ5.0 (c=
1
ꢀ
ꢀ
0.1 in CHCl3); H NMR (250 MHz, CDCl3): d=7.72 (m, 4H; -Si Ar H),
7.30 (m, 6H; -Si Ar H), 5.46 (d, 3J(H,H)=8.2 Hz, 1H; -CH=C(CH3)-),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
4.35 (brs, 1H; -O CH CH(OH)-), 3.95 (m, 1H; -CH(OH) CH2 O Si-),
11.9 Hz, 1H; Ar CHaHbO-), 4.45 (d, 2J(H,H)=11.9 Hz, 1H; Ar
3.79 (dd, 2J(H,H)=10.8 Hz, J(H,H)=3.7 Hz, 1H; -CH(OH) CHaHb
3
ꢀ
ꢀ
ꢀ
ꢀ
3
OSi-), 3.68 (dd, 2J(H,H)=10.8 Hz, J(H,H)=7.8 Hz, 1H; -CH(OH)
3
ꢀ
CHaHbO-), 4.13 (d, J(H,H)=6.0 Hz, 1H; -OCH CH(OH)-), 4.05 (d,
ꢀ
2J(H,H)=11.5 Hz, 1H; CH2=C CHaHbOCH2-), 3.92 (d, 2J(H,H)=
ꢀ
ꢀ
3
ꢀ
CHaHb OSi-), 2.46 (d, J(H,H)=7.8 Hz, 1H; -CH(OH) CH2OSi-), 2.15
11.5 Hz, 1H; CH2=C CHaHbOCH2-), 3.86 (dd, 3J(H,H)=4.9 Hz,
ꢀ
(m, 1H; -CHaHb CH=C(CH3)-), 1.91 (dd, 2J(H,H)=17.1 Hz, 3J(H,H)=
ꢀ
3J(H,H)=12.8 Hz, 1H; -CH(Br)-), 3.81 (s, 3H; CH3O-Ar), 3.70 3.50 (m,
ꢀ
8.2 Hz, 1H; -CHaHb CH=C(CH3)-), 1.64 (d, 3J(H,H)=10.0 Hz, 1H;
ꢀ
ꢀ
3H; -CH(OH) CH2OH), 2.50 2.33 (m, 2H; -CH CH=CH2), 2.22 2.00
ꢀ
-C(CH3)2 CH-), 1.55 (brs, 3H; -CH=C(CH3)-), 1.66 1.14 (m, 6H;
-(CH2)3-), 1.12 (s, 3H; -(CH3)C O-), 1.07 (s, 9H; -SiC(CH3)3), 0.91 (s,
(m, 2H; -CH2 CH(Br)-), 1.93 (ddd, 2J(H,H)=13.4 Hz, 3J(H,H)=
ꢀ
ꢀ
13.4 Hz, 3J(H,H)=3.4 Hz, 1H; -CHaxHeq C(CH3)O), 1.71 (ddd,
3H; -C(CH3)eq(CH3)ax), 0.76 ppm (s, 3H; -C(CH3)eq(CH3)ax); 13C NMR
(62.5 MHz, CDCl3): d=136.3, 135.7, 133.6, 129.6, 129.5, 129.1, 127.6,
127.5, 78.3, 72.8, 72.4, 65.1, 52.8, 40.8, 36.1, 35.1, 33.0, 26.8, 24.3, 22.1,
20.9, 20.8, 19.2 ppm; IR (neat): n˜ =3654, 2963, 2933, 2856, 1476, 1465,
1426, 1113, 1079, 705, 506, 487 cmꢀ1; HRMS (MALDI-FTMS): m/z calcd
for C32H46O3Si [M+Na]+: 529.3108; found: 529.3111.
ꢀ
2J(H,H)=13.4 Hz, 3J(H,H)=3.5 Hz, 3J(H,H)=3.5 Hz, 1H; -CHaxHeq
-
ꢀ
ꢀ
C(CH3)O-), 1.50 (m, 1H; -C(CH3)2 CH-), 1.18 (s, 3H; -(CH3)C O-),
1.07 (s, 3H; -C(CH3)a(CH3)b), 0.96 ppm (s, 3H; -C(CH3)a(CH3)b);
13C NMR (62.5 MHz, CDCl3): d=159.3, 146.0, 141.8, 129.4, 129.3, 117.8,
113.8, 113.4, 79.5, 73.1, 72.7, 69.7, 66.7, 62.9, 56.5, 55.2, 41.1, 39.4, 31.8,
31.7, 30.5, 18.0, 17.7 ppm; IR (neat): n˜ =3425, 2955, 2933, 2876, 1615,
1514, 1465, 1386, 1250, 1084, 1042, 912, 821, 736, 703 cmꢀ1; HRMS
(MALDI-FTMS): m/z calcd for C26H39BrO5 [M+Na]+: 533.1873; found:
533.1871.
Compound 25c: Ring-closing metathesis of diene 23c (62.5 mg,
0.152 mmol) was performed as described for 23a, in this case by using
second-generation Grubbs catalyst (B in Scheme 5; 13 mg, 0.015 mmol)
in CH2Cl2 (25 mL) to afford, after purification, oxepene 25c (51 mg,
88%) as a colorless oil. Rf =0.28 (hexanes/EtOAc 9:1); [a]2D0 =ꢀ2.3 (c=
Compound 24b: Coupling of alcohol 4 (230 mg, 0.88 mmol) with allylic
epoxide 22b (123 mg, 0.35 mmol) was performed as described for 23a, by
using BF3¥OEt2 (4.5 mL, 0.035 mmol) in dry CH2Cl2 (40 mL) to afford,
after purification, diene 24b (117 mg, 54%) as a pale yellow oil and re-
1
3
0.4 in CHCl3); H NMR (250 MHz, CDCl3): d=5.52 (d, J(H,H)=7.8 Hz,
ꢀ
ꢀ
1H; -CH=C(CH3)-), 4.34 (brs, 1H; -O CH CH(OH)-), 3.85 (m, 1H;
-CH(OH) CH2O Si-), 3.74 (dd, 2J(H,H)=10.5 Hz, 3J(H,H)=3.0 Hz,
ꢀ
ꢀ
1H; -CHaHb O Si-), 3.58 (dd, 2J(H,H)=10.5 Hz, 3J(H,H)=7.8 Hz, 1H;
covered alcohol 4 (167 mg, 93%). Rf =0.42 (hexanes/EtOAc 9:1); [a]D20
=
ꢀ
ꢀ
3
+1.3 (c=0.8 in CHCl3); 1H NMR (250 MHz, CDCl3): d=7.65 (m, 4H;
-SiArH), 7.39 (m, 6H; -SiArH), 5.76 (m, 1H; -CH=CH2), 4.91 (brs, 1H;
-(CH3)C=CHaHb), 4.90 (brs, 1H; -(CH3)C=CHaHb), 4.88 (dd, 2J(H,H)=
1.5 Hz, 3J(H,H)=17.2 Hz, 1H; -CH=CHtransHcis), 4.79 (dd, 2J(H,H)=
1.5 Hz, 3J(H,H)=10.1 Hz, 1H; -CH=CHtransHcis), 4.00 (d, 3J(H,H)=
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
-CHaHb O Si-), 2.45 (d, J(H,H)=7.1 Hz, 1H; -CH(OH) CH2 O Si-),
2.20 (m, 1H; -CHaHb CH=C(CH3)-), 1.94 (dd, 2J(H,H)=17.2 Hz,
ꢀ
3J(H,H)=7.8 Hz, 1H; -CHaHb CH=C(CH3)-), 1.74 (brs, 3H; -CH=
ꢀ
3
ꢀ
C(CH3)-), 1.69 (d, J(H,H)=10.0 Hz, 1H; -C(CH3)2 CH-), 1.65 1.05 (m,
6H; -(CH2)3-), 1.19 (s, 3H; -(CH3)C O-), 0.93 (s, 3H; -C(CH3eq)(CH3ax)),
ꢀ
6.2 Hz, 1H; -OCH CH(OH)-), 3.91 (dd, 3J(H,H)=4.5 Hz, 3J(H,H)=
ꢀ
0.90 (brs, 9H; -SiC(CH3)3), 0.77 (s, 3H; -C(CH3)eq(CH3)ax), 0.07 ppm
(brs, 6H; -Si(CH3)2); 13C NMR (62.5 MHz, CDCl3): d=136.7, 129.2, 78.4,
72.6, 72.5, 64.6, 52.6, 40.9, 36.3, 35.1, 33.0, 25.9, 24.5, 22.2, 21.1, 21.0, 20.9,
3.7, 3.6 ppm; IR (neat): n˜ =3658, 2954, 2929, 2855, 1463, 1257, 1107, 1078,
ꢀ
12.9 Hz, 1H; -CH(Br)-), 3.80 3.60 (m, 2H; -CH2 OSi-), 3.57 (m, 1H;
ꢀ
ꢀ
ꢀ
-CH(OH) CH2 OSi-), 2.35 2.00 (m, 5H; -CH(OH)-, -CH2 CHBr,
-CH2 CH=CH2), 1.92 (ddd, 2J(H,H)=13.2 Hz, 3J(H,H)=13.2 Hz,
ꢀ
3J(H,H)=3.5 Hz, 1H; -CHaxHeq C(CH3)O-), 1.76 (ddd, 2J(H,H)=
ꢀ
840, 779 cmꢀ1
; HRMS (MALDI-FTMS): m/z calcd for C22H42O3Si
13.2 Hz, 3J(H,H)=3.8 Hz, 3J(H,H)=3.8 Hz, 1H; -CHaxHeq C(CH3)O-),
ꢀ
[M+Na]+: 405.2795; found: 405.2785.
ꢀ
1.72 (brs, 3H, -C=C(CH3)-), 1.51 (m, 1H; -C(CH3)2 CH-), 1.25 (s, 3H;
-(CH3)C O-), 1.08 (s, 3H; -C(CH3)a(CH3)b), 1.07 (brs, 9H, -C(CH3)3),
Compound 25d: Ring-closing metathesis of diene 23d (22 mg,
0.055 mmol) was performed as described for 23a, in this case by using
first-generation Grubbs catalyst (A in Scheme 5;6.4 mg, 0.008 mmol) in
CH2Cl2 (9 mL) at 258C for 1 h to afford, after purification, oxepene 25d
ꢀ
0.93 ppm (s, 3H; -C(CH3)a(CH3)b); 13C NMR (62.5 MHz, CDCl3): d=
146.0, 141.9, 135.6, 135.5, 129.7, 127.7, 113.8, 113.1, 79.0, 74.4, 72.8, 67.0,
64.6, 56.4, 41.1, 39.4, 31.8,31.7, 30.6, 26.9, 18.4, 18.1, 17.8 ppm; IR (neat):
n˜ =3573, 3071, 2958, 2931, 2859, 1475, 1464, 1427, 1392, 1116, 1078, 1055,
908, 763, 741, 701, 616 cmꢀ1; HRMS (MALDI-FTMS): m/z calcd for
C34H49BrO3Si [M+Na]+: 635.2526; found: 635.2511.
(17 mg, 88%) as
a
colorless liquid. Rf =0.27 (hexane/EtOAc 9:1);
1
ꢀ
H NMR (250 MHz, CDCl3): d=5.84 (m, 2H; -CH2 CH=CH-), 4.26
(brs, 1H; -O CH CH(OH)-), 3.76 (dd, 3J(H,H)=3.7 Hz, 2J(H,H)=
ꢀ
ꢀ
10.0 Hz, 1H; -CHaHb O Si-), 3.67 (dd, 3J(H,H)=5.2 Hz, 2J(H,H)=
ꢀ
ꢀ
ꢀ
ꢀ
10.0 Hz, 1H; -CHaHb O Si-), 3.47 (m, 1H; -CH(OH)-), 2.46 (d,
Representative procedure for oxepene ring formation through ring-clos-
ing metathesis: Second-generation Grubbs catalyst (B in Scheme 5;
1.7 mg, 0.002 mmol) was added to a solution of diene 23a (8.5 mg,
0.013 mmol) in CH2Cl2 (2.2 mL) at 258C under argon. The mixture was
stirred at 358C for 1 h. After cooling at 258C, the reaction was stirred in
air for 16 h and concentrated in vacuo. Purification by flash column chro-
matography silica gel, hexanes/EtOAc 8:2) yielded oxepene 25a (7 mg,
78%) as a pale yellow oil. Rf =0.21 (hexanes/EtOAc 8:2); 1H NMR
3
ꢀ
J(H,H)=6.3 Hz, 1H; -CH(OH)-), 2.33 2.04 (m, 2H; -CH2 CH=CH-),
1.84 (d, 3J(H,H)=10.0 Hz, 1H; -C(CH3)2 CH-), 1.70 1.12 (m, 6H;
ꢀ
ꢀ
-(CH2)3-), 1.21 (s, 3H; -(CH3)C O-), 0.95 (s, 3H; -C(CH3)eq(CH3)ax), 0.91
(brs, 9H; -SiC(CH3)3), 0.80 (s, 3H; -C(CH3)eq(CH3)ax), 0.08 ppm (brs,
6H; -Si(CH3)2); HRMS (MALDI-FTMS): m/z calcd for C21H40O3Si
[M+Na]+: 391.2639; found: 391.2632.
Compound 26a: Ring-closing metathesis of the desilylated form of diene
24a (67 mg, 0.131 mmol) was performed as described for 23a, in this case
by using the second-generation Grubbs catalyst (B in Scheme 5; 17 mg,
0.020 mmol) in CH2Cl2 (21 mL) to afford, after purification, oxepene 26a
ꢀ
ꢀ
(250 MHz, CDCl3): d=7.69 (m, 4H; -Si ArH), 7.39 (m, 6H; -Si ArH),
3
3
7.24 (d, J(H,H)=8.6 Hz, 2H; CH3OArH), 6.86 (d, J(H,H)=8.6 Hz, 2H;
3
ꢀ
CH3OArH), 5.77 (d, J(H,H)=7.8 Hz, 1H; -CH=C-), 4.50 (brs, 1H; -O
ꢀ
ꢀ
ꢀ
ꢀ
CH CH(OH)-), 4.35 (brs, 2H; -CH2 O CH2 Ar), 4.07 (m, 3H; -CH=
(51 mg, 80%) as a pale yellow oil. Rf =0.2 (hexanes/EtOAc 6:4); [a]D20
=
Chem. Eur. J. 2004, 10, 3822 3835
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3831

E. A. Couladouros and V. P. Vidali
FULL PAPER
ꢀ3.7 (c=1.2 in CHCl3); 1H NMR (250 MHz, CDCl3): d=7.23 (d,
3J(H,H)=8.6 Hz, 2H; ArH), 6.88 (d, 3J(H,H)=8.6 Hz, 2H; ArH), 5.88
(d, 3J(H,H)=8.2 Hz, 1H; -C=CH-), 4.52 (brs, 1H; -O-CH-), 4.39 (s, 2H;
2121, 1612, 1514, 1464, 1249, 1078, 1038, 756 cmꢀ1; HRMS (MALDI-
FTMS): m/z calcd for C24H35BrO5 [M+Na]+: 505.1560; found: 505.1564.
Synthesis of alcohols 27a and 27b:
ArCH2 O-), 4.06 (d, 2J(H,H)=11.2 Hz, 1H; -CHaHbOPMB), 3.87 (dd,
ꢀ
Compound 27a: NaIO4 (24 mg, 0.112 mmol) was added to a solution of
diol 26a (9 mg, 0.019 mmol) in a mixture of MeOH/H2O 2:1 (1.5 mL) at
258C. After 20 min of stirring the reaction mixture was cooled at 08C
and NaBH4 (10 mg, 0.3 mmol) was added. Stirring was continued for 1 h.
A saturated aqueous solution of NH4Cl (5 mL) was then added and the
mixture was extracted with EtOAc (2î5 mL). The combined organic ex-
tracts were washed successively with water and brine, dried over Na2SO4,
and concentrated in vacuo. Flash column chromatography of the crude
mixture (silica gel, hexanes/EtOAc 7:3) afforded pure alcohol 27a
3J(H,H)=4.9 Hz, 3J(H,H)=12.9 Hz, 1H; -CH(Br)-), 3.84 (d, 2J(H,H)=
11.2 Hz, 1H; -CHaHbOPMB), 3.81 (s, 3H; CH3O-Ar), 3.73 3.60 (m, 2H;
-CH(OH)-CHaHbOH), 3.53 (d, 2J(H,H)=8.2 Hz, 1H; -CHaHbOH), 2.58
(brs, 1H; -CH(OH)-), 2.39 2.22 (m, 2H, -CH2CH=C-), 2.20 1.98 (m,
2H; -CH2CH(Br)-), 1.84 (ddd, 2J(H,H)=13.4 Hz, 3J(H,H)=13.4 Hz,
3J(H,H)=3.5 Hz, 1H; -CHaxHeq C(CH3)O-), 1.81 (d, 3J(H,H)=9.7 Hz,
ꢀ
1H; -C(CH3)2 CH-), 1.50 (ddd, 2J(H,H)=13.4 Hz, 3J(H,H)=3.4 Hz,
ꢀ
3J(H,H)=3.4 Hz, 1H; -CHaxHeq C(CH3)O-), 1.26 (s, 3H; -C(CH3) O-),
1.12 (s, 3H; -C(CH3)eq(CH3)ax), 0.89 ppm (s, 3H; -C(CH3)eq(CH3)ax);
13C NMR (62.5 MHz, CDCl3): d=159.4, 137.1, 135.2, 129.6, 129.4,
113.9, 78.1, 74.0, 73.2, 71.9, 70.2, 65.5, 64.0, 55.3, 52.0, 40.7, 36.5, 32.7,
30.5, 25.7, 22.2, 18.0 ppm; IR (neat): n˜ =3409, 2937, 2875, 1614, 1520,
1457, 1390, 1374, 1251, 1174, 1155, 1063, 1040, 872, 822 cmꢀ1; HRMS
(MALDI-FTMS): m/z calcd for C24H35BrO5 [M+Na]+: 505.1560; found:
505.1588.
ꢀ
ꢀ
(6.5 mg, 75%) as a pale yellow oil. Rf =0.46 (hexanes/EtOAc 6:4); [a]D20
=
ꢀ1.4 (c=2.0 in CHCl3); 1H NMR (250 MHz, CDCl3): d=7.24 (d,
3J(H,H)=8.6 Hz, 2H; ArH), 6.87 (d, 3J(H,H)=8.6 Hz, 2H; ArH), 5.85
3
ꢀ
ꢀ
(d, J(H,H)=7.9 Hz, 1H; -C=CH-), 4.43 (brs, 1H; -O CH CH2OH),
4.39 (s, 2H; ArCH2 O-), 3.97 (d, 2J(H,H)=11.2 Hz, 1H; -CHaHbO-
ꢀ
CH2OPMB), 3.88 (dd, 3J(H,H)=4.8 Hz, 3J(H,H)=12.5 Hz, 1H;
-CH(Br)-), 3.80 (brs, m, 4H; CH3OAr, -CHaHbOH), 3.76 (d, 2J(H,H)=
11.2 Hz, 1H; -CHaHbOCH2OPMB), 3.62 (dd, 2J(H,H)=10.9 Hz,
3J(H,H)=6.8 Hz, 1H; -CHaHbOH), 2.27 2.01 (m, 2H; -CH2CH=C-),
2.45 2.28 (m, 2H; -CH2CH(Br)-), 1.79 (ddd, 2J(H,H)=13.2 Hz,
Compound 26b: Ring-closing metathesis of diene 24b (130 mg,
0.212 mmol) was performed as described for 23a, in this case by using
the second-generation Grubbs catalyst (B in Scheme 5; 27 mg,
0.030 mmol) in CH2Cl2 (35 mL) to afford, after purification, silylated oxe-
pene (112 mg, 90%) as a pale yellow oil. TBAF (1m solution in THF,
0.11 mL, 0.11 mmol) was added to a solution of the silylated oxepene
(55.6 mg, 0.095 mmol) in THF (0.16 mL) at 258C. After 2 h of stirring,
the reaction mixture was partitioned between a saturated ammonium
chloride solution and ethyl acetate. The organic phase was separated, the
aqueous phase was washed with EtOAc (2î10 mL), and the combined
organic extracts were washed successively with water and brine, dried
over Na2SO4 and concentrated in vacuo. Flash column chromatography
on the crude mixture (hexanes/EtOAc 7:3) afforded pure 26b (29.7 mg,
90%), as a pale yellow oil. Rf =0.65 (hexanes/EtOAc 6:4); [a]2D0 =+3.5
(c=1.2 in CHCl3); 1H NMR (250 MHz, CDCl3): d=5.61 (d, 3J(H,H)=
3J(H,H)=13.2 Hz, 3J(H,H)=3.8 Hz, 1H; -CHaxHeq C(CH3)O-), 1.87 (d,
ꢀ
3J(H,H)=9.7 Hz, 1H; C(CH3)2-CH-), 1.50 (ddd, 2J(H,H)=13.2 Hz,
3J(H,H)=3.4 Hz, 3J(H,H)=3.4 Hz, 1H; -CHaxHeq-C(CH3)O-), 1.29 (s,
3H; -C(CH3)-O-), 1.12 (s, 3H; -C(CH3)eq(CH3)ax), 0.90 ppm (s, 3H;
-C(CH3)eq(CH3)ax); 13C NMR (62.5 MHz, CDCl3): d=159.3, 137.3, 133.8,
129.9, 129.5, 113.8, 77.6, 72.8, 72.0, 70.1, 65.8, 63.4, 55.2, 52.1, 40.7, 36.8,
32.7, 30.5, 25.8, 22.1, 18.0 ppm; IR (neat): n˜ =3464, 2952, 2926, 2855,
1612, 1515, 1464, 1249, 1174, 1152, 1065, 1036, 821, 759, 701 cmꢀ1; HRMS
(MALDI-FTMS): m/z calcd for C23H33BrO4 [M+Na]+: 475.1454; found:
475.1458.
Compound 27b: The above procedure was followed with diol 26b
(11.7 mg, 0.034 mmol), NaIO4 (43.2 mg, 0.202 mmol), NaBH4 (15.5 mg,
0.408 mmol), in MeOH (1.8 mL) and H2O (0.9 mL). Alcohol 27b was iso-
lated as pale yellow oil (9.7 mg, 90%). Rf =0.65 (hexanes/EtOAc 6:4);
ꢀ
ꢀ
8.1 Hz, 1H; -C=CH-), 4.50 (brs, 1H; -O CH CH(OH)-), 3.95 3.72 (m,
3H; -CH(Br)-, -CH2OH), 3.61 (ddd, 3J(H,H)=3.9 Hz, 3J(H,H)=10.2 Hz,
3J(H,H)=10.5 Hz, 1H; -CH(OH)-), 2.73 (d, 3J(H,H)=10.3 Hz, 1H;
[a]2D0 =ꢀ0.8 (c=1.0 in CHCl3); 1H NMR (250 MHz, CDCl3): d=5.56 (d,
3
3
-CH(OH)-), 2.59 (d, J(H,H)=10.4 Hz, 1H; -CH2OH), 2.39 2.22 (m, 2H;
ꢀ
ꢀ
J(H,H)=8.2 Hz, 1H; -C=CH-), 4.36 (brs, 1H; -O CH CH2OH), 3.91
(dd, 3J(H,H)=4.8 Hz, 3J(H,H)=12.7 Hz, 1H; -CH(Br)-), 3.72 (m, 1H;
-CHaHbOH), 3.52 (dd, 2J(H,H)=11.2 Hz, 3J(H,H)=8.8 Hz, 1H; -CHaHb-
-CHaHbCH=C-, -CHaHbCH(Br)-), 2.21 1.94 (m, 2H; -CHaHbCH=C-,
CHaHbCH(Br)-), 1.85 (ddd, 2J(H,H)=12.9 Hz, 3J(H,H)=12.9 Hz,
3J(H,H)=4.3 Hz, 1H; -CHaxHeq-C(CH3)O-), 1.72 (d, 3J(H,H)=10.2 Hz,
1H; -C(CH3)2-CH-), 1.62 (brs, 3H; -CH=C-CH3), 1.49 (ddd, 2J(H,H)=
OH), 2.40 2.19 (m, 2H; -CH2CH(Br)-), 2.19 2.00 (m, 2H; -CH2CH=C-),
3
1.85 (d, J(H,H)=10.0 Hz, 1H; -C(CH3)2 CH-), 1.82 (ddd, 2J(H,H)=
ꢀ
12.9 Hz, 3J(H,H)=3.4 Hz, 3J(H,H)=3.4 Hz, 1H; -CHaxHeq C(CH3)O-),
13.2 Hz, 3J(H,H)=13.2 Hz, 3J(H,H)=5.2 Hz, 1H; -CHaxHeq C(CH3)O-),
ꢀ
ꢀ
1.61 (brs, 3H; -CH=C(CH3)-), 1.51 (ddd, 2J(H,H)=13.2 Hz, 3J(H,H)=
ꢀ
1.27 (s, 3H; -C(CH3) O-), 1.11 (s, 3H; -C(CH3)eq(CH3)ax), 0.89 ppm (s,
3H; -C(CH3)eq(CH3)ax); 13C NMR (62.5 MHz, CDCl3): d=135.1, 129.9,
78.1, 76.1, 70.1, 65.7, 63.3, 53.3, 40.7, 36.4, 32.7, 30.6, 25.3, 22.5, 20.8,
18.1 ppm; IR (neat): n˜ =3397, 2972, 2947, 2923, 2874, 1464, 1456, 1386,
1377, 1151, 1056, 1030, 768, 703, 692 cmꢀ1; HRMS (MALDI-FTMS): m/z
calcd for C16H27BrO3 [M+Na]+: 369.1036; found: 369.1038.
3.5 Hz, 3J(H,H)=3.5 Hz, 1H; -CHaxHeq C(CH3)O-), 1.31 (s, 3H;
ꢀ
ꢀ
-C(CH3) O-), 1.13 (s, 3H; -C(CH3)eq(CH3)ax), 0.91 ppm (s, 3H;
-C(CH3)eq(CH3)ax); 13C NMR (62.5 MHz, CDCl3): d=135.8, 128.6, 77.7,
71.3, 66.1, 63.5, 52.7, 40.7, 37.0, 32.8, 30.6, 25.8, 22.2, 19.9, 18.0 ppm; IR
(neat): n˜ =3476, 2977, 2947, 2871, 1468, 1453, 1384, 1225, 1154, 1064,
1030, 965, 871, 770, 703, 627, 582 cmꢀ1; HRMS (MALDI-FTMS): m/z
calcd for C15H25BrO2 [M+Na]+: 339.0930; found: 339.0942.
Compound epi-26a: Ring-closing metathesis of epi-24a (14 mg,
0.027 mmol), prepared from alcohol 4 and ent-22a (see procedure for
24a), was performed according to the procedure described for 26a, in
this case by using the second-generation Grubbs catalyst (B in Scheme 5;
3.4 mg, 0.004 mmol) in CH2Cl2 (4.5 mL) to afford, after purification, oxe-
pene epi-26a (10 mg, 76%) as a yellow oil. Rf =0.11 (hexanes/EtOAc
7:3); [a]2D0 =+52.0 (c=0.2 in CHCl3); 1H NMR (250 MHz, CDCl3): d=
Synthesis of (+)-Palisadin B (28): Pyridine (3.5 mL, 0.044 mmol) and TsCl
(7.1 mg, 0.037 mmol) were added to a solution of alcohol 27b (9.1 mg,
0.029 mmol) in dry CH2Cl2 (0.1 mL) at 258C under argon. After 12 h of
stirring, a saturated ammonium chloride solution (5 mL) was added. The
reaction was extracted with ethyl acetate (2î5 mL) and the combined or-
ganic extracts were washed successively with water and brine dried over
Na2SO4 and concentrated in vacuo. Flash column chromatography of the
crude mixture (silica gel, hexanes/EtOAc 8:2) afforded the pure tosylated
form of alcohol 27b (12.3 mg, 90%) as a pale yellow oil. Rf =0.4 (hex-
anes/EtOAc 8:2); [a]2D0 =+40.4 (c=1.1 in CHCl3); 1H NMR (250 MHz,
CDCl3): d=7.79 (d, 3J(H,H)=8.4 Hz, 2H; ArH), 7.33 (d, 3J(H,H)=
8.4 Hz, 2H; ArH), 5.53 (d, 3J(H,H)=7.8 Hz, 1H; -C=CH-), 4.51 (brs,
7.24 (d, 3J(H,H)=8.6 Hz, 2H; ArH), 6.88 (d, 3J(H,H)=8.6 Hz, 2H;
3
ꢀ
ꢀ
ArH), 6.07 (t, J(H,H)=6.3 Hz, 1H; -CH=C-), 4.51 (brs, 1H; -O CH
2
ꢀ
ꢀ
CH(OH)-), 4.46 (d, J(H,H)=11.2 Hz, 1H; -O CHaHb Ar), 4.38 (d,
J(H,H)=11.2 Hz, 1H; -O CHaHb Ar), 4.25 (d, 2J(H,H)=11.5 Hz, 1H;
2
ꢀ
ꢀ
-CH=C CHaHb O-), 3.86 (m, 1H; -CH(OH)-), 3.94 (dd, 3J(H,H)=
4.8 Hz, 3J(H,H)=11.9 Hz, 1H; -CH(Br)-), 3.84 (d, 2J(H,H)=11.5 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
1H; -CH=C CHaHb O-), 3.80 (s, 3H; CH3O Ar-), 3.69 (m, 2H;
1H; -O CH CH2OTs), 4.28 (dd, 2J(H,H)=10.4 Hz, 3J(H,H)=3.0 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
-CH2OH), 2.59 1.93 (m, 4H; -CH2 CH=C-, -CH2 CH(Br)-), 1.69 (ddd,
2J(H,H)=13.0 Hz, 3J(H,H)=3.7 Hz, 3J(H,H)=3.7 Hz, 1H; -CHaxHeq
1H; -CHaHb OTs-), 3.92 (dd, 2J(H,H)=10.4 Hz, 3J(H,H)=8.6 Hz, 1H;
ꢀ
ꢀ
C(CH3)O-), 1.59 (m, 1H; -C(CH3)2 CH-), 1.51 (ddd, 2J(H,H)=13.0 Hz,
-CHaHbOTs-) 3.86 (dd, 3J(H,H)=5.2 Hz, 3J(H,H)=12.9 Hz, 1H;
ꢀ
3J(H,H)=13.0 Hz, 3J(H,H)=3.4 Hz, 1H; -CHaxHeq C(CH3)O-), 1.38 (s,
ꢀ
ꢀ
-CH(Br)-), 2.44 (s, 3H; CH3 Ar-), 2.31 2.15 (m, 2H; -CH2CH(Br)-),
2.15 1.97 (m, 2H; -CH2CH=C-), 1.75 (d, 3J (H,H)=9.6 Hz, 1H;
ꢀ
3H; -(CH3)C O-), 1.11 (s, 3H; -C(CH3)eq(CH3)ax), 0.89 ppm (s, 3H;
-C(CH3)eq(CH3)ax); 13C NMR (62.5 MHz, CDCl3): d=139.2, 137.2, 129.7,
129.0, 114.0, 79.3, 73.5, 72.6, 71.8, 70.3, 66.5, 64.3, 55.3, 54.4, 42.5, 40.2,
32.1, 30.0, 26.0, 18.9, 17.3 ppm; IR (neat): n˜ =3374, 2959, 2926, 2857,
-C(CH3)2 CH-), 1.69 (ddd, 2J (H,H)=12.9 Hz, 3J(H,H)=12.9 Hz,
ꢀ
3J(H,H)=4.8 Hz, 1H; -CHaxHeq C(CH3)O-), 1.59 (brs, 3H; -CH=
ꢀ
C(CH3)-), 1.44 (ddd, 2J(H,H)=12.9 Hz, 3J(H,H)=3.5 Hz, 3J(H,H)=
3832
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3822 3835

Oxepene Cyclogeranyl Systems
3822 3835
ꢀ
ꢀ
ꢀ
3.5 Hz, 1H; -CHaxHeq C(CH3)O-), 1.16 (s, 3H; -C(CH3) O-), 1.10 (s,
3H; -C(CH3)eq(CH3)ax), 0.87 ppm (s, 3H; -C(CH3)eq(CH3)ax); 13C NMR
(62.5 MHz, CDCl3): d=144.7, 134.5, 130.0, 129.7, 129.6, 128.0, 77.6, 71.2,
68.6, 66.1, 52.3, 40.7, 36.4, 32.8, 30.6, 25.9, 21.8, 21.6, 20.5, 17.9 ppm; IR
(neat): n˜ =2953, 2918, 2849, 1599, 1454, 1445, 1362, 1189, 1176, 1151,
1098, 1085, 984, 759, 669, 555, 571 cmꢀ1; HRMS (MALDI-FTMS): m/z
calcd for C22H31BrO4S [M+Na]+: 493.1018; found: 493.1031.
CH3O Ar), 3.80 (dd, 2J(H,H)=10.4 Hz, 3J(H,H)=2.8 Hz, 1H;
-CHaHbBr), 3.79 (d, 2J(H,H)=11.5 Hz, 1H; -CHaHbOPMB), 3.42 (dd,
2J(H,H)=10.4 Hz, 3J(H,H)=8.5 Hz, 1H; -CHaHbBr), 2.46 2.22 (m, 2H;
-CH2CH(Br)-), 2.21 2.00 (m, 2H; -CH2CH=C-), 1.78 (d, 3J(H,H)=
9.4 Hz, 1H; -C(CH3)2-CH-), 1.77 (ddd, 2J(H,H)=12.5 Hz, 3J(H,H)=
12.5 Hz, 3J(H,H)=3.8 Hz, 1H; -CHaxHeq C(CH3)O-), 1.64 (ddd,
ꢀ
2J(H,H)=12.5 Hz, 3J(H,H)=3.5 Hz, 3J(H,H)=3.5 Hz, 1H; -CHaxHeq
-
C(CH3)O-), 1.29 (s, 3H; -C(CH3)-O-), 1.12 (s, 3H; -C(CH3)eq(CH3)ax),
0.90 ppm (s, 3H; -C(CH3)eq(CH3)ax); 13C NMR (62.5 MHz, CDCl3): d=
159.4, 137.7, 129.5, 113.9, 77.5, 73.2, 71.9, 69.6, 66.1, 55.3, 52.3, 40.8, 36.6,
35.9, 32.9, 30.6, 25.9, 22.0, 18.0 ppm; IR (neat): n˜ =2957, 2925, 2852, 1616,
1589, 1514, 1463, 1455, 1440, 1386, 1248, 1172, 1153, 1053, 1037, 827, 759,
668 cmꢀ1; HRMS (MALDI-FTMS): m/z calcd for C23H32Br2O3 [M+Na]+:
537.0610; found: 537.0603.
The above tosylated alcohol (11.0 mg, 0.023 mmol), was dissolved in
HMPA (70 mL), and LiBr (10 mg, 0.12 mmol), was added. The reaction
mixture was stirred at 408C, under argon, for 16 h. A saturated aqueous
solution of sodium bicarbonate (10 mL) was added to the warm solution
and the mixture was extracted with ethyl acetate (2î10 mL). The com-
bined organic extracts were washed successively with water and brine,
dried over Na2SO4, and concentrated in vacuo. Subjection of the crude
mixture to flash column chromatography (silica gel, hexanes/EtOAc
95:5) afforded pure (+)-Palisadin B (28) as a pale yellow oil (6.5 mg,
75%). Rf =0.67 (hexanes/EtOAc 9:1); [a]2D0 =+6.5 (c=0.4 in CHCl3),
Synthesis of (+)-12-hydroxy-Palisadin B (30): 2,3-Dicloro-5,6-dicyano-
1,4-benzoquinone (DDQ; 5.9 mg, 0.026 mmol) was added to a solution of
bromide 29 (6.6 mg, 0.013 mmol) in a mixture of CH2Cl2/H2O 10:1
(0.1 mL) at 258C. After 30 min of vigorous stirring, a saturated solution
of sodium bicarbonate (5 mL) was added. The reaction was extracted
with EtOAc (2î5 mL) and the combined organic extracts were washed
successively with water and brine, dried over Na2SO4, and concentrated
in vacuo. Flash column chromatography of the crude mixture (silica gel,
hexanes/EtOAc 9:1) afforded pure (+)-12-hydroxy-Palisadin B (30)
(lit.:[4b] [a]D =+8.8 (c=1.3 in CHCl3)); 1H NMR (250 MHz, CDCl3): d=
3
ꢀ
ꢀ
5.61 (d, J(H,H)=7.8 Hz, 1H; -C=CH-), 4.49 (brs, 1H; -O CH CH2Br),
3.91 (dd, 3J(H,H)=5.2 Hz, 3J(H,H)=12.9 Hz, 1H; -CH(Br)-), 3.69 (dd,
2J(H,H)=10.4 Hz, J(H,H)=2.6 Hz, 1H; -CHaHbBr), 3.37 (dd, J(H,H)=
10.4 Hz, 3J(H,H)=8.6 Hz, 1H; -CHaHbBr), 2.42 2.22 (m, 2H; -CHa-
HbCH(Br)-, -CHaHbCH=C-), 2.21 1.94 (m, 2H; -CHaHbCH(Br)-,
-CHaHbCH=C-), 1.80 (ddd, 2J(H,H)=12.9 Hz, 3J(H,H)=12.9 Hz,
3
2
(4.0 mg, 78%) as a yellow oil. Rf =0.28 (hexanes/EtOAc 8:2); [a]D20
=
3J(H,H)=4.4 Hz, 1H; -CHaxHeq C(CH3)O-), 1.77 (d, 3J(H,H)=9.7 Hz,
ꢀ
+17.0 (c=0.28 in CHCl3) (lit.:[4b] [a]D =+19.7 (c=0.4 in CHCl3));
3
2
ꢀ
1H NMR (250 MHz, CDCl3): d=5.88 (d, J(H,H)=7.8 Hz, 1H; -C=CH-),
1H; -C(CH3)2 CH-), 1.69 (brs, 3H; -CH=C(CH3)-), 1.65 (ddd, J(H,H)=
12.9 Hz, 3J(H,H)=3.5 Hz, 3J(H,H)=3.5 Hz, 1H; -CHaxHeq C(CH3)O-),
ꢀ
ꢀ
4.66 (brs, 1H; -O CH-CH2Br), 4.20 (d, 2J(H,H)=12.8 Hz, 1H; -CHaHb-
ꢀ
OH), 4.00 (d, 2J(H,H)=12.8 Hz, 1H; -CHaHbOH), 3.90 (dd, 3J(H,H)=
4.8 Hz, 3J(H,H)=11.9 Hz, 1H; -CH(Br)-), 3.89 (dd, 2J(H,H)=10.4 Hz,
1.30 (s, 3H; -C(CH3) O-), 1.12 (s, 3H; -C(CH3)eq(CH3)ax), 0.90 ppm (s,
3H; -C(CH3)eq(CH3)ax); 13C NMR (62.5 MHz, CDCl3): d=136.1, 129.4,
77.5, 70.7, 66.3, 52.8, 40.8, 36.7, 36.2, 32.9, 30.7, 25.9, 22.0, 21.0, 18.0 ppm;
IR (neat): n˜ =2971, 2924, 2859, 1455, 1386, 1374, 1155, 1086, 1055, 865,
2
3
3J(H,H)=2.6 Hz, 1H; -CHaHbBr), 3.49 (dd, J(H,H)=10.4 Hz, J(H,H)=
8.9 Hz, 1H; -CHaHbBr), 2.40 2.02 (m, 4H; -CH2CH(Br)-, -CH2CH=C-),
1.83 (ddd, 2J(H,H)=13.4 Hz, 3J(H,H)=13.4 Hz, 3J(H,H)=4.1 Hz, 1H;
769, 672 cmꢀ1
;
HRMS (EI): m/z calcd for C15H24Br2O2, [M+H]+:
3
ꢀ
ꢀ
-CHaxHeq C(CH3)O-), 1.82 (d, J(H,H)=9.7 Hz, 1H; -C(CH3)2 CH-),
380.0350; found: 380.0190.
1.67 (ddd, 2J(H,H)=12.7 Hz, 3J(H,H)=3.7 Hz, 3J(H,H)=3.7 Hz, 1H;
Synthesis of bromide 29: Alcohol 26a (11 mg, 0.025 mmol) was tosylated
following the procedure described for 26b, in this case by using TsCl
(6.1 mg, 0.032 mmol) and pyridine (3 mL, 0.038 mmol) in dry CH2Cl2
(0.11 mL). Tosylated form of alcohol 26b was isolated as a pale yellow
oil (13 mg, 85%). Rf =0.23 (hexanes/EtOAc 7:3); [a]2D0 =+13.6 (c=0.5 in
CHCl3); 1H NMR (250 MHz, CDCl3): d=7.76 (d, 3J(H,H)=8.6 Hz, 2H;
ꢀ
ꢀ
-CHaxHeq C(CH3)O-), 1.31 (s, 3H; -C(CH3) O-), 1.13 (s, 3H;
-C(CH3)eq(CH3)ax), 0.91 ppm (s, 3H; -C(CH3)eq(CH3)ax); 13C NMR
(62.5 MHz, CDCl3): d=140.4, 133.2, 77.6, 69.5, 66.1, 66.0, 52.3, 40.8, 36.6,
35.8, 32.9, 30.7, 25.9, 22.0, 18.0 ppm; IR (neat): n˜ =3411, 2973, 2951, 2928,
2874, 1468, 1390, 1377, 1151, 1090, 1054, 1000, 871, 759 cmꢀ1; HRMS
(EI): m/z calcd for C15H24Br2O2 [M+Na]+: 417.0035; found: 417.0036.
-SO2 ArH), 7.30 (d, 3J(H,H)=8.6 Hz, 2H; -SO2 ArH), 7.19 (d,
ꢀ
ꢀ
3J(H,H)=8.6 Hz, 2H; CH3OArH), 6.87 (d, 3J(H,H)=8.6 Hz, 2H;
Synthesis of hydroxytosylate 31: DDQ (4.6 mg, 0.020 mmol) was added
to a solution of the tosylated form of alcohol 27a (5.5 mg, 0.009 mmol),
prepared as described in the synthesis of bromide 29, in a mixture of
CH2Cl2/H2O 10:1 (0.1 mL) at 258C. After 30 min of vigorous stirring, a
saturated solution of sodium bicarbonate (5 mL) was added. The reaction
mixture was extracted by ethyl acetate (2î5 mL), and the combined or-
ganic extracts were washed successively with water and brine, dried over
Na2SO4, and concentrated in vacuo. Flash chromatography to the crude
mixture (silica gel, hexanes/EtOAc 8:2) afforded pure 31 (3.7 mg, 80%)
as a yellow oil. Rf =0.22 (hexanes/EtOAc 8:2); [a]2D0 =+26.0 (c=0.3 in
CHCl3); 1H NMR (250 MHz, CDCl3): d=7.80 (d, 3J(H,H)=8.2 Hz, 2H;
3
ꢀ
CH3OArH), 5.79 (d, J(H,H)=7.5 Hz, 1H; -C=CH-), 4.58 (brs, 1H; -O
CH CH2OSO2-), 4.41 (dd, 2J(H,H)=10.5 Hz, 3J(H,H)=2.8 Hz, 1H;
ꢀ
-CHaHbOSO2-), 4.34 (d, 2J(H,H)=11.2 Hz, 1H; -CHaHbOArOCH3), 4.27
(d, 2J(H,H)=11.2 Hz, 1H; -CHaHbOArOCH3), 4.03 (dd, 2J(H,H)=
10.5 Hz, 3J(H,H)=8.6 Hz, 1H; -CHaHbOSO2-), 3.85 (dd, 3J(H,H)=
3
4.7 Hz, J(H,H)=12.5 Hz, 1H; -CH(Br)-), 3.82 (s, 3H; CH3OAr), 3.80 (d,
2J(H,H)=10.7 Hz, 1H; -CHaHb-OPMB), 3.74 (d, 2J(H,H)=10.7 Hz, 1H;
ꢀ
-CHaHbOPMB), 2.43 (s, 3H; CH3 ArSO2-), 2.34 2.18 (m, 2H;
-CH2CH(Br)-), 2.18 1.96 (m, 2H; -CH2CH=C-), 1.76 (d, 3J(H,H)=
9.8 Hz, 1H; C(CH3)2 CH-), 1.67 (ddd, 2J(H,H)=12.9 Hz, 3J(H,H)=
ꢀ
-SO2 ArH), 7.33 (d, 3J(H,H)=8.2 Hz, 2H; -SO2 ArH), 5.82 (d,
12.9 Hz, 3J(H,H)=3.8 Hz, 1H; -CHaxHeq C(CH3)O-), 1.44 (ddd,
ꢀ
ꢀ
ꢀ
3
2J(H,H)=12.9 Hz, 3J(H,H)=3.5 Hz, 3J(H,H)=3.5 Hz, 1H; -CHaxHeq
-
ꢀ
ꢀ
ꢀ
ꢀ
J(H,H)=7.8 Hz, 1H; -CH=C CH2OH), 4.67 (brs, 1H; -O CH CH2
OSO2-), 4.47 (dd, 2J(H,H)=10.2 Hz, 3J(H,H)=2.9 Hz, 1H; -CHaHb
ꢀ
C(CH3)O-), 1.16 (s, 3H; -C(CH3)-O-), 1.09 (s, 3H; -C(CH3)eq(CH3)ax),
0.87 ppm (s, 3H; -C(CH3)eq(CH3)ax); 13C NMR (62.5 MHz, CDCl3): d=
159.3, 144.5, 136.0, 134.6, 133.3, 129.8, 129.5, 128.0, 113.9, 77.2, 72.7, 71.3,
67.7, 65.9, 55.3, 51.8, 40.7, 36.2, 32.7, 30.6, 25.9, 21.7, 21.6, 17.9 ppm; IR
(neat): n˜ =2950, 2862, 1614, 1589, 1514, 1464, 1361, 1248, 1177, 976, 818,
OSO2-), 4.08 (dd, 2J(H,H)=10.2 Hz, 3J(H,H)=8.2 Hz 1H; -CHaHb
ꢀ
2
2
ꢀ
OSO2-), 4.04 (d, J(H,H)=10.5 Hz, 1H; -CHaHb OH), 3.93 (d, J(H,H)=
10.5 Hz, 1H; -CHaHb OH), 3.87 (dd, 3J(H,H)=4.8 Hz, 3J(H,H)=
ꢀ
ꢀ
12.9 Hz, 1H; -CH(Br)-), 2.44 (s, 3H; CH3 ArSO2-), 2.36 2.00 (m, 4H;
3
665, 554 cmꢀ1
; HRMS (MALDI-FTMS): m/z calcd for C30H39BrO6S
ꢀ
-CH2CH(Br)-, -CH2CH=C-), 1.80 (d, J(H,H)=9.6 Hz, 1H; -C(CH3)2
CH-), 1.72 (ddd, 2J(H,H)=13.5 Hz, 3J(H,H)=13.5 Hz, 3J(H,H)=4.8 Hz,
[M+Na]+: 629.1543; found: 629.1551.
1H; -CHaxHeq C(CH3)O-), 1.48 (ddd, 2J(H,H)=13.5 Hz, 3J(H,H)=
ꢀ
The above tosylate (5.5 mg, 0.009 mmol) was brominated following the
procedure described for the synthesis of (+)-Palisadin B, in this case by
using anhydrous LiBr (3.7 mg, 0.043 mmol) in HMPA (30 mL) at 508C
for 20 h. Subjection of the crude mixture to flash column chromatogra-
phy (silica gel, hexanes/EtOAc 9:1) afforded pure bromide 29 (3.7 mg,
80%) as a yellow oil. Rf =0.62 (hexanes/EtOAc 8:2); [a]2D0 =ꢀ1.1 (c=0.4
in CHCl3); 1H NMR (250 MHz, CDCl3): d=7.23 (d, 3J(H,H)=8.6 Hz,
2H; CH3OArH), 6.89 (d, 3J(H,H)=8.6 Hz, 2H; CH3OArH), 5.85 (d,
3J(H,H)=7.5 Hz, 1H; -C=CH-), 4.56 (brs, 1H; -O-CH-CH2Br), 4.41 (d,
2J(H,H)=11.5 Hz, 1H; -CHaHbOPMB), 4.38 (brs, 2H; CH2OAr), 3.88
(dd, 3J(H,H)=4.8 Hz, 3J(H,H)=12.8 Hz, 1H; -CH(Br)-), 3.81 (s, 3H;
3.2 Hz, 3J(H,H)=3.2 Hz, 1H; -CHaxHeq C(CH3)O-), 1.19 (s, 3H;
ꢀ
ꢀ
-C(CH3) O-), 1.10 (s, 3H; -C(CH3)eq(CH3)ax), 0.88 ppm (s, 3H;
-C(CH3)eq(CH3)ax); 13C NMR (62.5 MHz, CDCl3): d=144.7, 138.8, 133.7,
129.7, 128.0, 77.7, 71.3, 68.0, 65.9, 65.5, 51.9, 40.7, 36.3, 32.7, 30.6, 25.9,
21.7, 21.6, 17.9 ppm; HRMS (MALDI-FTMS): m/z calcd for
C22H31BrO5S [M+Na]+: 509.0968; found: 509.0977.
Synthesis of (+)-Palisadin A (32):
Method A: Tosylate 31 (8.0 mg, 0.016 mmol) was treated with a 10% sol-
ution of anhydrous potassium carbonate in dry MeOH (1 mL) for 30 min
at 258C. The reaction mixture was then partitioned between EtOAc
Chem. Eur. J. 2004, 10, 3822 3835
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3833

E. A. Couladouros and V. P. Vidali
FULL PAPER
3
ꢀ
ꢀ
ꢀ
(5 mL) and water (5 mL). After separation of the organic phase, the
aqueous phase was washed with ethyl acetate (2î5 mL), and the com-
bined organic extracts were washed successively with water and brine,
dried over Na2SO4, and concentrated in vacuo. Subjection of the crude
mixture to flash chromatography (silica gel, hexanes/EtOAc 95:5) afford-
ed (+)-Palisadin A (32) (4.8 mg, 96%), as a pale yellow oil.
8.9 Hz, J(H,H)=7.0 Hz, 1H; -O CH CHaHb O-), 2.60 2.51 (m, 2H;
-CH2CH=C-), 2.29 (dddd, 2J(H,H)=13.5 Hz, 3J(H,H)=4.1 Hz, 3J(H,H)=
3
2
ꢀ
4.1 Hz, J(H,H)=4.1 Hz, 1H; -CHaxHeq CH(Br)-), 2.11 (dddd, J(H,H)=
13.5 Hz, 3J(H,H)=13.5 Hz, 3J(H,H)=13.5 Hz, 3J(H,H)=4.1 Hz, 1H;
-CHaxHeq CH(Br)-), 2.05 (dd, 3J(H,H)=4.1 Hz, 3J(H,H)=7.8 Hz, 1H;
ꢀ
-C(CH3)2 CH-), 1.79 (ddd, 2J(H,H)=12.7 Hz, 3J(H,H)=12.7 Hz,
ꢀ
3J(H,H)=3.4 Hz, 1H; -CHaxHeq C(CH3)O-), 1.62 (ddd, 2J(H,H)=
ꢀ
Method B: The above procedure was followed, treating (+)-12-hydroxy-
Palisadin B (30) (5 mg, 0.013 mmol) with a 10% solution of anhydrous
potassium carbonate in dry MeOH (1 mL) for 30 min. (+)-Palisadin A
(32) was isolated as a pale yellow oil (3.9 mg, 95%). Rf =0.6 (hexanes/
EtOAc 8:2); [a]2D0 =+15.7 (c=0.2 in CHCl3) (lit.:[4b] [a]D =+19.5, (c=1.5
12.7 Hz, 3J(H,H)=3.7 Hz, 3J(H,H)=3.7 Hz, 1H; -CHaxHeq C(CH3)O-),
ꢀ
ꢀ
1.29 (s, 3H; -C(CH3) O-), 1.18 (s, 3H; -C(CH3)eq(CH3)ax), 0.96 ppm (s,
3H; -C(CH3)eq(CH3)ax); 13C NMR (62.5 MHz, CDCl3): d=169.2, 143.1,
131.9, 79.0, 69.9, 66.8, 65.1, 51.2, 41.0, 37.6, 32.4, 30.7, 27.2, 21.7,
18.0 ppm; IR (neat): n˜ =2984, 2945, 2928, 1758, 1675, 1391, 1381, 1230,
1206, 1118, 1018, 998, 752, 708, 594 cmꢀ1; HRMS (MALDI-FTMS): m/z
calcd for C15H21BrO3 [M+H]+: 329.0747; found: 329.0756.
1
in CHCl3)); H NMR (250 MHz, CDCl3): d=5.55 (m, 1H; -CH=C-), 4.83
2
ꢀ
ꢀ
ꢀ
ꢀ
(brs, 1H; -O CH CH2 O-), 4.42 (d, J(H,H)=12.9 Hz, 1H; -CH=C
2
ꢀ
ꢀ
ꢀ
CHaHb O-), 4.34 (d, J(H,H)=12.9 Hz, 1H; -CH=C CHaHb O-), 4.07
(dd, 2J(H,H)=8.2 Hz, 3J(H,H)=8.2 Hz, 1H; -O-CH-CHaHb-O-), 3.96
(dd, 3J(H,H)=4.8 Hz, 3J(H,H)=12.7 Hz, 1H; -CH(Br)-), 3.44 (dd,
2J(H,H)=8.2 Hz, J(H,H)=8.2 Hz, 1H; -O CH CHaHb-), 2.45 2.01 (m,
3
ꢀ
ꢀ
5H; -C(CH3)2 CH-, -CH2CH(Br), -CH2CH=C-), 1.80 (ddd, 2J(H,H)=
ꢀ
Acknowledgement
13.0 Hz, 3J(H,H)=13.0 Hz, 3J(H,H)=4.4 Hz, 1H; -CHaxHeq C(CH3)O-),
ꢀ
1.56 (ddd, 2J(H,H)=13.0 Hz, 3J(H,H)=3.3 Hz, 3J(H,H)=3.3 Hz, 1H;
The authors would like to thank Prof. T. Higa for providing full NMR
spectroscopic data of the title natural products. We also thank Dr. M.
Sagnou for her valuable discussions and comments. This work was sup-
ported in part by the program ™Advanced Functional Materials∫ (1422/
B1/3.3.1/362/15.04.2002) co-funded by the General Secretariat for Re-
search and Technology of the Greek Ministry of Development and the
European Community.
ꢀ
-CHaxHeq C(CH3)O-), 1.28 (s, 3H; -C(CH3)-O), 1.17 (s, 3H; -C(CH3)eq
-
(CH3)ax), 0.94 ppm (s, 3H; -C(CH3)eq(CH3)ax); 13C NMR (62.5 MHz,
CDCl3): d=141.9, 121.1, 78.0, 72.0, 71.0, 70.1, 66.3, 51.8, 41.0, 37.5, 32.7,
30.8, 26.3, 21.9, 18.0 ppm; IR (neat): n˜ =2976, 2946, 2917, 2852, 1464,
1386, 1152, 1103, 1059, 918, 869, 768, 703, 624, 583 cmꢀ1; HRMS (EI):
m/z calcd for C15H23BrO2 [M+Na]+: 337.0077; found: 337.0077.
Synthesis of diol 33: DDQ (47.7 mg, 0.21 mmol) was added to a solution
of alcohol 27a (9.4 mg, 0.021 mmol) in a mixture of CH2Cl2/H2O 10:1
(0.11 mL) at 258C. After 3 h of vigorous stirring, a saturated solution of
sodium bicarbonate (10 mL) was added. The reaction was extracted by
ethyl acetate (3î5 mL), and the combined organic extracts were washed
successively with water and brine, dried over Na2SO4, and concentrated
in vacuo. Flash chromatography of the crude mixture (silica gel, hexanes/
EtOAc 6:4) afforded pure diol 33 (5.3 mg, 76%), as a pale yellow oil.
Rf =0.16 (hexanes/EtOAc 6:4); [a]2D0 =+5.0 (c=0.3 in CHCl3); 1H NMR
[1] For a review on marine polyether toxins, see: T. Yasumoto, M.
Murata, Chem. Rev. 1993, 93, 1897 1909.
[2] a) R. Sakowicz, M. S. Berdelis, K. Ray, C. L. Blackburn, C. Hop-
mann, D. J. Faulkner, L. S. B. Goldstein, Science 1998, 280, 292 295;
b) C. L. Blackburn, C. Hopmann, R. Sakowicz, M. S. Berdelis,
L. S. B. Goldstein, D. J. Faulkner, J. Org. Chem. 1999, 64, 5565
5570; c) J. A. Kalitzis, P. de Almeida Leone, L. Harris, M. S. Butler,
A. Ngo, J. N. A. Hooper, R. J. Quinn, J. Org. Chem. 1999, 64, 5571
5574.
[3] S. Isaacs, A. Hizi, Y. Kashman, Tetrahedron 1993, 49, 4275 4282.
[4] For isolation and structure elucidation of (ꢀ)-Aplysistatin and relat-
ed bromosesquiterpenoids see: a) G. R. Pettit, C. L. Herald, M. S.
Allen, R. B. Von Dreele, L. D. Vanell, J. P. Y. Kao, W. Blake, J. Am.
Chem. Soc. 1977, 99, 262 263; b) V. J. Paul, W. Fenical, Tetrahedron
Lett. 1980, 21, 2787 2790; c) R. Capon, E. L. Ghisalberti, P. R. Jeff-
eries, B. W. Skelton, A. H. White, Tetrahedron 1981, 37, 1613 1621;
d) J.-Y. Su, Y.-L. Zhong, L.- M. Zeng, H.-M. Wu, K. Ma, Phyto-
chemistry 1995, 40, 195 197; e) M. Koniyoshi, M. S. Marma, T.
Higa, G. Bernardinelli, C. W. Jefford, J. Nat. Prod. 2001, 64, 696
700; for bioactivity see: f) G. B. Kˆnig, A. D. Wright, O. G. Sticher,
C. K. Angerhofer, J. M. Pezzuto, Planta Med. 1994, 60, 532 537;
g) G. B. Kˆnig, A. D. Wright, S. G. Franzblau, Planta Med. 2000, 66,
337 342.
(250 MHz, CDCl3): d=5.90 (d, 3J(H,H)=7.8 Hz, 1H; -CH=C-), 4.48
2
ꢀ
ꢀ
ꢀ
(brs, 1H; -O CH CH2OH), 4.09 (d, J(H,H)=11.9 Hz, 1H; -CH=C
2
ꢀ
CHaHbOH), 3.99 (d, J(H,H)=11.9 Hz, 1H; -CH=C CHaHbOH), 3.90
(dd, 3J(H,H)=4.8 Hz, 3J(H,H)=12.5 Hz, 1H; -CH(Br)-), 3.84 (dd,
2J(H,H)=10.8 Hz, J(H,H)=3.4 Hz, 1H; -O CH CHaHbOH), 3.73 (dd,
3
ꢀ
ꢀ
2J(H,H)=10.8 Hz, 3J(H,H)=6.2 Hz, 1H; -O CH CHaHb OH), 2.49
ꢀ
ꢀ
ꢀ
3
2.08 (m, 4H; -CH2CH(Br)-, -CH2CH=C-), 1.88 (d, J(H,H)=9.7 Hz, 1H;
-C(CH3)2 CH-), 1.80 (ddd, 2J(H,H)=13.2 Hz, 3J(H,H)=13.3 Hz,
ꢀ
3J(H,H)=3.5 Hz, 1H; -CHaxHeq C(CH3)O-), 1.53 (ddd, 2J(H,H)=
ꢀ
13.2 Hz, 3J(H,H)=3.3 Hz, 3J(H,H)=3.3 Hz, 1H; -CHaxHeq C(CH3)O-),
ꢀ
ꢀ
1.31 (s, 3H; -C(CH3) O-), 1.14 (s, 3H; -C(CH3)eq(CH3)ax), 0.92 ppm (s,
3H; -C(CH3)eq(CH3)ax); 13C NMR (62.5 MHz, CDCl3): d=140.0, 133.4,
77.7, 69.8, 65.8, 65.4, 63.9, 52.1, 40.7, 36.9, 32.7, 30.6, 25.9, 22.1, 18.0 ppm;
IR (neat): n˜ =3384, 2956, 2927, 2876, 2857, 1466, 1386, 1373, 1263, 1220,
1153, 1066, 1055, 998, 758 cmꢀ1; HRMS (MALDI-FTMS): m/z calcd for
C15H25BrO3 [M+Na]+: 355.0879; found: 335.0880.
[5] For reviews on the synthesis of polycyclic ethers, including the con-
struction of oxepanes, see: a) E. Alvarez, M.-L. Candenas, R. Pÿrez,
J. L. Ravelo, J. D. Martin, Chem. Rev. 1995, 95, 1953 1980; b) K. C.
Nicolaou, Angew. Chem. 1996, 108, 644 664; Angew. Chem. Int. Ed.
Engl. 1996, 35, 589 607; c) J. O. Hoberg, Tetrahedron 1998, 54,
12631 12670; d) M. C. Elliot, E. Williams, J. Chem. Soc. Perkin
Trans. 1 2001, 2303 2340; e) M. C. Elliot, J. Chem. Soc. Perkin
Trans. 1 2002, 2301 2323.
[6] There are only some scattered exceptions in which trans syn 6,7-
ring systems have been observed, usually described as ™undesired∫
or ™unexpected∫ products. For some interesting examples, see: a) H.
Oguri, S. Tanaka, T. Oishi, M. Hirama, Tetrahedron Lett. 2000, 41,
975 978; b) K. Suzuki, H. Matsukura, G. Matsuo, H. Koshino, T.
Nakata, Tetrahedron Lett. 2002, 43, 8653 8655.
[7] For reports on the construction of trans anti 6,7-ring systems see
previous syntheses of (ꢀ)-Aplysistatin: a) T. R. Hoye, A. J. Caruso,
J. F. Dellaria, M. J. Kurth, J. Am. Chem. Soc. 1982, 104, 6704 6709;
b) J. D. White, T. Nishiguchi, R. W. Skeean, J. Am. Chem. Soc. 1982,
104, 3923 3928; c) H.-M. Shieh, G. D. Prestwich, Tetrahedron Lett.
1982, 23, 4643 4646; d) P. Gosselin, F. Rouessac, Tetrahedron Lett.
Synthesis of (ꢀ)-Aplysistatin (34):
Method A: Diol 33 (5 mg, 0.015 mmol) was dissolved in CH2Cl2 (0.1 mL),
and MnO2 (85%) (15 mg, 0.15 mmol) was added at 258C. After 2 h of
stirring, the reaction mixture was filtered through a short pad of Celite
and the filtrate was concentrated in vacuo. Flash column chromatography
(silica gel, hexanes/EtOAc 8:2) afforded (ꢀ)-Aplysistatin (34) (4.6 mg,
93%) as a white solid.
Method B: Pyridinium chlorochromate (PCC; 16 mg, 0.079 mmol) was
added to a solution of (+)-Palisadin A (32) (5 mg, 0.016 mmol) in dry
benzene (0.1 mL). The mixture was stirred for 48 h at 258C and filtered
through a short pad of Celite; the filtrate was concentrated in vacuo.
Flash column chromatography of the crude mixture (silica gel, hexanes/
EtOAc 8:2) afforded (ꢀ)-Aplysistatin (2.4 mg, 50%) as a white solid and
recovered (+)-Palisadin A (2 mg, 90%). Rf =0.67 (hexane-ethyl acetate
6:4); m.p.=157 1598 (lit.:[4e] 160 1618); [a]2D0 =ꢀ27.5 (c=0.38 in MeOH)
(lit.:[4e] [a]D =ꢀ29, (c=0.030 in MeOH)); 1H NMR (250 MHz, CDCl3):
ꢀ
ꢀ
ꢀ
d=6.95 (m, 1H; -CH=C-), 5.14 (m, 1H; -O CH CH2 O-), 4.49 (dd,
3
2J(H,H)=8.9 Hz, J(H,H)=8.9 Hz, 1H; -O CH CHaHb O-), 3.92 (dd,
ꢀ
ꢀ
ꢀ
3J(H,H)=4.5 Hz, 3J(H,H)=12.7 Hz, 1H; -CH(Br)-), 3.87 (dd, 2J(H,H)=
3834
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3822 3835

Oxepene Cyclogeranyl Systems
3822 3835
1983, 24, 5515 5518; e) A. Tanaka, O. Soichiro, K. Yamashita,
Agric. Biol. Chem. 1984, 48, 2535 2540; for a previous synthesis of
Palisadin A and 12-hydroxy-Palisadin B see: f) A. Tanaka, M.
Suzuki, K. Yamashita, Agric. Biol. Chem. 1986, 50, 1069 1071.
[8] M. Bogenst‰tter, A. Limberg, L. E. Overman, A. L. Tomasi, J. Am.
Chem. Soc. 1999, 121, 12206 12207.
[14] For racemic syntheses and use of bromolactone 18, see: a) T. R.
Hoye, M. J. Kurth, J. Org. Chem. 1978, 43, 3693 3697; b) P. Gosse-
lin, F. Rouessac, Tetrahedron Lett. 1982, 23, 5145 5146; c) F. Roues-
sac, H. Zamarlik, N. Gnonlonfoun, Tetrahedron Lett. 1983, 24,
2247 2250; d) see also ref. [7a]; e) see also ref. [7d].
[15] K. Mori, Y. Funaki, Tetrahedron 1985, 41, 2369 2378.
[16] To the best of our knowledge there are only two methods leading to
pure (E)-homogeranic acid: a) P. Gosselin, C. Maignan, F. Rouesac,
Synthesis 1984, 876 881; b) A. Yanagisawa, S. Habaue, K. Yasue, H.
Yamamoto, J. Am. Chem. Soc. 1994, 116, 6130 6141; for other
methods see: c) D. Barnard, L. Baterman, J. Chem. Soc. 1950, 926;
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Received: April 26, 2004
Published online: June 30, 2004
Chem. Eur. J. 2004, 10, 3822 3835
www.chemeurj.org
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