Synthetic studies on the sarcodictyins: Synthesis of fully functionalized cyclization precursors

Article abstract of DOI:10.1016/S0040-4020(01)00739-6

A strategy featuring a key retrosynthetic disconnection at the C2-C3 position was applied to the total synthesis of the common diterpenoid tricyclic skeleton of sarcodictyins and eleutherobin. Fully functionalized cyclization precursors were accessed via a brief and convergent route, making use of unprecedented synthetic transformations.

Full text of DOI:10.1016/S0040-4020(01)00739-6

TETRAHEDRON
Pergamon
Tetrahedron 57 22001) 8531±8542
Synthetic studies on the sarcodictyins: synthesis of fully
functionalized cyclization precursors
Simona M. Ceccarelli,a,² Umberto Piarullib and Cesare Gennaria,p
a
Á
Dipartimento di Chimica Organica e Industriale, Universita di Milano, Centro CNR per lo Studio delle Sostanze Organiche Naturali,
via G. Venezian 21, 20133 Milano, Italy
b
Á
Dipartimento di Scienze Mat. Fis. e Chimiche, Universita dell'Insubria, via Valleggio 11, 22100 Como, Italy
Received 23 February 2001;revised 19 June 2001;accepted 12 July 2001
AbstractÐA strategy featuring a key retrosynthetic disconnection at the C2±C3 position was applied to the total synthesis of the common
diterpenoid tricyclic skeleton of sarcodictyins and eleutherobin. Fully functionalized cyclization precursors were accessed via a brief and
convergent route, making use of unprecedented synthetic transformations. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Eight years later, Fenical et al. reported isolation of the
diterpene glycoside 4, named eleutherobin, from an
Eleutherobia species of soft coral found near Bennet's
Shoul in Western Australia.4,5 While possessing the same
carbon skeleton of the sarcodictyins, eleutherobin contains a
b-linked 2-O-acetyl-d-arabinopyranose unit instead of the
alkyl ester of the other members of the family.
Since FDA approval for the use of Taxolw 2paclitaxel) 1
2Fig. 1) in the chemotherapeutic treatment of ovarian cancer
in 1992, this compound has become the drug of choice for
many solid tumors and it has proven to be particularly
effective at treating recurrent tumors as well as those
unresponsive to previous ®rst line therapies. The mode of
action of Taxol is characterized by suppression of micro-
tubule dynamics via unnatural promotion of tubulin
polymerization and over-stabilization of microtubules.1 Its
exceptional activity is however accompanied by a number
of side effects and limitations, which narrow its scope and
applicability in therapeutic programs.
The similarity in the terpenoid structure of sarcodictyins
and eleutherobin has suggested their inclusion in a
common family. It can be expected that the synthetic
strategies devised for one member of the family would
require only minor variation to be adapted for the
synthesis of the others, which differ only for variation in
appendages or side chains. This was indeed the case in
Nicolaou's synthesis of sarcodictyins,6,7 which was
completed in 1997. Also Danishefsky et al. have devised
an elegant approach to the tricyclic skeleton of this class of
compounds, which culminated in the total synthesis of
eleutherobin 4.8
In recent years, a number of natural compounds were
isolated that possess a mode of action similar to that of
Taxol.2 Among these, the marine diterpenoids sarcodictyin
A, B 22, 3) were isolated in 1987 by Pietra et al. from the
Mediterranean stoloniferan coral Sarcodictyon roseum.3
Figure 1.
Keywords: sarcodictyins;epoxidation;Wittig reaction;total synthesis.
Corresponding author. Tel.: 13902-2367593;fax: 13902-2663079;e-mail: cesare.gennari@unimi.it
Present address: Institut fuÈr Organische Chemie, RWTH-Aachen, Professor-Pirlet-Strasse 1, 52056 Aachen, Germany.
p
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020201)00739-6

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S. M. Ceccarelli et al. / Tetrahedron 57 02001) 8531±8542
The present paper reports studies towards the implementa-
tion of a new synthetic strategy to the sarcodictyins,
featuring a key disconnection at the C2±C3 double bond.9
Upon examination of the simpli®ed target 5, we
selected the C2±C3 double bond as the most promising
site for ring closure, with retrosynthetic analysis reveal-
ing an aldehyde or masked aldehyde in the C2 position.
The complementary C3 reactive site could bear a
nucleophilic character, as in intermediate 6, suggesting
an acid-catalyzed aldol type reaction as key cyclization
event. Alternatively, the C3 position could constitute the
carbonyl partner for application of a titanium catalyzed
reductive 2McMurry) coupling at the cyclization stage,
as evident in precursor 7.
2. Results and discussion
2.1. Retrosynthetic analysis
The feature that characterizes all the members of the
sarcodictyins family is the central tricyclic skeleton,
comprizing a six 2ring A), nine 2ring B) and ®ve 2ring C)
membered ring. The latter is easily recognized as an internal
hemiacetal system 2methyl acetal in the case of
eleutherobin). The scission of the acetal bond and retro-
synthetic disconnection of the N-methylurocanic appendage
leads to a simpli®ed target 5 2Scheme 1) which comprises
all the elements necessary to give access to the natural
compound2s). In the design of a synthetic route to the sarco-
dictyins, we directed our efforts towards this key tricyclic
structure, a potential convergence point for all members of
the sarcodictyins family.
For both substrates 6 and 7, introduction of the C3±C5
portion can be achieved via a Wittig type ole®nation reac-
tion in a single convergent step 2Scheme 2). The two oxyge-
nated stereogenic centres C7 and C8 may be regarded as the
result of a Sharpless asymmetric epoxidation/epoxide open-
ing sequence on allylic alcohol 9. The precursor aldehyde 10
is accessed via an original Claisen type rearrangement strat-
egy from silyl ketene acetal 11. This in turn originates from
the natural compound R-22)-carvone 12. This inexpensive
compound is commercially available from the chiral pool,
Scheme 1. Key retrosynthetic disconnections.
Scheme 2. Retrosynthetic analysis of the cyclization precursors.

S. M. Ceccarelli et al. / Tetrahedron 57 02001) 8531±8542
8533
and was selected as starting material and source of absolute
stereocontrol in this synthetic scheme.
Alcohol 16 was acetylated to afford the allyl ester 17 as
substrate for Ireland±Claisen rearrangement.14 After exten-
sive experimentation, the ketene t-butyldimethylsilyl acetal
11 could be accessed using LiN2TMS)2 as base and t-butyl-
dimethylsilylchloride as trapping agent in the presence of
DMPU.14b,15 This was isolated and redissolved in xylene.
Rearrangement occurred in 5±7 h upon heating to 1908C
in sealed vials or in a high pressure reactor. The inter-
mediate silyl ester was hydrolyzed to afford the correspond-
ing acid 18 282±90%). This intermediate not only possesses
the same stereochemical arrangement of the six membered
ring A in the natural products 2see Scheme 1), but also the
most adequate functional groups for completion of the
synthesis.
2.2. Synthesis of the six-membered ring
The six membered ring portion of the sarcodictyins contains
three adjacent stereogenic centres of the six present in the
terpenoidic sector of the molecules. The stereoselective
generation of this substitution pattern by synthesis would
most likely be complex and cumbersome. The use of
R-22)-carvone 12, which allows control over the absolute
stereochemistry of the whole synthetic process was there-
fore an intriguing possibility. This choice was mainly
determined by the availability of a method 2through iron
catalyzed formation of the dienolate)10 to functionalize the
g position of the ring 2with respect to the carbonyl group)
which would become the C1 stereocentre of the target
structure.
The absolute and relative stereochemistry of structure 18 is
secured by: 2a) the con®guration of the enantiomerically
pure starting material;2b) the directing in¯uence of the iso-
propyl group over the g-formylation reaction, which forces
the dimethylacetal group to be introduced anti to the iso-
propyl substituent;2c) the reduction of the a,b-unsaturated
ketone to the axial alcohol, granted by L-Selectridew;2d) the
stereospeci®city of the Ireland±Claisen rearrangement. The
stereochemical assignment was further secured by the
convergence with the compounds 222 and 23) prepared by
Magnus and coworkers via a completely different route.16
Accordingly, 12 was ®rst hydrogenated selectively at the
exocyclic 2less substituted) double bond with Wilkinson's
catalyst,11 to give dihydrocarvone 13, which was then
subjected to deprotonation with the combination
MeMgBr/FeCl3 2Scheme 3). The resulting dienolate anion
was trapped with trimethylsilyl chloride in the presence of
DMPU, to form the corresponding dienoxysilane 14. When
this was exposed to trimethylorthoformate in the presence of
BF3´Et2O, formylation in the g position was achieved to
give 15 with complete regio- and stereo-selectivity, albeit
in modest yield 230±45%).10 The use of different Lewis acid
catalysts and conditions did not lead to any signi®cative
improvement in the yield of this reaction, which however
occurs at a very early stage in the synthesis.
2.3. Formation of the C7 and C8 stereocentres by
Sharpless asymmetric epoxidation )SAE)
Acid 18 was converted to aldehyde 10 through a simple and
high yielding reduction±reoxidation sequence 2Scheme 4).
A Horner±Emmons reaction was then applied for the
obtainment of either the Z or the E trisubstituted double
bond. In the ®rst case, phosphonate 19 developed by Still
and Gennari was applied using KN2TMS)2/18-crown-6 as
base.17 This combination yielded the Z ester 20 in good yield
and with complete stereocontrol. The opposite stereo-
chemistry 2ester 21) was obtained in a 9:1 ratio using
triethylphosphonopropionate and NaH at room temperature
in DME.18 Both esters were easily reduced to the corre-
sponding allylic alcohols 22 and 23 with lithium aluminium
hydride.
The pseudo-axial alcohol 16 was accessed in good yield
by application of lithium tri-sec-butylborohydride
2L-Selectridew)12 at low temperature 2pseudo-axial/
pseudo-equatorial$95:5 diastereomeric ratio). As a matter
of interest, reduction with lithium aluminium hydride
provided, as expected, the reverse stereochemistry
2pseudo-equatorial/pseudo-axialˆ90:10
diastereomeric
ratio).13
Scheme 3. Synthesis of the six membered ring. Reagents and conditions: 2a) H2, 2Ph3P)3RhCl, C6H6, rt, 5±12 h;2b) MeMgBr, FeCl 3 21.5%), TMSCl, TEA,
DMPU, Et2O, 2208C to rt, 20 h;2c) 2MeO) CH, BF3´Et2O, CH2Cl2, 2788C to rt, 1.5 h;2d) L-Selectride w, THF, 2788C, 40 min;2e) Ac O, TEA, DMAP,
CH2Cl2, rt, 3 h;2f) LiN2TMS) 2, TBSCl, DMPU, THF, 2788C to rt, 45 min;2g) xylenes, 190 8C, 5 h;2h) i. NaOH, 3 h;ii. HCl.
3
2

8534
S. M. Ceccarelli et al. / Tetrahedron 57 02001) 8531±8542
Scheme 4. Reagents and conditions: 2a) LiAlH4 22 molar equiv.), Et2O, rt, 50 min;2b) Dess±Martin Periodinane 2DMP), CH 2Cl2, rt, 30 min;2c) 19,
KN2TMS)2, 18-c-6, THF, 2788C, then aldehyde 10, 1 h;2d) triethylphosphonopropionate, NaH, DME, rt, then aldehyde 10;1 h;2e) LiAlH 4, Et2O, rt, 1 h.
The bias of the preexisting stereogenic centres towards
epoxidation in substrates 22 and 23 could not be foreseen.
Moreover, epoxide opening could imply inversion at the
tertiary or secondary position. For these reasons, we decided
to explore the generation of all possible stereoisomeric
epoxides by employing both 22)- and 21)-diethyltartrate
2DET) on both the Z and E allylic alcohols.19,20 The results
are reported in detail in Table 1 and Scheme 5.
upon epoxidation. In particular, reaction with 22)-DET
was a completely mismatched case, yielding as major
isomer the same compound 24 obtained in the reaction
with 21)-DET. The E alkene 23 was much more prone to
reagent control, and good diasteroisomeric excess for
epoxides 26 and 27 were obtained with 21)- or 22)-diethyl-
tartrate, respectively. In the latter case, a peculiar by-
product 28 was also formed, in which the dimethyl acetal
in the south chain is involved.21
The Z substrate 22 exerted a strong stereochemical bias
Installation of the 7S,8S stereochemistry present in the
natural targets would require either opening at the secondary
2C8) position of epoxide 24 or opening at the tertiary 2C7)
position of epoxide 25 with inversion of con®guration. The
®rst option was soon demonstrated to be impractical, since
all attempts to perform a titanium-promoted regioselective
opening22 on epoxide 24 resulted in decomposition of the
substrate or, at best, in formation of bicyclic acetals
analogous to the by-product 28 observed in one of the
SAEs.21 Examination of the alternative opening at the
tertiary position resulted in an unexpected transformation
that considerably abbreviated the planned route.
Table 1. Summary of the results obtained from SAE
Ligand
21)-DET
22)-DET
Substrate
Yield 2%)a
d.r.
22
60 225)
9:1
23
95 259)
10:1
22
89 272)
55:45
23
65 234)
.95:5
Major productb,c 24 27S,8R) 26 27S,8S)
24 27S,8R) 27 27R,8R)
28 215)
By-productsd
±
±
±
a
Yields are normalized to the amount of starting material recovered,
reported in parenthesis.
Absolute con®guration of the stereocentres is reported in parenthesis.
Sarcodictyin numbering.
Yield in parenthesis.
b
c
d
The reagent 23-ethoxycarbonyl-2-oxopropylidene)triphenyl-
Scheme 5. Reagents and conditions: 2a) TBHP, DET 212%), Ti2Oi-Pr)4 210%), MS, CH2Cl2, 2208C, 18 h.

S. M. Ceccarelli et al. / Tetrahedron 57 02001) 8531±8542
8535
Scheme 6. Reagents and conditions: 2a) DMP, CH2Cl2, rt, 1 h;2b) 29, NaN2TMS)2, THF, then aldehyde, 08C, 10 min.
phosphorane 29 can be deprotonated at the activated C3
methylene position by the action of a base. The resulting
anionic ylide reacts with aldehydes at the phosphorous-bear-
ing C1 carbon in a Wittig reaction;the formation of the
enolate at the b-ketoester unit strongly reduces the ylide
stabilization and consequently induces a substantial Z
selectivity.23 Use of epoxide 25, which would yield the
correct 7S,8S stereochemistry 2sarcodictyin numbering) was
not considered due to the scarce ef®ciency of the correspond-
ing epoxidation reaction 225 is always obtained as a minor
diastereoisomer, see Table 1). Aldehyde 30, synthesized by
oxidation of epoxide 27, reacted with phosphorane 29 in the
presence of NaN2TMS)2 as base, under anhydrous conditions
2Scheme 6): to our surprise and delight, the major product of
the reaction was hydrofuran 31, in which the oxirane ring was
opened by intramolecular enolate-oxygen attack at the
epoxide tertiary position. Apparently, the proximity of the
enolate oxygen to the oxirane ring favors this SN2 type attack
with concurrent ring opening 2oxirane) and ring closing
2hydrofuran). The reaction is general and can be performed
also on other substrates. Aldehyde 32, for example, derived
from epoxide 24, reacts generating the cyclic product 33
260%) plus a minor amount of the trans isomer 34 210%)
which cannot cyclize.
present in 31 2or derivatives protected at the C8 hydroxyl)
and either the dimethylacetal or the aldehyde in the `south'
chain was successful. Indeed, the C2 position 2sarcodictyin
numbering) demonstrated a very poor reactivity in a variety
of reactions, probably due to steric hindrance exerted by the
isopropyl substituent in the six-membered ring.
2.4. Studies towards application of the McMurry
reaction
A metal catalyzed reaction, such as the McMurry reaction,24
appeared as a very promising alternative for the generation
of the disfavored medium-sized ring of the target structures.
Accordingly, some preliminary studies were performed to
de®ne a synthetic route towards a cyclization precursor
bearing two carbonyl groups at the C2 and C3 position
2see 7 in Scheme 1). This intermediate appeared as a
synthetic elaboration of the enol ether moiety of hydrofuran
31.
Using a route similar to that illustrated above, compound 35
2eeˆ75%) was synthesized as a model,25 and the ester group
was reduced with lithium aluminium hydride to the labile
alcohol 36 2Scheme 7). In the allylic alcohol 36 the
enolether double bond, which is electronically enriched by
the geminal oxygen substituent, was selectively oxidized by
dimethyldioxirane 2DMDO),26 which is known to selec-
tively oxidize electron-rich double bonds.27 The preference
of DMDO for oxidizing allylic alcohols28 is not operative
here, as the reaction was conducted in MeOH/acetone, a
solvent mixture which is known to disrupt the hydrogen-
bond interaction between the allylic hydroxyl and the
dioxirane.29 The intermediate epoxides 37 were opened
solvolytically in situ to yield the acetal diols 38 as a
1.9:1.6:1 mixture of three diastereoisomers. The primary
hydroxyl of these diols was selectively protected with a
Installation of the 7S,8S stereochemistry present in the
natural targets would require inversion of the secondary
oxygenated stereocentre 2C8) of 31 27S,8R;sarcodictyin
numbering). The enolether moiety present in structure 31
could in principle be involved in an Aldol-type cyclization
reaction. Though embedded in a hydrofuran ring, this
enolether indeed demonstrated some reactivity: when
exposed to Lewis or protic acids a clean isomerization of
the C3±C4 double bond 2sarcodictyin numbering) was
observed. Unfortunately, to date no attempt to induce an
intramolecular Aldol-type reaction between the enolether

8536
S. M. Ceccarelli et al. / Tetrahedron 57 02001) 8531±8542
Scheme 7. Reagents and conditions: 2a) LiAlH4, Et2O, 08C, 1 h;2b) DMDO, acetone/MeOH, 0 8C, 5 min, 1.9:1.6:1.0 d.r.;2c) i. TBDPSCl, Im, CH 2Cl2, rt, 1 h;
ii. DMP, CH2Cl2, rt, 2 h, 1.8:1.0 d.r.
sterically encumbered silylating agent 2TBDPS), and the
secondary hydroxyl was oxidized with Dess±Martin
periodinane 2DMP)30 to give the ketones 39 as a mixture
of two epimers at the acetal carbon, in a 1.8:1 ratio.
phenone ketyl under nitrogen. Acetonitrile, CH2Cl2,
ethanol, methanol, hexane, TEA, DIPEA, HN2TMS)2,
DMPU, NMP were distilled from CaH2 under nitrogen
prior to use. Acetone was distilled from preactivated 4 A
molecular sieves immediately before use.
Ê
Following these model experiments, a viable route to the
generation of a dicarbonyl cyclization precursor was set 2cf.
7 in Scheme 1). Studies on the implementation of the
sequence on substrate 31 and on the ensuing McMurry
cyclization reaction are currently underway.
NMR spectra were measured on a Bruker AC300 21H at
300 MHz, 13C at 75 MHz) or a Bruker AC200 21H at
200 MHz, 13C at 50 MHz) magnetic resonance spectro-
meter. Proton NMR spectra are reported as chemical shifts
in parts per million 2ppm) down®eld from tetramethylsilane
20 ppm). The following abbreviations are used to describe
spin multiplicity: sˆsinglet, dˆdoublet, tˆtriplet,
qˆquartet, mˆmultiplet, bˆbroad, ddˆdoublet of doublets,
dtˆdoublet of triplets, dqˆdoublet of quartets, dddˆ
doublet of doublet of doublets. Coupling constants 2J) are
reported in Hertz 2Hz). Carbon-13 NMR spectra are
reported as chemical shifts in ppm based on the middle
peak of chloroform-d 277.0 ppm) and were recorded with
complete 2proton) heterodecoupling. Gas chromatograms
were registered on a DANI 6500 instrument, equipped
with a ¯ame ionization detector and a capillary column
OV1 in fused silica 210 m, 46£250 nm), using H2 as
transport gas.
3. Conclusions
A new retrosynthetic strategy towards the central tricyclic
skeleton of the sarcodictyins and eleutherobin was devised,
featuring a key cyclization step at the C2±C3 position of the
natural targets. Implementation of this strategy in the
forward direction allowed a fast and ef®cient synthesis of
the fully functionalized cyclization precursor 31. A new
transformation of epoxyaldehydes was identi®ed in the
course of these investigations, which allowed the conver-
gent introduction of the C3±C5 portion of the target with
concurrent epoxide opening. Model studies towards the
generation of a viable precursor for application of a
McMurry cyclization reaction were also performed.
4.1.1. Dihydrocarvone )13). A two necked 100 mL ¯ask is
charged with 3.0 g of R-22)-carvone 12 220 mmol) and
24 mL of thiophene free benzene. One neck is sealed and
the other is ®tted with a three way stopcock connected to an
atmospheric pressure hydrogenation apparatus and to a
vacuum pump. The solution is accurately degassed and
purged with hydrogen before adding 350 mg of freshly
prepared 2Ph3P)3RhCl 20.35 mmol). The system is then
purged and ®lled with hydrogen. The reaction is monitored
by removing small aliquots of the mixture for GC analysis.
The reaction is complete within 5±12 h. The solution is then
®ltered through a dry column 22 cm diameter) of 40 g of
4. Experimental
4.1. General
All reactions were performed in pre-dried glassware, under
an inert atmosphere of nitrogen or argon. All commercially
available reagents were used without further puri®cation
unless otherwise noted. Diethyl ether, THF, benzene,
toluene and xylene were distilled from sodium benzo-

S. M. Ceccarelli et al. / Tetrahedron 57 02001) 8531±8542
8537
Florisil 260±100 mesh). The column is eluted with diethyl
ether until no product can be detected by TLC analysis, and
the combined solvent fractions are concentrated under
reduced pressure. Vacuum distillation of the yellow residue
through a vigreux column [Bp 1108C 220 mmHg);lit 11 100±
1028C 214 mmHg)] affords 2.51 g of the title compound 13
to 45% have been obtained on smaller scale experiments).
20
[a]D ˆ1146.4 2c 0.98, EtOAc); nmax 2®lm) 2961, 2834,
1676 2CvO), 1456, 1370, 1105 2C±O), 1074
1
2C±O) cm21; H NMR 2200 MHz, CDCl3): d 6.77±6.74
21H, m), 4.45 21H, d, Jˆ4.7 Hz), 3.44 26H, s), 2.67±2.60
21H, m), 2.55 21H, dd, Jˆ4.7, 16.8 Hz), 2.29 21H, dd,
Jˆ8.6, 16.8 Hz), 2.10±1.80 22H, m), 1.81±1.79 23H, m),
0.92 23H, d, Jˆ8.0 Hz), 0.89 23H, d, Jˆ8.2 Hz); 13C NMR
250 MHz, CDCl3): d 199.3, 143.5, 135.7, 105.4, 55.6, 54.4,
42.2, 41.2, 37.1, 28.2, 20.7, 17.7, 15.5. Anal. Calcd for
C13H22O3: C, 68.99;H, 9.80. Found: C, 69.07;H, 9.62.
1
as a colorless oil 282%). H NMR 2200 MHz, CDCl3): d
6.75±6.70 21H, m), 2.57±1.80 25H, m), 1.76±1.74 23H,
m), 1.60±1.50 21H, m), 0.90 26H, d, Jˆ6.6 Hz); 13C NMR
250 MHz, CDCl3): d 153.2, 145.1, 95.6, 41.9, 41.8, 31.9;
29.7, 19.4, 15.5.
4.1.2. )4R,5R)-4-Dimethoxymethyl-5-isopropyl-2-methyl-
cyclohex-2-enone )15). A 250 mL three-necked ¯ask
equipped with a three way stopcock and a dropping funnel
with pressure equalizer is ¯ame dried under vacuum then
¯ushed with argon. The apparatus is charged with 151 mg
20.93 mmol) of dry FeCl3 and 12 mL of dry Et2O. The dark
suspension is cooled to 2208C and MeMgBr 23.0 M in
Et2O, 24.5 mL, 73.6 mmol) is added dropwise via the
dropping funnel over 15 min, while precipitation of a
black solid is observed. A solution of 9.2 g 261.3 mmol)
of dihydrocarvone 13 in 10 mL of ether is added, and the
mixture stirred for 30 min at 2208C. The cooling bath is
substituted with an ice/water bath and TMSCl 29.3 mL,
8.0 g, 73.6 mmol), triethylamine 25.7 mL) and dry DMPU
25.7 mL) are added in sequence via the dropping funnel over
30 min. The cooling bath is removed and stirring is main-
tained at 258C overnight under an argon atmosphere. After
about 12 h, TLC analysis shows no starting material left.
Saturated aqueous NaHCO3 2100 mL) is added and the
gray suspension is ®ltered through a short pad of celite,
which is accurately washed with diethyl ether. The two
phases are separated and the aqueous phase extracted with
ether 23£30 mL). The combined organic extracts are
washed thoroughly with saturated NaCl 2to completely
remove DMPU), dried over Na2SO4 and the solvent is
evaporated under reduced pressure to give [05R)-5-iso-
propyl-2-methyl-cyclohexa-1,3-dienyloxy]-trimethyl-silane
14 213.1 g), which is used in the following step with no
4.1.3.
)1S,4R,5R)-4-Dimethoxymethyl-5-isopropyl-2-
methyl-cyclohex-2-enol )16). A ¯ame dried 250 mL
¯ask equipped with a rubber septum is ¯ushed with
nitrogen and charged with ketone 15 21.5 g, 6.63 mmol)
and dry THF 2130 mL). The solution is cooled to 2788C
and L-Selectridew 21.0 M solution in THF, 10 mL,
10 mmol) is added dropwise at 2788C via syringe over
25 min. The reaction is stirred for further 20 min at
2788C and shown to be complete by TLC analysis. The
reaction is quenched by adding ethanol 29.0 mL) and
water 25.0 mL) at 2788C. Temperature is raised to 08C
over 15 min, then 6.0 M NaOH 210 mL) and 30% hydrogen
peroxide 210 mL) are added in sequence. Stirring is main-
tained at room temperature for 1.0 h. The reaction mixture is
transferred to a separatory funnel and the aqueous phase
saturated with solid NaHCO3. The two clear phases are
separated and the aqueous phase is extracted with Et2O
25£10 mL). The combined organic extracts are dried over
Na2SO4 or MgSO4 and the solvent is evaporated under
reduced pressure. The residue is puri®ed by ¯ash chromato-
graphy 2hexanes/ethyl acetate 7:3) yielding the pseudo-axial
20
alcohol 16 as a colorless oil 21.05 g, 70%). [a]D ˆ153.9
2cˆ1.89, EtOAc); nmax 2®lm) 3420 2O±H), 2940, 2815,
1445, 1370, 1145 2C±O), 1110 2C±O), 1070 2C±O) cm21
;
1H NMR 2200 MHz, CDCl3): d 5.57±5.50 21H, m), 4.30
21H, d, Jˆ4.5 Hz), 3.98 21H, bt, Jˆ4.3 Hz), 3.44 23H, s),
3.41 23H, s), 2.48±2.36 21H, m), 1.90±1.50 24H, m), 1.82
23H, bs), 0.99 23H, d, Jˆ6.7 Hz), 0.87 23H, d, Jˆ6.7 Hz);
13C NMR 250 MHz, CDCl3): d 17.8, 20.6, 21.2, 27.8, 30.6,
35.5, 41.3, 54.7, 56.0, 67.4, 107.1, 123.0, 137.5. Anal. Calcd
for C13H24O3: C, 68.38;H, 10.59. Found: C, 69.02;H, 10.54.
The pseudo-equatorial alcohol 2less than 4% of the crude
reaction mixture) was characterized only by 1H NMR spec-
troscopy 2200 MHz, CDCl3): d 5.62±5.52 21H, m), 4.26
21H, d, Jˆ3.7 Hz), 4.22±4.10 21H, m), 3.41 23H, s), 3.40
23H, s), 2.48±2.36 21H, m), 1.90±1.50 24H, m), 1.87 23H,
bs), 0.96 23H, d, Jˆ6.9 Hz), 0.85 23H, d, Jˆ7.0 Hz).
1
further puri®cation. H NMR 2200 MHz, CDCl3): d 5.75
21H, dd, Jˆ1.5, 9.5 Hz), 5.38 21H, dd, Jˆ2.7, 9.5 Hz),
2.30±1.20 27H, m), 0.91 23H, d, Jˆ6.5 Hz), 0.89 23H, d,
Jˆ6.7 Hz), 0.24 26H, s), 0.22 23H, s). The crude silyldienol-
ether 2from 9.2 g of dihydrocarvone, see preceding prepara-
tion) is dissolved in 117 mL of dry dichloromethane and
transferred under argon to a ¯ame dried three necked ¯ask
equipped with a three way stopcock and a dropping funnel
with pressure equalizer. Freshly distilled trimethylortho-
formate 28.3 mL, 8.1 g, 76.0 mmol) is added and the
solution is cooled to 2788C in a dry ice/acetone bath.
BF3´Et2O 27.2 mL, 8.3 g, 58.5 mmol) is added dropwise
via the dropping funnel over 1.5 h. Stirring is maintained
at 2788C for 30 min, after which reaction is complete by
TLC analysis. Saturated aqueous NaHCO3 2130 mL) is
added dropwise at 2788C over 30 min, and temperature is
raised to rt over 1 h. The two phases are separated and the
aqueous phase is extracted with methylene chloride
23£30 mL). The combined organic extracts are dried over
Na2SO4 and the solvent is evaporated under reduced pres-
sure. The residue is puri®ed by ¯ash chromatography
2hexanes/ethyl acetate 9:1±8:2), yielding 4.18 g of the title
compound 15 as a colorless oil 230% overall yield;yields up
4.1.4. Acetic acid )1S,4R,5R)-4-dimethoxymethyl-5-iso-
propyl-2-methyl-cyclohex-2-enyl ester )17). A 100 mL
¯ask equipped with a rubber septum is ¯ushed with nitrogen
and charged with alcohol 16 2900 mg, 3.90 mmol) and dry
dichloromethane 239 mL). The solution is cooled to 08C and
triethylamine 21.1 mL, 7.89 mmol) and dimethylamino-
pyridine 2DMAP) 20.2 M solution in dry dichloromethane,
1.9 mL, 0.39 mmol) are added, followed by freshly distilled
acetic anhydride 20.55 mL, 5.90 mmol). Stirring is main-
tained at 258C under a nitrogen atmosphere for 3 h, after
which the reaction is complete by TLC analysis. Saturated
NaHCO3 is added 235 mL), and after stirring for 15 min, the
two phases are separated and the aqueous phase is extracted

8538
S. M. Ceccarelli et al. / Tetrahedron 57 02001) 8531±8542
with dichloromethane 23£10 mL). The combined organic
extracts are dried over Na2SO4 and the solvent is evaporated
under reduced pressure. The residue is puri®ed by ¯ash
chromatography 2hexanes/diethyl ether 9:1±8:2), yielding
1.02 g of the title compound 17 as a colorless oil 295%).
suf®ciently pure for following usage with no further puri®-
20
cation. [a]D ˆ148.6 2cˆ0.81, EtOAc); nmax 2CCl4) 2960,
2825, 1705 2CvO), 1540, 1440, 1390, 1370, 1215, 1110
2C±O), 1075 2C±O), 1005 cm21 1H NMR 2200 MHz,
;
CDCl3): d 5.38 21H, bs), 4.40 21H, d, Jˆ5.6 Hz), 3.39
23H, s), 3.37 23H, s), 2.85±2.74 22H, m), 2.52±2.30 21H,
m), 2.17±2.05 21H, m), 1.98±1.55 24H, m), 1.70 23H, bs),
0.95 23H, d, Jˆ6.6 Hz), 0.86 23H, d, Jˆ6.6 Hz); 13C NMR
250 MHz, CDCl3): d 179.3, 134.7, 122.0, 106.0, 54.4, 53.2,
39.4, 36.8, 35.6, 34.4, 27.0, 24.3, 21.8, 20.9, 18.1. Anal.
Calcd for C15H26O4: C, 66.64;H, 9.69. Found: C, 67.11;
H, 9.91.
20
[a]D ˆ158.3 2c 0.98, EtOAc); nmax 2®lm) 2957, 2832,
1734 2CvO), 1458, 1372, 1242 2C±O), 1117 2C±O),
1076 2C±O), 1019, 965 cm21
;
1H NMR 2200 MHz,
CDCl3):d 5.72±5.65 21H, m), 5.26 21H, bt, Jˆ4.4 Hz),
4.34 21H, d, Jˆ5.5 Hz), 3.43 23H, s), 3.39 23H, s), 2.33±
2.31 21H, m), 2.08 23H, s), 1.80±1.50 24H, m), 1.70 23H, d,
Jˆ0.6 Hz), 0.94 23H, d, Jˆ7.1 Hz), 0.90 23H, d, Jˆ7.1 Hz);
13C NMR 250 MHz, CDCl3): d 18.1, 20.1, 21.2, 21.4, 27.1,
27.5, 37.1, 41.1, 54.0, 55.3, 70.0, 106.4, 126.2, 133.3, 171.0.
Anal. Calcd for C15H26O4: C, 66.64;H, 9.69. Found: C,
66.71;H, 9.75.
4.1.6.
[)1R,5R,6R)-6-Dimethoxymethyl-5-isopropyl-2-
methyl-cyclohex-2-enyl]-acetaldehyde )10). To a stirred
suspension of LiAlH4 2882 mg, 23.24 mmol) in Et2O
250 mL) under nitrogen at 08C is added a solution of acid
18 23.12 g, 11.54 mmol) in Et2O 240 mL) via cannula. The
suspension is warmed to room temperature, stirred for 2 h
and then cooled to 08C. H2O 20.9 mL), 15% NaOH aq
20.9 mL), H2O 22.7 mL) and Na2SO4 25.9 g) are added
successively and the resulting suspension is stirred at
room temperature until powdery solids separate 2about
1.5±2 h). The suspension is then ®ltered, washed with
Et2O, and the ®ltrate evaporated under reduced pressure,
yielding the primary alcohol as a colorless oil 22.91 g,
4.1.5.
[)1R,5R,6R)-6-Dimethoxymethyl-5-isopropyl-2-
methyl-cyclohex-2-enyl]-acetic acid )18). A 500 mL two
necked ¯ask is equipped with a magnetic stirring bar, a
dropping funnel 2with pressure equalizer) and a three way
stopcock. The apparatus is ¯ame dried under vacuum,
¯ushed with argon and charged with HN2TMS)2 27.7 mL,
36.6 mmol) and dry THF 233 mL). The solution is cooled to
08C, and n-BuLi 21.6 M hexanes solution, 21.3 mL,
34.2 mmol) is added dropwise with stirring. The mixture
is stirred at 08C for 30 min, then cooled to 2788C. A solu-
tion of the acetate 17 23.3 g, 12.2 mmol) in THF 240 mL) is
added dropwise, and the resulting solution is stirred at
2788C for 30 min. tert-Butyl dimethyl silyl chloride
25.5 g, 36.6 mmol) is dissolved in dry DMPU 226 mL)
with the aid of a small quantity of THF 22 mL). The result-
ing solution is added dropwise to the reaction mixture, and
stirring is maintained at 2788C for 45 min. After warming
to room temperature over 40 min, the mixture is transferred
to a separatory funnel with pentane 2260 mL) and washed
with phosphate buffer solution 23£100 mL) and brine
230 mL). The combined aqueous phases are back extracted
with pentane 260 mL) and the combined organic phases are
dried 2Na2SO4) and evaporated. Formation of the silyl
ketene acetal 11 can be ascertained by analysis of diagnostic
signals in the NMR spectrum of the crude. 1H NMR
2200 MHz, CDCl3): d 2selected signals) 3.31 21H, d,
Jˆ2.2 Hz), 3.20 21H, d, Jˆ2.2 Hz). The crude light yellow
oil is dissolved in dry xylenes 250 mL) and transferred to a
high pressure stainless steel reactor 2Ashcroft, 250 mL),
equipped with a magnetic stirring bar. The reactor is purged
and ¯ushed with argon three times, then warmed to 1908C
and stirred for 5 h, after which the reaction is complete by
TLC analysis. The solvent is evaporated and the residue is
dissolved in THF 235 mL) and treated at room temperature
with 2.0 M NaOH 230 mL). Desilylation is complete in
about 3 h. The reaction mixture is transferred to a separatory
funnel and diethyl ether is added 250 mL) the two phases are
separated and the organic phase is extracted with 2.0 M
NaOH 22£35 mL). The combined aqueous phases are
washed with diethyl ether 22£25 mL), and then carefully
acidi®ed to pH 3 with 10% aqueous HCl. The suspension
is immediately extracted with diethyl ether 25£40 mL) and
the combined organic extracts are dried over Na2SO4 and
evaporated under reduced pressure to give the title
compound 18 22.7 g, 82%;yields up to 90% have been
obtained on smaller scale experiments), which is considered
20
98%). [a]D ˆ186.4 2cˆ1.48, EtOAc); nmax 2®lm) 3380
2OH), 2940, 2815, 1445, 1375, 1180 2C±O), 1150 2C±O),
1110 2C±O), 1070 2C±O) cm21 1H NMR 2200 MHz,
;
CDCl3): d 5.26 21H, bs), 4.33 21H, d, Jˆ5.9 Hz), 3.70±
3.63 22H, m), 3.33 23H, s), 3.32 23H, s), 2.89 21H, bs,
OH), 2.30±2.25 21H, m), 2.10±1.60 27H, m), 1.65 23H, d,
Jˆ1.1 Hz), 0.92 23H, d, Jˆ6.8 Hz), 0.83 23H, d, Jˆ6.6 Hz);
13C NMR 250 MHz, CDCl3): d 137.2, 120.6, 106.9, 62.6,
54.6, 54.5, 40.7, 36.2, 35.8, 33.4, 26.9, 24.3, 22.4, 21.2,
16.5. Anal. Calcd for C15H28O3: C, 70.27;H, 11.01.
Found: C, 70.41;H, 10.95. To a stirred suspension of
Dess±Martin periodinane 2DMP) 27.08 g, 16.69 mmol) in
CH2Cl2 260 mL) under nitrogen at room temperature is
added a solution of the alcohol 23.12 g, 11.54 mmol) in
CH2Cl2 240 mL) via cannula. After 45 min 2 M NaOH aq
270 mL) and Et2O 270 mL) are added successively and the
suspension stirred at room temperature for 30 min. The two
layers are separated and the aqueous layer extracted with
Et2O 22£80 mL). The combined organic layers are washed
with brine 280 mL), dried 2Na2SO4) and the solvent evapo-
rated under reduced pressure to give the title aldehyde 10 as
a clear oil 22.74 g, 97%). nmax 2®lm): 1720 cm21 2CvO); 1H
NMR 2200 MHz, CDCl3): d 9.72 21H, bs), 5.38 21H, bs),
4.32 21H, d, Jˆ4.8 Hz), 3.35 23H, s), 3.32 23H, s), 2.83 21H,
bs), 2.74 21H, dd, Jˆ2.5, 9.9 Hz), 2.31±2.19 21H, m), 2.10±
1.60 25H, m), 1.66 23H, d, Jˆ1.5 Hz), 0.94 23H, d,
Jˆ6.8 Hz), 0.84 23H, d, Jˆ6.7 Hz); 13C NMR 250 MHz,
CDCl3):d 201.3, 135.2, 121.8, 106.9, 54.8, 54.6, 44.6,
40.5, 35.6, 33.5, 26.6, 24.2, 21.8, 21.1, 16.5. Anal. Calcd
for C15H26O3: C, 70.83;H, 10.30. Found: C, 71.03;H,
10.01.
4.1.7. )Z)-4-[)1R,5R,6R)-6-Dimethoxymethyl-5-isopropyl-
2-methyl-cyclohex-2-enyl]-2-methyl-but-2-enoic
acid
ethyl ester )20). A solution of phosphonate 19 2155 mg,
0.45 mmol) and 18-crown-6 2148 mg, 0.56 mmol) in THF
23.5 mL) is ¯ushed with nitrogen and cooled to 2788C.

S. M. Ceccarelli et al. / Tetrahedron 57 02001) 8531±8542
8539
KN2TMS)2 215% w/v solution in toluene, 0.62 mL,
0.41 mmol) is added, followed by a solution of the aldehyde
10 294.5 mg, 0.37 mmol) in THF 24.0 mL). The mixture is
stirred at 2788C for 1.0 h, after which the reaction is
complete by TLC analysis. The reaction is quenched with
saturated NH4Cl 24.5 mL) and the mixture is partitioned
between water and Et2O. Drying 2Na2SO4) and evaporation
of the solvent affords a crude oil, which is puri®ed by ¯ash
chromatography 2hexanes/ethyl acetate 9:1), yielding the
The organic ®ltrates are evaporated under reduced pressure,
yielding the title compound 22 as a colorless oil16 278 mg,
1
92%). nmax 2®lm) 3420, 2960 cm21; H NMR 2200 MHz,
CDCl3): d 5.40±5.30 22H, m), 4.32 21H, d, Jˆ5.3 Hz),
4.07 21H, d, Jˆ11.6 Hz), 3.95 21H, d, Jˆ11.6 Hz), 3.36
23H, s), 3.34 23H, s), 2.60±2.40 21H, m), 2.35±2.10 22H,
m), 2.05±1.60 25H, m), 1.77 23H, bs), 1.67 23H, bs), 0.86
23H, d, Jˆ6.5 Hz), 0.77 23H, d, Jˆ6.3 Hz); 13C NMR
250 MHz, CDCl3): d 137.1, 134.0, 128.6, 121.2, 107.4,
61.3, 54.8, 54.7, 40.8, 39.2, 35.9, 28.6, 27.1, 24.4, 22.9,
21.9, 21.1, 16.4. Anal. Calcd for C18H32O3: C, 72.93;H,
10.88. Found: C, 73.07;H, 10.64.
1
title compound 20 as a colorless oil 2110 mg, 87%). H
NMR 2200 MHz, CDCl3): d 6.10 21H, bt, Jˆ6.7 Hz), 5.33
21H, bs), 4.31 21H, d, Jˆ5.8 Hz), 4.18 22H, q, Jˆ7.0 Hz),
3.33 23H, s), 3.32 23H, s), 2.91±2.75 21H, m), 2.67±2.56
21H, m), 2.39±2.22 21H, m), 2.04±1.57 25H, m), 1.94 23H,
bs), 1.66 23H, bs), 1.23 23H, t, Jˆ7.0 Hz), 0.87 23H, d,
Jˆ6.7 Hz), 0.80 23H, d, Jˆ6.5 Hz); 13C NMR 250 MHz,
CDCl3): d 168.2, 144.1, 136.3, 125.7, 121.3, 106.8, 59.7,
54.6, 54.0, 40.6, 39.3, 36.5, 30.6, 27.2, 24.4, 22.5, 21.1,
20.7, 17.0, 14.2. Anal. Calcd for C20H34O4: C, 70.97;H,
10.12. Found: C, 71.09;H, 10.42.
4.1.10. )E)-4-[)1R,5R,6R)-6-Dimethoxymethyl-5-isopropyl-
2-methyl-cyclohex-2-enyl]-2-methyl-but-2-en-1-ol )23).
Ester 21 2105 mg, 0.31 mmol) is reduced with lithium
aluminium hydride 212 mg, 0.31 mmol) as described
above for ester 20. The crude, containing both the E and Z
allylic alcohols, is puri®ed by ¯ash chromatography
2hexanes/ethyl acetate 8:2), yielding the title compound 23
as a colorless oil16 267 mg, 72%) and the Z allyl alcohol 22
29.2 mg, 9.9%). 23: nmax 2®lm) 3380, 2960 cm21; 1H NMR
2200 MHz, CDCl3): d 5.53 21H, bt, Jˆ6.9 Hz), 5.32 21H,
bs), 4.31 21H, d, Jˆ5.7 Hz), 3.98 22H, s), 3.34 26H, s), 2.35±
2.20 23H, m), 2.05±1.65 25H, m), 1.66 26H, s), 0.88 23H, d,
Jˆ6.7 Hz), 0.79 23H, d, Jˆ6.5 Hz); 13C NMR 250 MHz,
CDCl3). d 137.1, 133.7, 127.3, 121.1, 107.0, 69.2, 54.4,
54.2, 40.8, 39.1, 36.3, 28.8, 27.3, 24.4, 22.9, 21.2, 16.7,
13.7. Anal. Calcd for C18H32O3: C, 72.93;H, 10.88.
Found: C, 73.04;H, 10.69.
4.1.8. )E)-4-[)1R,5R,6R)-6-Dimethoxymethyl-5-isopropyl-
acid
2-methyl-cyclohex-2-enyl]-2-methyl-but-2-enoic
ethyl ester )21). To a stirred suspension of sodium hydride
260% dispersion in mineral oil) 2519 mg, 12.98 mmol) in
DME 260 mL) under nitrogen at room temperature is
added triethylphosphonopropionate 23.9 mL, 18.19 mmol).
After 10 min the suspension becomes a clear solution which
is stirred for a further 20 min and then a solution of aldehyde
10 22.74 g, 10.77 mmol) in DME 240 mL) is added via
cannula. After 1.0 h the reaction is completed by TLC
analysis, sat. NH4Cl aq 220 mL) is added and the suspension
partitioned between Et2O 250 mL) and H2O 250 mL). The
aqueous layer is extracted with Et2O 23£80 mL), the
combined organic layers are washed with brine 280 mL),
dried 2Na2SO4), ®ltered, the solvent removed and the
residue puri®ed by ¯ash chromatography 2hexanes/ethyl
acetate 9:1) to give a colorless oil which contains the title
compound 21 plus the corresponding Z isomer 20 23.10 g,
85%, 89:11 E/Z), which are separated at a later stage, i.e.
after reduction of the ester group. 21: nmax 2®lm): 1705
4.1.11. {)2S,3R)-3-[)1R,5R,6R)-6-Dimethoxymethyl-5-iso-
propyl-2-methyl-cyclohex-2-enylmethyl]-2-methyl-oxi-
Ê
ranyl}-methanol )24). A suspension of powdered 3 A
molecular sieves 250 mg) in dichloromethane 21.0 mL) is
cooled to 2208C and treated with 21)-DET 20.2 M solution
in dichloromethane, 0.15 mL, 0.030 mmol), Ti2Oi-Pr)4
20.0075 mL, 7.1 mg, 0.025 mmol) and TBHP 25.5 M in
nonane, 0.091 mL, 0.5 mmol). The mixture is stirred at
2208C for 25 min, after which a solution of the alcohol
22 270 mg, 0.24 mmol) in CH2Cl2 21.0 mL) over molecular
sieves is added dropwise. The reaction mixture is stirred at
2208C for 18 h, then H2O 21.0 mL) is added, and the
temperature is raised to rt over 30 min. NaOH 30% satu-
rated with NaCl 20.2 mL) is added and the emulsion stirred
vigorously until two clear phases separate 2about 15 min).
The lower organic phase is separated from the upper sieve-
containing aqueous phase, which is extracted twice with
dichloromethane. The combined organic extracts are dried
2Na2SO4) and evaporated under reduced pressure. Flash
chromatography 2hexanes/ethyl acetate 7:3) affords the
epoxide 233.6 mg, 45%) as a mixture of the two isomers
24 and 25 290:10), plus recovered starting material
217.5 mg, 25%). The two isomers can be separated by chro-
matography with CH2Cl2/ethyl ether 8:2. Title compound
1
2CvO), 1640 2CvC) cm21; H NMR 2200 MHz, CDCl3):
d 6.92 21H, bt, Jˆ7.0 Hz), 5.36 21H, bs), 4.31 21H, d,
Jˆ5.2 Hz), 4.17 22H, q, Jˆ7.0 Hz), 3.35 23H, s), 3.34
23H, s), 2.57±2.32 23H, m), 2.10±1.60 25H, m), 1.81 23H,
bs), 1.65 23H, bs), 1.27 23H, t, Jˆ7.0 Hz), 0.88 23H, d,
Jˆ6.7 Hz), 0.79 23H, d, Jˆ6.5 Hz); 13C NMR 250 MHz,
CDCl3): d 168.3, 143.6, 136.3, 126.2, 121.7, 101.0, 60.0,
54.9, 54.6, 41.1, 38.6, 35.7, 30.1, 27.0, 24.2, 22.7, 21.1,
16.2, 14.2, 12.3. Anal. Calcd for C20H34O4: C, 70.97;H,
10.12. Found: C, 71.03;H, 10.01.
4.1.9. )Z)-4-[)1R,5R,6R)-6-Dimethoxymethyl-5-isopropyl-
2-methyl-cyclohex-2-enyl]-2-methyl-but-2-en-1-ol )22).
A suspension of lithium aluminium hydride 211 mg,
0.29 mmol) in Et2O 21.0 mL) is ¯ushed with nitrogen and
cooled to 08C. A solution of ester 20 298 mg, 0.29 mmol) in
Et2O 22.0 mL) is added dropwise. The cooling bath is
removed, and the mixture stirred at room temperature for
1 h. The reaction mixture is diluted by Et2O, cooled to 08C
and quenched with a few drops of saturated NH4Cl. Solid
Na2SO4 2500 mg) is added, and the mixture is stirred for
75 min, then the salts are ®ltered and washed with Et2O.
1
24: H NMR 2200 MHz, CDCl3): d 5.45 21H, bs), 4.32
21H, d, Jˆ4.5 Hz), 3.62 21H, d, Jˆ12.0 Hz), 3.54 21H, d,
Jˆ12.0 Hz), 3.40 26H, s), 2.97 21H, dd, Jˆ3.4 Hz,
Jˆ8.9 Hz), 2.53±2.40 21H, m), 2.20±2.10 22H, m), 2.10±
1.50 25H, m), 1.77 23H, d, Jˆ1.2 Hz), 1.39 23H, s), 0.91
23H, d, Jˆ6.6 Hz), 0.80 23H, d, Jˆ6.6 Hz). Anal. Calcd
for C18H32O4: C, 69.19;H, 10.32. Found: C, 69.45;H,
10.12.

8540
S. M. Ceccarelli et al. / Tetrahedron 57 02001) 8531±8542
4.1.12. {)2R,3S)-3-[)1R,5R,6R)-6-Dimethoxymethyl-5-iso-
propyl-2-methyl-cyclohex-2-enylmethyl]-2-methyl-oxi-
ranyl}-methanol )25). Alcohol 22 250 mg, 0.17 mmol) is
epoxidized as described above using 22)-DET 24.2 mg,
0.020 mmol) as chiral ligand. Standard workup and ¯ash
chromatography affords the epoxides 213.5 mg, 25%) as a
mixture of the two isomers 255:45 in favor of distereoisomer
24) plus recovered starting material 236 mg, 72%). The two
isomers can be separated by ¯ash chromatography with
CH2Cl2/ethyl ether 8:2. Title compound 25: 1H NMR
2200 MHz, CDCl3) d 5.35 21H, bs), 4.36 21H, d,
Jˆ4.7 Hz), 3.65±3.55 22H, m), 3.41 26H, s), 3.02 21H, dd,
Jˆ4.3 Hz, Jˆ8.6 Hz), 2.40±2.30 21H, m), 1.77 23H, bs),
2.2±1.5 27H, m), 1.45 23H, s), 0.91 23H, d, Jˆ6.5 Hz),
0.82 23H, d, Jˆ6.5 Hz).
23H, s), 1.05±0.95 21H, m), 0.95 23H, d, Jˆ6.5 Hz), 0.93
23H, d, Jˆ6.6 Hz).
4.1.15. )2S,3R)-3-[)1R,5R,6R)-6-Dimethoxymethyl-5-iso-
propyl-2-methyl-cyclohex-2-enylmethyl)-2-methyl-oxi-
rane-2-carbaldehyde )30). A solution of alcohol 27
29.0 mg, 0.029 mmol) in CH2Cl2 20.42 mL) is treated with
Dess±Martin periodinane 2DMP) 218 mg, 0.042 mmol) and
the mixture stirred at room temperature for 1.0 h. The
reaction mixture is then poured into a separatory funnel
containing 1.0 M NaOH 20.3 mL) and Et2O 21.0 mL). The
two phases are separated and the organic phase is washed
twice with water, dried 2Na2SO4) and evaporated to give the
title aldehyde 30 28.5 mg, 96%), which is used in the follow-
1
ing step with no further puri®cation. H NMR 2200 MHz,
CDCl3): d 8.88 21H, s), 5.40 21H, bs), 4.33 21H, d,
Jˆ4.9 Hz), 3.39 23H, s), 3.37 23H, s), 2.41±2.26 21H, m),
2.24±1.60 28H, m), 1.69 23H, s), 1.39 23H, s), 0.89 23H, d,
Jˆ6.9 Hz), 0.81 23H, d, Jˆ6.7 Hz).
4.1.13. {)2S,3S)-3-[)1R,5R,6R)-6-Dimethoxymethyl-5-iso-
propyl-2-methyl-cyclohex-2-enylmethyl]-2-methyl-oxi-
ranyl}-methanol )26). Alcohol 23 227 mg, 0.091 mmol) is
oxidized using 21)-DET as chiral ligand, as described
above. Due to the scale, Ti2Oi-Pr)4 is added as a solution
in CH2Cl2 22.7% v/v). Puri®cation by ¯ash chromatography
2hexanes/ethyl acetate 7:3) yields the epoxide 211 mg, 39%)
as a mixture of the two isomers 2ratio 10:1) plus recovered
starting material 216 mg, 59%). The two isomers can be
separated by ¯ash chromatography 2CH2Cl2/ethyl ether
8:2) to give the title compound 26 2major isomer) as a color-
less oil. 1H NMR 2200 MHz, CDCl3): d 5.36 21H, bs), 4.34
21H, d, Jˆ5.6 Hz), 3.67±3.57 22H, m), 3.36 26H, s), 3.23
21H, dd, Jˆ4.6 Hz, Jˆ7.0 Hz), 2.41±2.38 21H, m), 2.12±
1.60 27H, m), 1.74 23H, bs), 1.30 23H, s), 0.93 23H, d,
Jˆ6.7 Hz), 0.82 23H, d, Jˆ6.6 Hz).
4.1.16.
)Z)-{)5S)-5-[)1R)-2-))1R,5R,6R)-6-Dimethoxy-
methyl-5-isopropyl-2-methyl-cyclohex-2-enyl)-1-hydroxy-
ethyl]-5-methyl-5H-furan-2-ylidene}-acetic acid ethyl
ester )31). Phosphorane 29 216.4 mg, 0.042 mmol) is
dissolved in THF 20.20 mL) under nitrogen, cooled to
08C and treated with NaN2TMS)2 21.0 M solution in THF,
0.033 mL, 0.033 mmol). After stirring for 1.0 h, aldehyde
30 28.5 mg, 0.027 mmol) is added via cannula as a solution
in THF 20.30 mL). The mixture is stirred at 08C for
,10 min. Water is added 20.30 mL) and the mixture is
warmed to room temperature. After diluting with Et2O
and water, the two phases are separated, and the organic
phase washed with brine, dried 2Na2SO4) and evaporated.
The crude is puri®ed by ¯ash chromatography 2hexanes/
acetate 7:3) yielding the cyclic title compound 31 25.0 mg,
44%). 1H NMR 2200 MHz, CDCl3): d 6.81 21H, d,
Jˆ5.8 Hz), 6.12 21H, d, Jˆ5.8 Hz), 5.27 21H, bs), 4.86
21H, s), 4.41 21H, d, Jˆ5.7 Hz), 4.20±4.10 22H, m), 3.64
21H, dd, Jˆ9.2 Hz, Jˆ1.6 Hz), 3.39 23H, s), 3.38 23H, s),
2.35±2.30 21H, m), 2.20±1.58 27H, m), 1.69 23H, d,
Jˆ1.5 Hz), 1.44 23H, s), 1.25 23H, t, Jˆ7.0 Hz), 0.93 23H,
d, Jˆ6.8 Hz), 0.83 23H, d, Jˆ6.6 Hz).
4.1.14. {)2R,3R)-3-[)1R,5R,6R)-6-Dimethoxymethyl-5-iso-
propyl-2-methyl-cyclohex-2-enylmethyl]-2-methyl-oxi-
ranyl}-methanol )27); [)1R,3R,4S,5aR,9R,9aR)-9-iso-
propyl-1,4-dimethoxy-3,6-dimethyl-1,3,4,5,5a,8,9,9a-octa-
hydro-benzo[c]oxepin-3-yl]-methanol )28). Alcohol 23
220 mg, 0.067 mmol) is oxidized as described above
using 22)-DET 21.7 mg, 0.0081 mmol). Due to the scale,
Ti2Oi-Pr)4 is added as a solution in CH2Cl2 22.4% v/v).
Puri®cation by ¯ash chromatography 2CH2Cl2/ethyl ether
85:15±7:3) yields the epoxide 2716 29.1 mg, 43%) as a
single isomer, the rearranged product 2816 22.1 mg, 10%)
plus recovered starting material 26.8 mg, 34%). 27:
4.1.17. )2R,3R)-3-[)1R,5R,6R)-6-Dimethoxymethyl-5-iso-
propyl-2-methyl-cyclohex-2-enylmethyl)-2-methyl-oxi-
rane-2-carbaldehyde )32). Alcohol 24 211 mg, 0.035
mmol) is oxidized as described above for alcohol 27. The
crude aldehyde 32 210.5 mg, 96%) is used in the following
step with no further puri®cation.
colorless oil;16 nmax 2®lm) 3450, 2960 cm21 1H NMR
;
2200 MHz, CDCl3): d 5.37 21H, bs), 4.33 21H, d,
Jˆ5.1 Hz), 3.61±3.40 22H, m), 3.38 23H, s), 3.37 23H, s),
3.24 21H, dd, Jˆ5.0 Hz, Jˆ7.6 Hz), 2.46±2.30 21H, m),
2.11±1.49 27H, m), 1.71 23H, d, Jˆ1.2 Hz), 1.29 23H, s),
0.91 23H, d, Jˆ6.9 Hz), 0.81 23H, d, Jˆ6.6 Hz); 13C NMR
2CDCl3): d 136.3, 122.1, 106.9, 66.3, 61.6, 60.3, 55.1,
54.6, 41.2, 36.3, 35.3, 28.8, 27.0, 24.0, 22.7, 21.1, 16.0,
4.1.18.
)Z)-{)5R)-5-[)1R)-2-))1R,5R,6R)-6-Dimethoxy-
methyl-5-isopropyl-2-methyl-cyclohex-2-enyl)-1-hydroxy-
ethyl]-5-methyl-5H-furan-2-ylidene}-acetic acid ethyl
ester )33). Aldehyde 32 210.5 mg, 0.034 mmol) is exposed
to the phosphorane 29 as described above for aldehyde 30.
Puri®cation of the crude by ¯ash chromatography 2hexanes/
acetate 9:1±6:4) affords the acyclic trans isomer 34 21.4 mg,
10%) 2as a mixture of the keto and enol tautomers) and the
cyclic title compound 33 28.6 mg, 60%). 33: 1H NMR
2200 MHz, CDCl3): d 6.68 21H, d, Jˆ5.7 Hz), 6.16 21H,
d, Jˆ5.7 Hz), 5.25 21H, bs), 4.86 21H, s), 4.41 21H, d,
Jˆ5.8 Hz), 4.2±4.1 22H, m), 3.88 21H, d, Jˆ9.6 Hz), 3.39
23H, s), 3.38 23H, s), 2.37±2.28 21H, m), 2.10±1.40 27H, m),
1
14.4. 28: colorless oil;16 nmax 2®lm) 3465, 2935 cm21; H
NMR 2200 MHz, CDCl3): d 5.38 21H, bs), 4.51 21H,
d, Jˆ7.1 Hz), 3.59 22H, s), 3.47 21H, dd, Jˆ3.4,
11.7 Hz), 3.38 23H, s), 3.33 23H, s), 2.20±2.10 21H, m),
2.10±1.40 26H, m), 1.71 23H, s), 1.18 23H, s), 0.98 23H,
d, Jˆ6.6 Hz), 0.95±0.85 21H, m), 0.81 23H, d, Jˆ6.7 Hz);
1H NMR 2C6D6): d 5.33 21H, bs), 4.42 21H, d, Jˆ7.0 Hz),
3.8±3.6 22H, m), 3.49 21H, dd, Jˆ3.2 Hz, Jˆ11.8 Hz),
3.09 23H, s), 3.07 23H, s), 2.35 2OH, bs), 2.20 21H,
t, Jˆ7.9 Hz), 2.1±2.0 21H, m), 2.0±1.2 28H, m), 1.06

S. M. Ceccarelli et al. / Tetrahedron 57 02001) 8531±8542
8541
1.70 23H, d, Jˆ1.2 Hz), 1.54 23H, s), 1.27 23H, t, Jˆ7.1 Hz),
by a solution of the protected alcohol mixture 2260 mg,
0.40 mmol). The mixture is stirred at room temperature
for 2 h, then partitioned between Et2O and 2.0 M NaOH.
The crude is puri®ed by ¯ash chromatography 2hexanes/
ethyl acetate 95:5) yielding the title compound 39 as a
mixture of the two acetal epimers 21.8:1) 2140 mg, 53%).
1
0.92 23H, d, Jˆ6.8 Hz), 0.82 23H, d, Jˆ6.9 Hz). 34: H
NMR 2200 MHz, CDCl3): d [26.81, d, Jˆ17.2 Hz), 26.61,
d, Jˆ15.9 Hz), 1H corresponding to keto1enol tautomer];
[26.35, d, Jˆ15.9 Hz), 26.01, dd, Jˆ17.2, 1.3 Hz), 1H corre-
sponding to keto1enol tautomer];5.37 21H, bs);[25.08, s),
23.58, s), 2H corresponding to keto1enol tautomer];4.30
21H, d, Jˆ5.2 Hz);4.18±4.12 22H, m);3.38 26H, s);3.32±
3.21 21H, m);2.49±2.28 21H, m);2.19±1.62 27H, m);
[21.50, s), 21.48, s), 3H corresponding to keto1enol
20
39 21.8:1 mixture of epimers): [a]D ˆ216.4 2c 1.23,
EtOAc); nmax 2®lm) 2957, 2878, 1746 2CvO), 1458,
1427, 1242 2C±O), 1113 2C±O), 1067 2C±O), 1047, 1019,
740, 702 cm21 1H NMR 2200 MHz, CDCl3): d 2major
;
tautomer];1.33±1.25 23H, m);0.89 23H, d,
0.81 23H, d, Jˆ6.6 Hz).
Jˆ7.7 Hz);
epimer) 7.72±7.15 215H, m), 6.61 21H, d, Jˆ4.8 Hz), 5.63
21H, d, Jˆ4.8 Hz), 4.92 21H, d, Jˆ18.4 Hz), 4.65 21H, d,
Jˆ18.4 Hz), 3.69 21H, dd, Jˆ4.1, 7.8 Hz), 3.09 23H, s),
2.95±2.75 21H, m), 2.62±2.43 21H, m), 1.75±1.55 22H,
m), 1.37 23H, s), 1.10 29H, s), 0.97 29H, q, Jˆ7.4 Hz),
4.1.19. 1-[)5S)-2-Methoxy-5-methyl-5-)3-phenyl-1S-tri-
ethylsilanyloxy-propyl)-2,5-dihydrofuran-2-yl]-ethane
diol )38). A solution of ester 3525 2171 mg, 0.41 mmol) in
Et2O 25.0 mL) is cooled to 08C and treated with LiAlH4
223 mg, 0.63 mmol). The mixture is stirred at 08C for 1 h,
then quenched by diluting with Et2O saturated with NaOH
6.0 M. Na2SO4 is added, and the salts ®ltered and washed
with Et2O. The solution is evaporated under reduced
pressure to give the crude alcohol 36 2152 mg) which is
highly unstable and is processed immediately to the follow-
ing reaction. Crude alcohol 36 2152 mg, 0.41 mmol) is
dissolved in dry MeOH 24.4 mL) and cooled to 08C. A
freshly prepared solution of DMDO in acetone 20.0845 M,
5.2 mL, 0.44 mmol) is added dropwise, and the mixture
stirred at 08C for 5 min. DMDO is removed under a stream
of nitrogen, then the volatiles are evaporated. The crude,
consisting of mixture of three isomers 38 2approx.
1.9:1.6:1) 2168 mg, 97%), is pure enough for subsequent
1
0.64 26H, t, Jˆ7.4 Hz). H NMR 2200 MHz, CDCl3): d
2minor epimer) 7.72±7.15 215H, m), 6.61 21H, d,
Jˆ4.8 Hz), 5.69 21H, d, Jˆ4.8 Hz), 4.77 22H, bs), 3.71
21H, dd, Jˆ4.1, 7.8 Hz), 3.12 23H, s), 2.95±2.75 21H, m),
2.62±2.43 21H, m), 1.75±1.55 22H, m), 1.52 23H, s), 1.09
29H, s), 1.2±0.79 29H, m), 0.71±0.58 26H, m). Anal. Calcd
for C39H54O5Si2: C, 71.08;H, 8.26. Found: C, 71.14;H,
8.19.
Acknowledgements
A graduate fellowship is gratefully acknowledged by S.
Ceccarelli 2Pharmacia and Upjohn, Nerviano-Milano,
Italy). We thank the European Commission 2IHP Network
grant `Design and synthesis of microtubule stabilizing anti-
cancer agents' HPRN-CT-2000-00018), Merck 2Merck's
Academic Development Program Award to C. Gennari,
2000), and M. U. R. S. T. COFIN 2000 2`Sintesi di mimetici
e analoghi di sostanze naturali biologicamente attive' prot.
MM 03155477) for ®nancial support.
1
transformations. H NMR 2200 MHz, CDCl3): d 2major
isomer) 7.37±7.12 25H, m), 6.07 21H, d, Jˆ5.1 Hz), 5.64
21H, d, Jˆ5.1 Hz), 4.12 21H, dd, Jˆ4.1 Hz, Jˆ8.3 Hz),
3.86±3.72 23H, m), 3.22 23H, s), 3.10±2.90 21H, m),
2.75±2.60 21H, m), 2.10±1.95 22H, m), 1.42 23H, s),
1.10±0.95 29H, m), 0.75±0.55 26H, m). 1H NMR
2200 MHz, CDCl3): d 2middle isomer) 7.37±7.12 25H, m),
6.13 21H, d, Jˆ5.1 Hz), 5.68 21H, d, Jˆ5.1 Hz), 4.00±3.66
24H, m), 3.25 23H, s), 3.05±2.85 21H, m), 2.65±2.50 21H,
m), 1.85±1.65 22H, m), 1.32 23H, s), 1.10±0.95 29H, m),
0.75±0.55 26H, m). 1H NMR 2200 MHz, CDCl3): d 2minor
isomer) 7.37±7.12 25H, m), 6.05 21H, d, Jˆ5.5 Hz), 5.80
21H, d, Jˆ5.5 Hz), 4.45±4.37 21H, m), 3.86±3.72 23H, m),
3.23 23H, s), 3.10±2.90 21H, m), 2.75±2.60 21H, m), 2.10±
1.95 22H, m), 1.41 23H, s), 1.10±0.95 29H, m), 0.75±0.55
26H, m).
References
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Chemistry and Biochemistry, University of Texas at Austin)
for exchange of information and experimental procedures
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via the following route: 2a) 19, KN2TMS)2, 18-c-6, THF,
2788C, then hydrocinnamic aldehyde, 1 h 284%);
2b) LiAlH4, Et2O, 08C to rt, 1 h 288%);2c) TBHP, 2 2)-DET
212%), Ti2Oi-Pr)4 210%), MS, CH2Cl2, 2208C, 18 h 296%);
2d) DMP, CH2Cl2, rt, 15 min 286%);2e) 29, NaN2TMS)2, THF,
then aldehyde, 258C, 10 min 269% hydrofuran118% acyclic
trans isomer as a mixture of the keto and enol tautomers);
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1
2f) TESCl, imidazole, CH2Cl2, rt, 1.5 h 285%). 35: H NMR
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Jˆ5.7 Hz), 6.18 21H, d, Jˆ5.7 Hz), 4.91 21H, s), 4.18 22H,
q, Jˆ6.7 Hz), 3.90 21H, dd, Jˆ6.0, 4.7 Hz), 2.89±2.72 21H,
m), 2.69±2.51 21H, m), 1.72±1.60 22H, m), 1.52 23H, s), 1.29
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dation 2Ref. 19) was evaluated by acetylation of the epoxy-
alcohol and NMR analysis of the resulting acetate in the
presence of the chiral shift reagent Europium tris[3-2hepta-
¯uoropropylhydroxymethylene)-21)-camphorate] [Eu2hfc)3],
and shown to be 75%. The reference opposite enantiomer
was prepared by reaction of the allylic alcohol with TBHP,
21)-DET 212%), Ti2Oi-Pr)4 210%), MS, CH2Cl2, 2208C, 18 h
292%), while the reference racemic mixture was prepared by
reaction of the allylic alcohol with TBHP, vanadyl acetyl-
acetonate [VO2acac)2] 24%), CH2Cl2, rt, 30 min 298%).
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