Chromium-mediated dearomatization: Application to the synthesis of racemic 15-acetoxytubipofuran and asymmetric synthesis of both enantiomers

Article abstract of DOI:10.1002/hlca.200590078

An efficient dearomatization process of [Cr(arene)(CO)₃] complexes initiated by a nucleophilic acetaldehyde equivalent is detailed. It generates in a one-pot reaction three C-C bonds and two stereogenic centers. This process allowed a rapid assembly of a cis-decalin ring system incorporating a homoannular diene unit in just two steps starting from aromatic precursors (Scheme 2). The method was applied to the total synthesis of the eudesmane-type marine furanosesquiterpene (±)-15-acetoxytubipofuran (2). Two routes were successfully used to synthesize the γ-lactone precursor of the furan ring. The key step in the first approach was a Pd-catalyzed allylic substitution (Scheme 3), while in the second approach, an Eschenmoser-Claisen rearrangement was highly successful (Scheme 4). The Pd-catalyzed allylic substitution could be directed to give either the (normal) product with overall retention as major diastereoisomer or the unusual product with inversion of configuration (see Table). For the synthesis of the (-)-enantiomer (R,R)-2 of 15- acetoxytubipofuran, an enantioselective dearomatization in the presence of a chiral diether ligand was implemented (Scheme 7), while the (+)-enantiomer (S,S)-2 was obtained via a diastereoselective dearomatization of an arene-bound chiral imine auxiliary (Scheme 8). Chiroptical data suggest that a revision of the previously assigned absolute configuration of the natural product is required.

Full text of DOI:10.1002/hlca.200590078

Helvetica Chimica Acta ± Vol. 88 (2005)
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Chromium-Mediated Dearomatization: Application to the Synthesis of
Racemic 15-Acetoxytubipofuran and Asymmetric Synthesis of Both
Enantiomers
by E. Peter Kündig*, Mundruppady S. Laxmisha, Rita Cannas, Sylvie Tchertchian, and Liu Ronggang
Department of Organic Chemistry, University of Geneva, 30, Quai Ernest Ansermet, CH-1211 Geneva 4
(e-mail: peter.kundig@chiorg.unige.ch)
An efficient dearomatization process of [Cr(arene)(CO)3] complexes initiated by
a nucleophilic
acetaldehyde equivalent is detailed. It generates in a one-pot reaction three CÀC bonds and two stereogenic
centers. This process allowed a rapid assembly of a cis-decalin ring system incorporating a homoannular diene
unit in just two steps starting from aromatic precursors (Scheme 2). The method was applied to the total
synthesis of the eudesmane-type marine furanosesquiterpene (Æ)-15-acetoxytubipofuran (2). Two routes were
successfully used to synthesize the g-lactone precursor of the furan ring. The key step in the first approach was a
Pd-catalyzed allylic substitution (Scheme 3), while in the second approach, an Eschenmoser ± Claisen
rearrangement was highly successful (Scheme 4). The Pd-catalyzed allylic substitution could be directed to
give either the (normal) product with overall retention as major diastereoisomer or the unusual product with
inversion of configuration (see Table). For the synthesis of the (À)-enantiomer (R,R)-2 of 15-acetoxytubipo-
furan, an enantioselective dearomatization in the presence of a chiral diether ligand was implemented
(Scheme 7), while the (‡)-enantiomer (S,S)-2 was obtained via a diastereoselective dearomatization of an
arene-bound chiral imine auxiliary (Scheme 8). Chiroptical data suggest that a revision of the previously
assigned absolute configuration of the natural product is required.
Introduction. ± Tricarbonylchromium-mediated dearomatization provides an
efficient access to polysubstituted cyclohexadienes [1]. Up to three C-substituents
can be added across an arene double bond in a one-pot procedure in a regio- and
stereoselective manner by a sequential nucleophilic/electrophilic addition or by a
nucleophilic addition followed by an acylation/alkylation sequence [2]. This dearoma-
tization method has seen considerable development, with recent efforts mainly directed
towards asymmetric variants of this reaction to give enantiomerically enriched
products. Four different asymmetric methods have been developed: asymmetric
induction with complexes of arenes bearing a chiral auxiliary as substituent [3], use of
arene complexes possessing planar chirality [4], use of prochiral complexes with chiral
nucleophiles [5], and use of complexes containing a chiral ligand at the chromium atom
[6]. Benchmark enantio-and diastereoselectivities have been obtained in dearoma-
tizations with these methods. In all but the last method, asymmetric induction takes
place during the nucleophilic addition step. The third method offers an enantioselective
variant in that chirality can be centered on an external ligand rather than on the
nucleophile itself, and first results of the use of substoichiometric quantities of chiral
information have been realized [7].
In all of the dearomatization processes mentioned above, the products possess a
homoannular cyclohexadiene moiety. This subunit embedded in a cis-decalin ring
ꢀ 2005 Verlag Helvetica Chimica Acta AG, Zürich

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system is a characteristic structural feature of many eudesmane-type marine
furanosesquiterpenes, and thus a dearomatization process would appear to be ideal
for the synthesis of this class of natural products. We here report the total synthesis of
15-acetoxytubipofuran in both racemic and enantiomerically pure form, in which the
chromium-mediated dearomatization serves as the key transformation. A preliminary
report of part of this work has been published [8].
The furanosesquiterpenes tubipofuran (1) and 15-acetoxytubipofuran (2) were
isolated from Japanese stolonifer Tubipora musica Linnaeus in 1986 and were shown to
be eudesmane-type marine sesquiterpenoids having a cis-decalin ring with a
homoannular 1,3-diene unit [9]. The compounds show ichtiotoxicity toward killifish
(Orizias latipes), and 15-acetoxytubipofuran (2) shows cytotoxicity against B-16
melanoma cells in vitro (IC50 33 mg/ml). On the basis of the diene helicity rule, the
(4aS,8aR) absolute configuration was originally assigned to (‡)-1, but the work of
Pedro and co-workers, who converted santonin into tubipofuran, showed that this has
to be revised and that tubipofuran (‡)-1 has the (4aR,8aS) absolute configuration as
shown in structure 1 [10]. A synthesis of racemic tubipofurans was reported by
Kanematsu and co-workers in 1994 [11].
The salient features of our synthetic strategy are shown in Scheme 1. In terms of the
synthesis end game, it was envisioned that iodolactone 9, obtained by the iodolacto-
nization of acid 7 or amide 8, could be processed to deliver the target compound 2 by
straightforward functional-group manipulations. Compounds 7 and 8 were seen to be
accessible from allylic alcohol 6 via a Pd-catalyzed allylic substitution reaction or via a
Claisen rearrangement. Alcohol 6 can in turn be obtained from the bicyclic enone 5,
itself accessible from keto aldehyde 4 by an intramolecular aldol condensation. Hence,
at the outset of our investigation, the key issue that needed to be addressed was the
nucleophilic addition of an acetaldehyde unit (or equivalent) to the ortho position of
[Cr(benzaldehyde)(CO)3] (3) (or a derivative thereof) followed by a regioselective
and stereoselective acylation/alkylation at C(5) to give diene 4. Enantiomerically pure
2 was envisioned to be available by an enantioselective nucleophilic addition to
complex 3 (or a derivative thereof) in the presence of a chiral ligand or by a
diastereoselective nucleophilic addition in the presence of an arene-bound chiral
auxiliary, followed by a diastereoselective acylation/alkylation sequence. The notable
features of this synthetic plan are: a) the generation of three CÀC bonds and two
stereogenic centers in a configurationally defined fashion in a one-pot operation, and
b) a rapid construction of the cis-decalin ring system featuring a homoannular
cyclohexadiene unit as required in 5, in just two steps from an aromatic precursor. To
study the feasibility of the projected synthesis, a synthesis of racemic 2 was undertaken
first. Its success then encouraged us to carry out asymmetric syntheses of both
enantiomers.

Helvetica Chimica Acta ± Vol. 88 (2005)
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Scheme 1. Strategy for the Synthesis of 15-Acetoxytubipofuran (2)
Results and Discussion. ± As our synthetic plan required the addition of a
nucleophilic acetaldehyde unit or its equivalent to the benzaldehyde complex 3, we first
sought to investigate methods to achieve this transformation. We selected the
benzaldimine complex 10 [12], which had been used successfully as substrate in
previous dearomatization studies [1], and which had shown excellent ortho-selectivity
in both nucleophilic addition reactions [12] and in lithiation reactions [13]. For the
nucleophilic addition, [(1Z)-2-ethoxyethenyl]lithium was chosen as the nucleophilic
acetaldehyde equivalent [14]. Thus, ortho-addition of [(1Z)-2-ethoxyethenyl]lithium
to imine complex 10 followed by an acylation/alkylation sequence and imine hydrolysis
gave aldehyde 11 with the correct relative configuration. Enol ether hydrolysis and
intramolecular aldol condensation were performed in a one-pot reaction under acidic
conditions to afford enone 5 with the anticipated cis-decalin skeleton. This method thus
gave a very rapid access to 5 possessing the homoannular diene moiety in just two steps
from the aromatic precursor complex 10. Reduction of enone 5 under Luche conditions
[15] furnished diol 12 as a single diastereoisomer by hydride addition to the ketone
from the more accessible, convex face of the molecule. To enable a regioselective
transformation of the secondary allylic alcohol, the primary hydroxy group in 12 was
protected by treatment with Et3N/DMAP/tBuMe2SiCl in DMF at 08 to give the silyloxy
derivative 13a or with NaH/4-MeO-C6H4CH2I in DMF at À 508 to give the
methoxybenzyloxy derivative 13b in good yield (Scheme 2).
Pd-Catalyzed Allylic Substitution. With allylic alcohols 13a,b in hand, we began to
explore efficient means of introducing a C3 side chain required for the projected
iodolactonization. Among the more-attractive options was a sequence involving a Pd-
catalyzed allylic substitution reaction of the allylic acetate 14 or carbonate 15 with
dimethyl methylmalonate anion (Scheme 3).
The acetate 14a and carbonates 15a and 15b were obtained by treatment of 13a,b
with Ac2O/pyridine or methyl carbonochloridate/pyridine/DMAP, respectively. Initial
reactions were carried out with the products 14a and 15a containing the silyl protecting
group. Subsequently we switched to the methoxybenzyl-protected alcohol 15b because

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Scheme 2. Synthesis of the cis-Fused Bicyclic Intermediate 13.
a) 1) (1Z)-1-Bromo-2-ethoxyethene, tBuLi, À 788, Et2O/THF; 2) MeI, hexamethylphosphoric triamide
(HMPA), CO, À 788 to r.t., 3) 2m NaOEt, MeI, À 788 to r.t., 66%. b) 2m HCl, THF, reflux; 89%. c) CeCl3 ´
7 H2O, NaBH4, MeOH, 08; 98%. d) Et3N, N,N-dimethylpyridin-4-amine (DMAP), tBuMe2SiCl, DMF, 08; 94%.
e) NaH, DMF, À 608, then 4-MeOC6H4CH2I, À 508; 88%.
Scheme 3. Diastereoselectivities in the Pd-Catalyzed Allylic Alkylation
a) Ac2O, pyridine, DMAP, CH2Cl2, 08; 91 %. b) ClCO2Me, pyridine, DMAP, CH2Cl2, 08; 95%.
of the higher stability of this protecting group under conditions of hydrolysis of diester
16. The Pd-catalyzed allylic substitution reaction was studied in detail with different Pd0
catalysts and the anion of dimethyl methylmalonate (18) as the nucleophile (Table).
When the reaction was carried out with acetate 14a and [Pd(PPh3)4] as catalyst, a 7:3
mixture of diastereoisomers 16a and 17a was obtained favoring the normal allylic

Helvetica Chimica Acta ± Vol. 88 (2005)
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substitution product 16a (Entry 1). This low diastereoselectivity was also found when
the reaction was carried out with carbonates 15a and 15b where the reaction
temperature could be lowered to room temperature (Entries 2 and 3). The reaction of
15b was also performed in the absence of external base with [Pd(PPh3)4] as the catalyst;
the reaction was slower in this case but heating to 608 solved this problem. Remarkably,
diastereoselectivity was reversed under these conditions affording 16b and 17b in a
15 :85 ratio (Entry 4). Reflecting on the origin of this change of selectivity (see below),
we switched to [Pd(dppe)2] as catalyst (dppe ˆ ethane-1,2-diylbis[diphenylphos-
phine]), and this afforded the normal substitution product with high diastereoselec-
tivity both in the presence and absence of an added external base (Entries 5 and 6). The
catalyst incorporating the bidentate ligand dppe thus largely suppressed the formation
of 17b in this substitution reaction.
Table. Diastereoselectivities in the Pd-Catalyzed Allylic Alkylation.
Entry
R2
T [8]
Base
Pd0
16/17a)
Yield [%]
1
2
3
4
5
6
Ac (14a)
60
25
25
60
25
50
NaH
NaH
NaH
none
NaH
none
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(dppe)2]
[Pd(dppe)2]
70 : 30b)
84
91
67
61
99
75
CO2Me (15a)
CO2Me (15b)
CO2Me (15b)
CO2Me (15b)
CO2Me (15b)
70 : 30c)
75 : 25c)
15 : 85d)
> 98 : > 2e)
92 : 8f)
a) Entries 1 and 2: products 16a/17a; Entries 3 ± 6: products 16b/17b; the reactions were carried out under the
conditions given in a) ± f); NMP ˆ 1-methylpyrrolidin-2-one, dppe ˆ ethane-1,2-diylbis[diphenylphosphine].
b) 14a (1.0 equiv.), [Pd(PPh3)4] (0.1 equiv.), NaH (3.0 equiv.), 18 (3.0 equiv.) in NMP; products 16a/17a. c) 15a
or 15b (1.0 equiv.), [Pd(PPh3)4] (0.1 equiv.), NaH (4.0 equiv.), 18 (4.0 equiv.) in NMP. d) 15b (1.0 equiv.),
[Pd(PPh3)4] (0.1 equiv.), 18 (3.0 equiv.) in NMP; products 16b/17b. e) 15b (1.0 equiv.), [Pd(dppe)2]
(0.1 equiv.), NaH (3.0 equiv.), 18 (3.0 equiv.) in NMP; product 16b. f) 15b (1.0 equiv.), [Pd(dppe)2]
(0.1 equiv.), 18 (3.0 equiv.) in NMP; products 16b/17b.
Oxidative addition of phosphinepalladium(0) complexes to allylic substrates to give
p-allyl complexes has been established to proceed with inversion of configuration after
prior coordination of the metal to the CˆC bond [16]. It has also been shown that this is
a reversible reaction for allyl acetates and even for allyl carbonates [17]. Subsequent
nucleophilic attack of stabilized carbanions on the (p-allyl)palladium complex occurs
on the face opposite to the metal and leads to the product with overall retention of
configuration. Erosion of stereospecificity in this reaction (usually < 10% when the
nucleophile is a carbanion) has been attributed to several competing reaction pathways
[18]. With cyclic substrates, an important pathway is the Pd0-catalyzed isomerization of
the intermediate p-allyl complex by a mechanism involving nucleophilic trans attack by
the [Pd0(phosphine)] complex fragment (Fig.) [17 ± 20]1).
In the examples studied, with both 14 and 15, the normal Pd-catalyzed substitution
by the anion of 18 (overall retention) giving 16 is the major pathway when the reaction
is performed in the presence of an external base (Table, Entries 1 ± 3) though lower
diastereoselectivities are found than those usually observed. This is readily attributed
to the requirement that the carbanion must approach from the concave side of the
1
)
First suggested in [19].

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Figure. Pd-Catalyzed isomerization of [Pd(p-allyl)] intermediates and model of the initially formed [Pd(allyl)]
complex from the reaction of 14 or 15 with a Pd0 complex. Phosphine ligands and H-atoms are omitted for
clarity.
molecule (Fig.). In the absence of an external base, the C-nucleophile concentration in
the reaction mixture is low. Under these conditions, the rate of Pd0-catalyzed
isomerization competes successfully with that of carbanion attack. After isomerization,
carbanion attack proceeds rapidly from the convex face of the molecule to give 17 as
the major product (Entry 4). The much higher selectivity observed with [Pd(dppe)2]
(Entries 5 and 6) is best explained by the much poorer leaving-group properties of the
[Pd(dppe)] fragment compared to [Pd(PPh3)2] as documented elegantly in [20 ± 22].
Eschenmoser± Claisen Rearrangement and Iodolactonization. In parallel to the Pd-
catalyzed substitution reaction, another attractive option for introducing the C3-side
chain involves a Claisen rearrangement. No product could be isolated under conditions
of the Johnson ± Claisen rearrangement applied to 13, presumably due to the sensitivity
of the substrate to mild acidic conditions at elevated temperature (mercuric salts or
propanoic acid). We therefore turned to the less explored Eschenmoser ± Claisen
rearrangement [23]2). The advantage of the Eschenmoser± Claisen rearrangement in
our synthetic sequence is that unlike the Claisen and the Johnson ± Claisen rearrange-
ments, the product can directly participate in the next step, the iodolactonization
reaction. In the event, heating a mixture of 13b and an excess of orthoamide 19 [24] in
xylene in a sealed tube furnished amide 20 as a 1:1 mixture of diastereoisomers in
nearly quantitative yield (Scheme 4). Iodolactonization of 20 with I2 in THF/H2O 2 :1
was straightforward, giving iodolactone 21 as a 1:1 mixture of diastereoisomers.
Iodolactone 21 was found to be identical to that obtained by the iodolactonization of
acid 22, in turn obtained by the hydrolysis and decarboxylation of diester 16b with
NaOH/DMSO. The Eschenmoser ± Claisen rearrangement offers a distinct advantage
over the Pd-catalyzed allylic substitution in that 21 can be obtained in fewer steps from
allylic alcohol 13b.
With a viable method for the introduction of the C3 side chain in hand, the synthesis
was carried on from iodolactone 21. The next focus in the synthetic sequence was the
conversion of the lactone unit in 21 to the corresponding furan. This conversion was
2
)
For some synthetic applications, see [23b,c].

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Scheme 4. Eschenmoser± Claisen Rearrangement and Iodolactonization
a) 19, xylene, 1508; 98%. b) I2, THF/H2O 2 :1; 73%. c) 6m NaOH, DMSO, 1308; 93%. d) I2, NaHCO3, H2O,
CH2Cl2; 94%.
expected to be straightforward from the corresponding butano-4-lactone, taking
advantage of the well-known aptitude of diisobutylaluminium hydride (DIBAL) to
reduce butano-4-lactones [25]. Toward this end, iodide 21 was reduced under radical
conditions with tributylstannane to afford lactone 23 in very good yield (Scheme 5).
Treatment of lactone 23 with LDA/PhSeCl followed by oxidation and selenoxide
Scheme 5
a) Bu3SnH, 2,2'-azobis[2-methylpropanenitrile] (AIBN), toluene; 91%. b) lithium diisopropylamide (LDA),
PhSeCl, THF, then H2O2, pyridine, CH2Cl2; 66%. c) 4,5-dichloro-3,6-dioxocyclohexadiene-1,2-dicarbonitrile
(DDQ), CH2Cl2/H2O 20 :1; 80%.

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elimination furnished a mixture of unsaturated lactones 24 and 25 in a 3 :2 ratio in a
respectable 66% overall yield. Although the projected DIBAL reaction can be
performed at this stage of the synthesis, this step was delayed until after the
deprotection of the methoxybenzyl group because of the known sensitivity of furan to
oxidative methoxybenzyl-deprotection conditions [26]. Consequently, the methoxy-
benzyl group in 24 and 25 was deprotected with DDQ in wet CH2Cl2 [27] to furnish a
mixture of alcohols 26 and 27 in a 3 :2 ratio.
The stage was now set for the crucial DIBAL-mediated conversion of lactone 26
into furan. Although 26 and 27 were not separable, it was reasoned that 27 would also
give the corresponding furan by the DIBAL-mediated reduction followed by CˆC
bond migration and dehydration. After some experimentation, the best result was
obtained by treating the mixture 26/27 with 6 equiv. of DIBAL in toluene at À 408
followed by workup with AcOH [28]. Under these conditions, furan 28 was obtained in
73% yield (Scheme 6). Finally, acetylation of the OH group with Ac2O and pyridine in
the presence of catalytic amounts of DMAP in CH2Cl2 gave 2 in high yield. Compound
2 exhibited spectral data fully consistent with those of the literature [9].
Scheme 6
a) DIBAL, toluene, À 408, then AcOH, À 408 to r.t.; 73%. b) Ac2O, pyridine, DMAP, CH2Cl2, 08; 93%.
Asymmetric Syntheses of Both Enantiomers of 2. With a viable synthetic sequence
for the target molecule in hand, we began to explore methods for the asymmetric
addition of [(1Z)-2-ethoxyethenyl]lithium to the imine complex 10. We first chose an
enantioselective nucleophilic addition in the presence of diether (S,S)-29. In our
previous study, this chiral ligand had been found to give high asymmetric induction
(> 90% ee) in nucleophilic additions of organolithium reagents to 10 in toluene [5].
However, nucleophilic addition of [(1Z)-2-ethoxyethenyl]lithium to 10 in the presence
of 29 in a mixture of Et2O and toluene gave (5R,6S)-11 in modest 42% yield and 76%
ee (Scheme 7). The need for Et2O as solvent in the generation of the organolithium
reagent by metal/bromide exchange and the low thermal stability of the nucleophile are
at the origin of the erosion of both enantioselectivity and yield. Fortunately,
recrystallization of (4aR,8aS)-5, obtained by a one-pot hydrolysis and aldol condensa-
tion, furnished a enantiomerically highly enriched product (> 99% ee). The sense of
asymmetric induction observed in this reaction is rationalized on the basis of transition-
state models for the nucleophilic addition. Of the two transition-state models I and II
corresponding to the addition of the nucleophile to the two enantiotopic ortho
positions, the preference for addition to the ortho rather than the ortho' position is
based on steric congestion between the Ph group of the chiral ligand and the [Cr(CO)3]
group in transition state II.

Helvetica Chimica Acta ± Vol. 88 (2005)
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Scheme 7
t
a) 1) (1Z)-1-Bromo-2-ethoxyethene, BuLi, À 788, 29, Et2O/toluene, À 788 to À 508; 2) MeI, HMPA, CO,
À 788 to r.t.; 3) 2m NaOEt, MeI, À 788 to r.t., 42% (one-pot). b) 2m HCl, THF, reflux, 89%.
Keto aldehyde (4aR,8aS)-5 was converted into (À)-(R,R)-2 by employing the same
sequence of reactions as described for the synthesis of rac-2, with the Pd-catalyzed
allylic substitution reaction as key step. Compound (R,R)-2 showed an [a]2D0 value of
À 120 (c ˆ 0.653, CHCl3), while the natural product was previously assigned the (R,R)-
configuration, and its [a]2D0 value was reported as ‡ 10.7 (c ˆ 0.5, CHCl3). The CD
spectrum of the synthetic sample showed a negative Cotton effect at lmax 274 (De À 3),
opposite to that reported (lmax 270 (De ‡ 3)) [9]. As mentioned before, the conversion
of santonin into (‡)-tubipofuran required a reassignment of the absolute configuration
in the natural product [10]. Moreover, the observed [a]2D0 value (‡ 33) of tubipofuran
was much larger than that reported earlier for the natural product (‡ 5.6), suggesting
that the natural product isolated may not have been optically pure. Our synthetic study
shows that a parallel situation exists for 15-acetoxytubipofuran and that the absolute
configuration assigned initially needs to be revised.
Although the synthesis of (À)-(R,R)-2 yielded the enantiomerically enriched form
by an enantioselective nucleophilic addition, the moderate induction observed in this
reaction offset the intrinsic advantage of this process over a chiral-auxiliary-mediated
diastereoselective addition. In an effort to improve the asymmetric induction in the
nucleophilic addition and being mindful of the need to synthesize the natural (‡)-(S,S)-
2 for comparison, we investigated a chiral-auxiliary-mediated diastereoselective
nucleophilic addition. We employed the valinol-derived benzaldimine complex 30 as
starting material for the nucleophilic addition3). Complex 30 was prepared by
condensation of benzaldehyde complex 3 with d-valinol followed by in situ methylation
3
)
For some previous examples on the use of valinol-derived chiral auxiliaries in asymmetric synthesis, see
[29].

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with NaH/MeI (Scheme 8). Diastereoselective nucleophilic addition followed by
acylation/alkylation and imine hydrolysis yielded (À)-(5S,6R)-11. Fortunately, both the
yield and the enantiomer purity of the product were superior to those obtained by the
enantioselective nucleophilic addition described before. In terms of diastereoselection,
this result represents a significant improvement over the previously reported
diastereoselective addition to arenes bearing chiral imine auxiliaries [3]. A one-pot
hydrolysis and aldol condensation of (5S,6R)-11 furnished keto aldehyde (4aS,8aR)-5.
A single recrystallization afforded enantiomerically highly enriched (‡)-5 (> 99% ee).
From here on, the synthesis followed the same route as described for the synthesis of
(À)-(R,R)-2, except that the four-step sequence involving formation of carbonate, Pd-
catalyzed allylic substitution reaction, hydrolysis/decarboxylation, and lactonization
was now replaced by the more efficient two-step Eschenmoser ± Claisen rearrangement
and lactonization sequence. (‡)-(S,S)-2 showed an [a]2D0 value of ‡ 100.3 (c ˆ 0.29,
CHCl3).
Scheme 8. Highly Diastereoselective Nucleophile Addition/Acylation/Alkylation of 30
a) 1) d-Valinol, Et2O, r.t., 2) NaH, MeI, THF, r.t., 73% (one-pot). b) 1) (1Z)-1-Bromo-2-ethoxyethene, tBuLi,
À 788; 2) MeI, HMPA, CO, À 788 to r.t.; 3) 2m NaOEt, MeI, À 788 to r.t.; 53% (one-pot). c) 2n HCl, THF, 808;
89%.
Conclusions. ± Through the total synthesis of 15-acetoxytubipofuran (2), we
illustrated the synthetic utility and demonstrated several new features of the
chromium-mediated dearomatization process involving a nucleophilic acetaldehyde
equivalent. The synthetic study presented here demonstrates the use of a chiral ligand
or an arene-bound chiral auxiliary to efficiently control the absolute, respectively, the
relative configuration in nucleophilic addition reactions. The highly asymmetric

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induction in the nucleophilic addition to valinol-derived imine complex 30 is a
significant advancement of the auxiliary-directed asymmetric dearomatization. The
stereochemical issues associated with the diastereoselective Pd-catalyzed allylic
substitution reaction with different Pd-catalysts were studied in some detail. The
asymmetric synthesis of 15-acetoxytubipofurans (À)-(R,R)-2 and (‡)-(S,S,)-2 detailed
in this article suggests that the absolute configuration assigned for the natural product
needs to be revised. The synthetic protocols described in this work are useful for the
transformation of simple aromatics into enantiomerically highly enriched alicyclic
compounds with functionality suitable for their use as building blocks for natural-
product synthesis. This is clearly demonstrated by the synthesis of both enantiomers of
15-acetoxytubipofuran.
We thank the Swiss National Science Foundation and Novartis for financial support of this work.
Experimental Part
General. Cr(CO)6 was from Strem Chemicals. Et2O and THF were distilled from Na/benzophenone ketyl
under N2, and toluene was distilled over Na under N2. BuLi (Fluka; 1.7m) was titrated before use [30]. d-Valinol
was prepared by a literature method [31]. [Cr(h6-benzaldehyde)(CO)3] (3) [12][32] and [Cr{(h6-benzylidene)-
cyclohexylamine}(CO)3] (10) [12] were prepared as previously reported. All other chemicals were purchased
from Aldrich or Fluka and were purified following standard literature procedures. Reactions and manipulations
involving organometallics were carried out under purified N2 by using an inert gas/vacuum double manifold and
standard Schlenk techniques [33]. Flash chromatography (FC) was carried out as described by Still (Merck-60
silica gel) [34]. GC: Hewlett-Packard 6890 gas chromatograph with FID detection; Permabond OV-1701-0.25
column (25 m  0.32 mm i.d.) or chiral MN-FS-Lipodex-E column (25 m  0.25 mm i.d.); tR in min. HPLC:
Jasco PU-980 chromatograph with a Jasco UV-975 detector; Chiralcel OD, Chiralcel OD-H, or Chiralcel OJ
columns tR in min. (Daicel Chemical Industries Ltd.; 25 cm  0.46 cm); M.p.: Büchi 510 apparatus; not
corrected. Optical rotation: Perkin-Elmer 241, quartz cell (l ˆ 10 cm), high-pressure lamps of sodium (l 589 nm)
and mercury (l 578 nm). IR: Perkin-Elmer 1650-FT-IR; nÄ in cmÀ1 1H-and 13C-NMR: Varian XL-200 and
.
Bruker 400 spectrometer; d in ppm, J in Hz. HR-MS: VG7070E spectrometer (data system 11 250, resoln. 7000);
in m/z (rel. int. in % of the base peak). Elemental analyses: H. Eder, Service de Microchimie, Section des
Â
Á
Sciences Pharmaceutiques, Universite de Geneve.
(5RS,6SR)-5-Acetyl-6-(2-ethoxyethenyl)-5-methylcyclohexa-1,3-diene-1-1carboxaldehyde (11). To a soln. of
(1Z)-1-bromo-2-ethoxyethene (5.3 ml, 50 mmol) and 3-(tert-butyl)-4-hydroxy-5-methylphenyl sulfide (ˆ4,4'-
thiobis[2-(tert-butyl)-6-methylphenol]; 20 mg) in Et2O (50 ml) in a 500-ml pressure-resistant flask at À 788, 1.7m
tBuLi in pentane (58.8 ml, 100 mmol) was added dropwise via cannula. After stirring at À 788 for 1 h, a cold
(À 788) soln. of complex 10 (8.0 g, 25 mmol) in THF (125 ml) was transferred via cannula. After stirring for 4 h
at À 788, MeI (15.5 ml, 250 mmol) and hexamethylphosphoric triamide (HMPA; 44.6 ml, 100 mmol) were
added, and 4 bar CO was pressed onto the mixture. The mixture was warmed slowly to r.t. and stirred overnight.
Excess CO was vented, and volatiles were evaporated. The residue was dissolved in THF (400 ml), and 2m
NaOEt in EtOH (18.7 ml, 37.5 mmol) was added at À 788. After stirring for 15 min, MeI (15.5 ml, 250 mmol)
was added, and the soln. was slowly warmed to r.t. over 2 h and stirred for an additional hour. Volatiles were
evaporated, and the residue was dissolved in Et2O and filtered through a short layer of silica gel. Purification by
FC (silica gel, pentane/Et2O 3 :1 ! 2 :1) afforded 11 (3.840 g, 66%). Yellow oil. IR (CHCl3): 1701, 1673, 1206.
1H-NMR (400 MHz, CDCl3): 1.19 (s, MeÀC(5)); 1.25 (t, J ˆ 7.0, MeCH2O); 2.19 (s, MeCO); 3.77 ± 3.87
(m, HÀC(6), CHˆCHOEt); 4.09 ± 4.18 (m, MeCH2O); 5.81 (d, J ˆ 5.7, HÀC(4)); 6.18 (dd, J ˆ 9.7, 5.3,
HÀC(3)); 6.67 ± 6.70 (m, HÀC(2), CHˆCHOEt); 9.52 (s, CHO). 13C-NMR (100 MHz, CDCl3): 15.3; 21.4;
‡
25.1; 33.5; 53.5; 68.1; 101.0; 121.8; 138.4; 139.1; 140.4; 146.4; 191.8; 209.8. MS (70 eV): 234 (27, M ), 205 (9), 145
‡
(90), 117 (100), 115 (44), 105 (40), 91 (73), 77 (35). HR-MS: 234.1258 (C14H18O3 ; calc. 234.1256).
(5R,6S)-5-Acetyl-6-(2-ethoxyethenyl)-5-methylcyclohexa-1,3-diene-1-carboxaldehyde ((5R,6S)-11). In a
t
pressure-resistant Schlenk tube, 1.5m BuLi in pentane (2.0 ml, 3.0 mmol) was added dropwise at À 788 to a
soln. of (1Z)-1-bromo-2-ethoxyethene (0.150 ml, 1.5 mmol) and 3-(tert-butyl)-4-hydroxy-5-methylphenyl
sulfide (2 mg) in Et2O (3 ml). After stirring for 1 h, a cold (À 788) soln. of complex 10 (323 mg, 1.0 mmol)

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Helvetica Chimica Acta ± Vol. 88 (2005)
and (S,S)-29 (484 mg, 2.0 mmol) in Et2O (5 ml) and toluene (2 ml) was transferred via cannula. The soln. was
stirred at À 508 for 20 h. After recooling to À 788, MeI (0.62 ml, 10.0 mmol) and HMPA (1.75 ml, 10.0 mmol)
were added. The rubber septum was replaced with an adaptor fitted with a small pressure gauge. After a freeze/
pump/thaw cycle, 2.5 bar CO was pressed onto the mixture. The mixture was warmed slowly to r.t. and stirred for
22 h. Excess CO was vented and volatiles were evaporated. The residue was dissolved in THF (10 ml), and 2m
NaOEt in EtOH (0.75 ml, 1.5 mmol) was added at À 788, followed, after stirring for 15 min, by MeI (0.62 ml,
10.0 mmol). The soln. was slowly warmed to r.t. over 2 h and stirred for an additional 3 h. Volatiles were
evaporated, the residue was dissolved in Et2O and filtered through a short layer of silica gel. Purification by FC
afforded (5R,6S)-11 (97 mg, 42%). Yellow oil. GC (Lipodex E, 1308, H2, 50 kPa): tR 32.6 ((5S,6R)-11, minor)
and 33.8 ((5R,6S)-11, major); ee 76%.
[(2R)-N-(h6-Benzylidene)-1-methoxy-3-methylbutan-2-amine]tricarbonylchromium (30). To a soln. of d-
valinol (8.57 g, 0.102 mol) in dry Et2O (180 ml) was added [Cr(benzaldehyde)(CO)3] (3; 16.8 g, 69.0 mmol) at
r.t. The mixture was stirred for 18 h and then evaporated. The residue was dissolved in dry THF (120 ml), and
55 ± 65% NaH dispersion in oil (3.32 g) was added in small portions at r.t. After stirring for 2 h, MeI (5.17 ml,
83.1 mmol) was added, and stirring was continued overnight. The solvent was evaporated, and the residue was
taken up in hexane and filtered through Celite under N2. Recrystallization from hexane furnished 30 (19.10 g,
80%). Orange crystals. M.p. 56 ± 598. [a]2D0 ˆ À157.6 (c ˆ 1.5, CHCl3). IR (CHCl3): 2964, 1976, 1645, 1602.
1H-NMR (200 MHz, CDCl3): 0.93 (d, J ˆ 6.7, 3 H, Me2CH); 1.03 (d, J ˆ 6.7, 3 H, Me2CH); 1.80 ± 1.98
(m, Me2CH); 3.00 ± 3.12 (m, HÀC(2)); 3.12 (s, MeO); 3.32 ± 3.48 (m, 2 HÀC(1)); 4.30 ± 4.4 (m, 3 arom. H);
5.17 (d, J ˆ 6.2, 1 arom. H); 5.42 (d, J ˆ 5.8, 1 arom. H); 7.40 (s, HÀCˆN). 13C-NMR (50 MHz, CDCl3): 18.9;
‡
20.4; 31.2; 59.1; 75.0; 76.3; 91.1; 91.3; 93.3; 93.8; 94.1; 101.2; 157.6; 233.0. MS (70 eV): 341 (1, M ), 285 (18), 257
‡
(91), 210 (11), 155 (100), 130 (15), 52 (80). HR-MS: 341.0721 (C16H19CrNO4 ; calc. 341.0719). Anal. calc. for
C16H19CrNO4: C 56.16, H 5.82, N 4.08; found: C 56.14, H 5.89, N 4.09.
(5S,6R)-5-Acetyl-6-(2-ethoxyethenyl)-5-methylcyclohexa-1,3-diene-1-carboxaldehyde ((5S,6R)-11). As de-
scribed for 11, with (1Z)-1-bromo-2-ethoxyethene (2.1 ml, 20 mmol), 3-(tert-butyl)-4-hydroxy-5-methylphenyl
t
sulfide (20 mg), Et2O (20 ml), and 1.7m BuLi in pentane (23.5 ml, 40 mmol); then with 30 (3.4 g, 10 mmol;
instead of 10) in THF (50 ml), MeI (6.23 ml, 100 mmol), HMPA (17.2 ml, 100 mmol), and 4 bar CO; then with
THF (150 ml), 2m NaOEt in EtOH (7.5 ml, 15 mmol), and MeI (6.2 ml, 250 mmol). FC (pentane/Et2O 3 :1,
2 :1) afforded (5S,6R)-11 (1.230 g, 53%). Yellow oil. GC (Lipodex E, 1308, H2, 50 kPa): tR 32.6 ((5S,6R)-11,
major) and 33.8 ((5R,6S)-11, minor); ee 95%. [a]2D0 ˆ À401.9 (c ˆ 1.05, CHCl3).
(4aS,8aR)-4a,5,8,8a-Tetrahydro-4a-methyl-5-oxonaphthalene-1-carboxaldehyde ((4aS,8aR)-5). To a soln. of
(5S,6R)-11 (2.720 g, 11.7 mmol) in THF (50 ml) was added 2m aq. HCl (50 ml), and the resulting mixture was
refluxed at 808 overnight. After cooling to r.t., the product was extracted with Et2O. The Et2O layer was dried
and evaporated and the residue purified by FC (silica gel, pentane/Et2O 2 :1, 1:1): (4aS,8aR)-5 (2.23 g, 89%).
Crystalline solid. GC (Lipodex E, 1308, H2, 50 kPa): tR 30.7 ((4aS,8aR)-5, major) and 33.8 ((4aR,8aS)-5, minor);
ee 99%. M.p. 89 ± 908 (hexane). [a]2D0 ˆ ‡685.9 (c ˆ 0.39, CHCl3). IR (CHCl3): 3019, 2821, 1669, 1560, 1216.
1H-NMR (CDCl3, 400 MHz): 1.22 (s, MeÀC(4a)); 2.19 (ddd, J ˆ 2.5, 11.3, 17.6, 1 HÀC(8)); 2.39 (ddd, J ˆ 5.8,
5.9, 17.3, 1 HÀC(8)); 3.30 (dd, J ˆ 11.3, 4.7, HÀC(8a)); 6.05 (d, J ˆ 9.3, HÀC(2)); 6.17 (dd, J ˆ 2.5, 10.1,
HÀC(6)); 6.39 (dd, J ˆ 9.3, 5.3, HÀC(3)); 6.87 (d, J ˆ 5.3, HÀC(4)); 7.12 (ddd, J ˆ 2.5, 6.2, 10.2, HÀC(7)); 9.62
(s, CHO). 13C-NMR (100 MHz, CDCl3): 20.9; 26.8; 35.9; 47.4; 123.7; 129.8; 139.4; 139.6; 140.3; 151.6; 192.0;
‡
‡
198.9. MS: 188 (0.2, M ), 160 (0.5), 145 (0.5), 119 (4), 91 (8), 68 (100), 65 (5). HR-MS: 188.0844 (C12H12O2
;
calc. 188.0837). Anal. calc. for C12H12O2 (188.08): C 76.57, H 6.43; found: C 76.57, H 6.47.
(1R,4aR,8aS)-1,4,4a,8a-Tetrahydro-5-(hydroxymethyl)-8a-methylnaphthalen-1-ol ((1R,4aR,8aS)-12). To a
soln. of (4aS,8aR)-5 (1.510 g, 8.0 mmol) and CeCl3 ´ 7 H2O (8.970 g, 24.0 mmol) in MeOH (140 ml), NaBH4
(0.900 g, 24.0 mmol) was added in portions at 08. After stirring for 1.5 h, H2O was added, the mixture extracted
with AcOEt, the org. phase evaporated, and the residue purified by FC (pentane/Et2O 1:2): (1R,4aR,8aS)-12
(1.49 g, 98%). White solid. M.p. 94 ± 968 (AcOEt). [a]2D0 ˆ À57.9 (c ˆ 0.33, CHCl3). IR (CHCl3): 3608, 3445,
1601, 1236. 1H-NMR (400 MHz, CDCl3): 1.14 (s, MeÀC(8a)); 1.88 ± 1.92 (m, HÀC(4a)); 2.15 ± 2.24
(m, 2 HÀC(4)); 4.09 ± 4.12 (m, HÀC(1)); 4.16 (d, J ˆ 4.3, CH2ÀC(5)); 5.52 ± 5.58 (m, J ˆ 10.1, HÀC(6));
5.79 ± 5.98 (m, HÀC(2), HÀC(3), HÀC(7), HÀC(8)). 13C-NMR (100 MHz, CDCl3): 22.2; 29.1; 39.2; 39.3;
‡
65.4; 73.3; 117.7; 123.7; 129.6; 130.8; 131.7; 141.5. MS: 192 (0.5, M ), 174 (7), 159 (2), 143 (4), 128 (5), 122 (4),
‡
107 (13), 105 (100), 91 (13), 77 (13), 70 (83). HR-MS: 192.1197 (C12H16O2 ; calc. 192.1150).
(4aR,8aS)-5 afforded (1S,4aS,8aR)-12: [a]2D0 ˆ ‡65.0 (c ˆ 0.09, CHCl3).
(1RS,4aRS,8aSR)-5-{{[(tert-Butyl)dimethylsilyl]oxy}methyl}-1,4,4a,8a-tetrahydro-8a-methylnaphthalen-1-
ol (13a). Et3N (785 ml, 5.63 mmol) was added to a stirred soln. (08) of 12 (0.900 g, 4.69 mmol) and DMAP
(0.115 g, 0.94 mmol) in DMF (10 ml). After 10 min at 08, (tert-butyl)chlorodimethylsilane (0.777 g, 5.16 mmol)

Helvetica Chimica Acta ± Vol. 88 (2005)
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was added. The mixture was warmed to r.t., stirred for 1.5 h, diluted with Et2O, and treated with a sat. NaHCO3
soln. The org. phase was washed with H2O and brine, dried (MgSO4), and evaporated, and the crude product
purified by FC (hexane/Et2O 1:1): 13a (1.35 g, 94%). Oil. IR (CHCl3). 3619, 2953, 2856, 1463, 1360, 1252, 1158,
1126, 1067, 1022, 930, 842. 1H-NMR (200 MHz, CDCl3): 0.08 (s, Me2Si); 0.91 (s, tBuSi); 1.12 (s, MeÀC(8a)); 1.67
(br. d, OH); 1.72 ± 1.95 (m, HÀC(4a)); 2.02 ± 2.12 (m, 2 HÀC(4)); 4.05 ± 4.09 (m, HÀC(1)); 4.10 ± 4.18
(m, CH2ÀC(5)); 5.52 ± 5.65 (m, HÀC(6)); 5.73 ± 6.00 (m, HÀC(2), HÀC(3), HÀC(7), HÀC(8)). 13C-NMR
(50 MHz, CDCl3): À 5.4; 18.5; 22.3; 25.9; 29.2; 39.1; 39.4; 65.4; 73.6; 116.2; 124.0; 129.5; 129.8; 131.9; 141.9. MS:
263 (8), 247 (17), 179 (59), 149 (31), 105 (100), 75 (94).
(1R,4aR,8aS)-1,4,4a,8a-Tetrahydro-5-{[(4-methoxybenzyl)oxy]methyl}-8a-methylnaphthalen-1-ol
((1R,4aR,8aS)-13b). A cold (À608) soln. of (1R,4aR,8aS)-12 (0.214 g, 1.1 mmol) in DMF (11 ml) was added to
NaH (38 mg, 1.44 mmol) at À 608. After stirring for 15 min, 4-methoxybenzyl iodide (0.36 g, 1.44 mmol) was
introduced in one portion, and the mixture was stirred for 3 h at À 508. After completion of the reaction (TLC
monitoring), H2O was added, and the product was extracted with Et2O. Evaporation followed by FC (silica gel,
pentane/Et2O 1:2) furnished (1R,4aR,8aS)-13 (0.310 g, 88%). Colorless oil. [a]2D0 ˆ À4.0 (c ˆ 0.9, CHCl3). IR
(CHCl3): 3444, 1610, 1248. 1H-NMR (CDCl3, 400 MHz): 1.17 (s, MeÀC(8a)); 1.87 ± 1.92 (m, 1 HÀC(4)); 2.16 ±
2.28 (m, HÀC(4a), 1 HÀC(4)); 3.82 (s, MeO); 3.95 (d, J ˆ 12.9, 1 H, CH2ÀC(5)); 4.08 (d, J ˆ 12.9, 1 H,
CH2ÀC(5)): 4.10 ± 4.12 (m, HÀC(1)); 4.42 (d, J ˆ 11.4, 1 H, ArCH2); 4.50 (d, J ˆ 11.4, 1 H, ArCH2); 5.60
(dd, J ˆ 10.2, 1.3, HÀC(2)); 5.83 ± 5.98 (m, HÀC(3), HÀC(6), HÀC(7), HÀC(8)); 6.90 (d, J ˆ 8.8, 2 arom. H);
7.29 (d, J ˆ 8.8, 2 arom. H). 13C-NMR (100 MHz, CDCl3): 22.6; 29.0; 39.4; 39.5; 55.2; 71.5; 72.2; 73.3; 113.7;
‡
119.5; 123.7; 129.2; 129.5; 130.4; 130.9; 131.8; 139.2; 159.1. MS: 242 (2, [M À CH2CHˆCHCHOH] ), 190 (1),
‡
137 (26), 122 (17) 121 (100), 106 (48), 70 (16). HR-MS: 242.1302 (C16H18O2 ; calc. 242.1307).
Acetic Acid 5-{{[(tert-Butyl)dimethylsilyl]oxy}methyl}-1,4,4a,8a-tetrahydro-8a-methylnaphthalen-1-yl Ester
(14a). Ac2O (310 ml, 3.27 mmol) was added dropwise to a soln. of 13a (500 mg, 1.63 mmol), pyridine (0.265 ml,
3.27 mmol), and a catalytic amount of DMAP (40 mg) in CH2Cl2 (10 ml) at 08. The mixture was stirred for 2 h at
r.t., then diluted with CH2Cl2, and washed with 1n HCl, sat. aq. NaHCO3 soln., and brine. The org. phase was
dried (MgSO4), and evaporated, and the residue purified by FC (pentane/Et2O 4 :1): 14a (520 mg, 91%).
1
Colorless oil. IR (CHCl3): 2935, 2857, 1736, 1721, 1462, 1371, 1252, 1158, 1079, 1023, 839. H-NMR (200 MHz,
CDCl3): 0.07 (s, Me2Si); 0.91 (s, tBuSi); 1.06 (s, MeÀC(8a)); 1.85 ± 2.20 (m, HÀC(4a), 2 HÀC(4)); 2.13
(s, MeCO); 4.14 (br. s, CH2ÀC(5)); 5.24 ± 5.30 (m, HÀC(2)); 5.42 ± 5.65 (m, HÀC(8)); 5.65 ± 5.83
(m, HÀC(6)); 5.95 ± 6.00 (m, HÀC(3), HÀC(7)). 13C-NMR (100 MHz, CDCl3): À 5.5; 18.4; 21.1; 22.0; 25.8;
29.0; 38.2; 39.1; 65.2; 75.7; 116.0; 123.9; 126.1; 129.9; 132.9; 141.8; 171.0. MS: 291 (7), 235 (8), 179 (16), 105 (97),
70 (88).
Carbonic Acid 5-{{[(tert-butyl)dimethylsilyl]oxy}methyl}-1,4,4a,8a-tetrahydro-8a-methylnaphthalen-1-yl
Methyl Ester (15a). Methyl carbonochloridate (0.464 ml, 6.01 mmol) was added dropwise to a soln. of 13a
(1.15 g, 3.73 mmol), pyridine (1.09 ml, 13.5 mmol), and a catalytic amount of DMAP in CH2Cl2 (8 ml) at 08. The
mixture was stirred for 2.5 h, then diluted with CH2Cl2, and washed with 1n HCl, sat. aq. NaHCO3 soln. and
brine. The org. phase was dried (MgSO4), and evaporated, and the residue purified by FC (pentane/Et2O 9 :1):
15a (1.279 g, 94%). Colorless oil. IR (CHCl3): 3041, 3008, 2953, 2943, 2856, 1741, 1708, 1442, 1365, 1268, 1158,
1077, 984, 837. 1H-NMR (200 MHz, CDCl3): 0.00 (s, Me2Si), 0.84 (s, tBuSi); 1.00 (s, MeÀC(8a)); 1.76 ± 1.88
(m, HÀC(4a)); 2.04 ± 2.15 (m, 2 HÀC(4)); 3.74 (s, MeO)); 5.02 ± 5.08 (m, HÀC(1)); 5.45 ± 5.52 (m, HÀC(5));
5.66 ± 5.70 (m, HÀC(3)); 5.78 ± 5.90 (m, HÀC(2), HÀC(6), HÀC(7)). 13C-NMR (50 MHz, CDCl3,): À 4.1;
18.9; 22.5; 29.7; 39.0; 39.6; 55.3; 65.8; 80.7; 116.7; 124.1; 126.1; 130.1; 133.9; 142.1; 156.6. MS: 288 (14), 235 (5),
179 (100), 157 (28), 105 (50).
Carbonic Acid (1S,4aS,8aR)-1,4,4a,8a-Tetrahydro-5-{[(4-methoxybenzyl)oxy]methyl}-8a-methylnaphtha-
len-1-yl Methyl Ester ((1S,4aS,8aR)-15b). Methyl carbonochloridate (0.18 ml, 2.3 mmol) was added dropwise
to a soln. of (1S,4aS,8aR)-13b (451 mg, 1.44 mmol), pyridine (0.42 ml, 5.2 mmol), and a catalytic amount of
DMAP in CH2Cl2 (3 ml) at 08. The mixture was stirred for 15 h, then diluted with CH2Cl2, and washed with 1n
HCl, sat. aq. NaHCO3 soln., and brine. The org. phase was dried (MgSO4) and evaporated, and the residue
purified by FC (pentane/Et2O 4 :1): (1S,4aS,8aR)-15b (522 mg, 95%). Colorless oil. [a]2D0 ˆ ‡61 (c ˆ 0.11,
CHCl3). IR (CHCl3): 3015, 1741, 1664, 1612, 1274. 1H-NMR (400 MHz, CDCl3): 1.15 (s, MeÀC(8a)); 1.87 ± 1.96
(m, 1 HÀC(4)); 2.19 ± 2.36 (m, HÀC(4a), 1 HÀC(4)); 3.83 (s, COOMe); 3.84 (s, MeO); 3.97 (dd, J ˆ 1.3, 12.9,
1 H, CH2ÀC(5)); 4.08 (dd, J ˆ 1.3, 13.1, 1 H, CH2ÀC(5)); 4.43 (d, J ˆ 11.4, 1 H, ArCH2); 4.51 (d, J ˆ 11.6, 1 H,
ArCH2); 5.15 ± 5.18 (m, HÀC(1)); 5.57 ± 5.62 (m, HÀC(2)); 5.83 ± 603 (m, HÀC(3), HÀC(6), HÀC(7),
HÀC(8)); 6.90 (d, J ˆ 8.6, 2 arom. H); 7.29 (d, J ˆ 8.6, 2 arom. H). 13C-NMR (100 MHz, CDCl3): 22.2; 28.9;
38.6; 39.4; 54.7; 55.2; 71.6; 72.1; 80.0; 113.8; 119.3; 123.7; 125.5; 129.2; 130.3; 130.7; 133.3; 139.0; 156.0; 159.1.
‡
‡
MS: 370 (0.2, M ), 242 (7), 137 (34), 121 (100), 106 (52), 77 (7). HR-MS: 370.1738 (C22H26O5 ; calc. 370.1781).

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Helvetica Chimica Acta ± Vol. 88 (2005)
Pd-Catalyzed Allylic Substitution of 14a with [Pd(PPh3)4] as Catalyst. A mixture of acetate 14a (696 mg,
2.0 mmol) and [Pd(PPh3)4] (219 mg, 0.20 mmol) in NMP (8 ml) was stirred at 608 for 5 h in the presence of the
sodium salt of dimethyl methylmalonate (18) (prepared from 18 (0.800 ml 6.00 mmol) and NaH (0.159 g,
6.00 mmol) in NMP (10 ml)). H2O was added, the mixture extracted with Et2O, the org. phase washed with H2O
and brine, dried (MgSO4), and evaporated and the residue purified by FC (pentane/Et2O): inseparable mixture
16a/17a 7 :3 (0.729 g, 84%). Colorless oil.
Partial Data of 16a: 1H-NMR (400 MHz, CDCl3): 0.09 (s, 6 H); 0.93 (s, 9 H); 1.00 (s, 3 H); 1.31 (s, 3 H);
1.35 ± 1.45 (m, 2 H); 1.97 (dd, J ˆ 3.8, 10.9, 1 H); 2.94 ± 3.03 (m, 1 H); 3.71 (s, 3 H); 3.72 (s, 3 H); 4.06 ± 4.18
(m, 2 H); 5.32 (d, J ˆ 9.5, 1 H); 5.44 ± 5.48 (m, 1 H); 5.57 (dd, J ˆ 2.5, 11.1, 1 H); 5.74 (dd, J ˆ 5.3, 9.4, 1 H);
5.77 ± 5.81 (m, 1 H). 13C-NMR (CDCl3, 100 MHz): À 5.5; 16.0; 18.4; 23.7; 24.9; 25.8; 36.2; 49.3; 40.6; 52.4; 56.7;
64.6; 116.4; 119.6; 125.7; 133.1; 136.4; 139.8; 171.6; 171.8.
1
Partial Data of 17a: H-NMR (400 MHz, CDCl3): 0.08 (s, 3 H); 0.10 (s, 3 H); 0.92 (s, 9 H); 1.04 (s, 3 H);
1.43 (s, 3 H); 1.49 ± 1.55 (m, 1 H); 1.75 ± 1.85 (m, 1 H); 2.05 (dd, J ˆ 3.4, 11.2, 1 H); 3.04 ± 3.09 (m, 1 H); 3.72
(s, 3 H); 3.74 (s, 3 H); 4.07 ± 4.19 (m, 2 H); 5.34 (d, J ˆ 9.1, 1 H); 5.51 (dd, J ˆ 3.0, 10.1, 1 H); 5.60 (dd, J ˆ 2.4,
10.1, 1 H); 5 ± 71-5.83 (m, 2 H).
Pd-Catalyzed Allylic Substitution of 15a with [Pd(PPh3)4] as Catalyst. As described above with carbonate
15a on a 2.2-mmol scale at r.t. for 4 h: 16a/17a 7:3 (865 mg, 91%).
Pd-Catalyzed Allylic Substitution of 15b with [Pd(PPh3)4] as Catalyst. As described above (15a ! 16a/17a),
with 15b on a 0.4-mmol scale: 16b/17b 75 :25 (0.120 g, 67%).
Data of Pure 16b (as obtained below from the reaction with [Pd(dppe)2]). IR (CHCl3): 3549, 3007, 2954,
1731, 1612, 1513, 1454, 1247, 1109, 909. 1H-NMR (400 MHz, CDCl3): 1.06 (s, Me); 1.31 (s, Me); 1.31 ± 1.42
(m, 2 HÀC(1)); 2.13 ± 2.17 (m, HÀC(8a); 2.96 ± 3.01 (m, HÀC(2)); 3.72 (s, CO2Me); 3.67 (s, CO2Me); 3.82
(s, MeO); 3.90 (d, J ˆ 13.4, 1 H); 4.11 (d, J ˆ 12.6, 1 H); 4.37 (d, J ˆ 11.4, 1 H); 4.51 (d, J ˆ 11.4, 1 H); 5.40
(d, J ˆ 9.6, HÀC(5)); 5.49 (dd, J ˆ 1.5, 10.1, HÀC(4)); 5.58 (dd, J ˆ 2.3, 10.1, HÀC(3)); 5.75 (dd, J ˆ 5.3, 9.4,
HÀC(6)); 5.85 (d, J ˆ 5.1, HÀC(7)); 6.91 (d, J ˆ 8.6, 2 arom. H); 7.29 (d, J ˆ 8.6, 2 arom. H). 13C-NMR
(100 MHz, CDCl3): 16.0; 23.4; 25.3; 36.4; 39.3; 40.9; 52.4; 55.2; 56.7; 71.3; 71.8; 113.7; 119.4; 119.6; 126.0; 129.2;
‡
130.4; 134.1; 135.9; 137.0; 159.1; 171.7; 171.8. MS: 440 (1, M ), 158 (1), 147 (3), 122 (10), 121 (100), 77 (6). HR-
‡
MS: 440.2206 (C26H32O6 ; calc. 440.2199).
Partial Data of 17b: 1H-NMR (400 MHz, CDCl3): 1.09 (s, 3 H); 1.42 (s, 3 H); 1.57 ± 1.67 (m, 1 H); 1.80 ± 1.90
(m, 1 H); 2.22 (dd, J ˆ 3.5, 10.9, 1 H); 3.03 ± 3.10 (m, 1 H); 3.71 (s, 3 H); 3.73 (s, 3 H); 3.83 (s, 3 H); 3.90 (d, J ˆ
12.6, 1 H); 4.11 (d, J ˆ 12.9, 1 H); 4.41 (d, J ˆ 11.4, 1 H); 4.50 (d, J ˆ 11.4, 1 H); 5.41 (d, J ˆ 9.4, 1 H); 5.50 ± 5.62
(m, 2 H); 5.72 ± 5.78 (m, 1 H); 5.86 (d, J ˆ 5.1, 1 H); 6.90 (d, J ˆ 8.4, 2 H); 7.29 (d, J ˆ 8.4, 2 H).
Pd-Catalyzed Allylic Substitution of 15b with [Pd(PPh3)4] as Catalyst in the Absence of Base. A mixture of
15b (0.150 g, 0.41 mmol) and [Pd(PPh3)4] (47 mg, 0.04 mmol) in NMP (3 ml) was treated with 18 (0.16 ml,
1.2 mmol) at r.t. for 24 h. After completion of the reaction (TLC monitoring), H2O was added, the mixture
extracted with Et2O, the org. phase washed with H2O and brine, dried (MgSO4), and evaporated, and the
residue purified by FC (pentane/Et2O 3 :1): 16b/17b 15 :85 (0.108 g, 61%).
Pd-Catalyzed Allylic Substitution of 15b with [Pd(dppe)2] as Catalyst in the Absence of Base. A mixture of
15b (0.150 g, 0.4 mmol) and [Pd(dppe)2] (36 mg, 0.04 mmol) in NMP (4 ml) was treated with 18 (0.16 ml
1.2 mmol) at 508 for 6 h. After completion of the reaction (TLC monitoring), H2O was added, the mixture
extracted with Et2O, the org. phase washed with H2O and, brine, dried (MgSO4), and evaporated, and the
residue purified by FC (pentane/Et2O 3 :1): 16b/17b 92 :8 (0.130 g, 75%).
2-{(2S,4aS,8aR)-1,2,4a,8a-Tetrahydro-8-{[(4-methoxybenzyl)oxy]methyl}-4a-methylnaphthalen-2-yl}-2-
methylpropanedioic Acid Dimethyl Ester ((2S,4aS,8aR)-16b).
A mixture of (1S,4aS,8aR)-15b (1.00 g,
2.70 mmol) and [Pd(dppe)2] (244 mg, 0.27 mmol) in NMP (8 ml) was treated with the sodium salt of 18
(prepared from 18 (1.08 ml, 8.1 mmol) and NaH (194 mg, 8.1 mmol) in NMP (8 ml)) for 24 h at r.t. After
completion of the reaction, H2O was added, the mixture extracted with Et2O, the org. phase washed with H2O
and brine, dried (MgSO4), and evaporated, and the residue purified by FC (pentane/Et2O 3 :1): (2S,4aS,8aR)-
16b (1.19 g, 99%). Colorless oil. [a]2D0 ˆ À113.8 (c ˆ 0.305, CHCl3). The diastereoisomer 17b was not observed
under these conditions.
2-{(2S,4aR,8aR)-1,2,4a,8a-Tetrahydro-8-{[(4-methoxybenzyl)oxy]methyl}-4a-methylnaphthalen-2-yl}pro-
panoic Acid ((2S,4aR,8aR)-22). A mixture of (2S,4aS,8aR)-16b (1.96 g, 4.45 mmol) and 6m aq. NaOH (2.2 ml,
13.3 mmol) in DMSO (16 ml) was heated at 1308 for 4 h. After cooling to r.t., the mixture was diluted with H2O
and acidified with 1n HCl. The mixture was extracted with AcOEt, the org. layer washed with H2O and brine,
dried (MgSO4), and evaporated, and the residue purified by FC (pentane/Et2O 1:1): (2S,4aR,8aR)-22 (1.53 g,
93%) as a 1:1 mixture of diastereoisomers. Colorless viscous liquid. [a]2D0 ˆ À148.9 (c ˆ 0.33, CHCl3). IR

Helvetica Chimica Acta ± Vol. 88 (2005)
1077
(CHCl3): 3016, 1707, 1612, 1513, 1206. 1H-NMR (400 MHz, CDCl3): 1.07 (s, 3 H); 1.13 (2d, J ˆ 6.8, 3 H); 1.28 ±
1.63 (m, 2 H); 2.09 ± 2.18 (m, 1 H); 2.51 ± 2.38 (m, 2 H); 3.83 (s, 3 H); 3.91 (d, J ˆ 12.9); 3.92 (2d, J ˆ 12.9, 12.4,
1 H); 4.15, 4.16 (2d, J ˆ 12.9, 12.6, 2 H); 4.38, 4.39 (2d, J ˆ 11.4, 2 H); 4.54 (d, J ˆ 11.4, 1 H); 5.43 (d, J ˆ 9.4,
1 H); 5.47 ± 5.60 (m, 2 H); 5.76 (dd, J ˆ 9.6, 5.3, 1 H); 5.87 (d, J ˆ 5.1, 1 H); 6.91 (d, J ˆ 8.6, 2 H); 7.30 (d, J ˆ 8.6,
2 H). 13C-NMR (100 MHz, CDCl3): 12.4; 12.9; 24.6; 25.5; 26.5; 36.5; 36.6; 37.2; 37.3; 40.9; 41.2; 43.2; 43.9; 53.3;
55.2; 71.2; 71.2; 71.5; 71.6; 113.7; 119.2; 119.3; 126.2; 127.9; 129.2; 130.4; 134.3; 135.3; 135.8; 137.1; 137.2; 159.1;
‡
‡
181.6; 181.7. MS: 368 (1, M ), 158 (1), 122 (11), 121 (100), 91 (3), 77 (3). HR-MS: 368.2021 (C23H28O4 ; calc.
368.1988).
(3aR,4aS,8aR,9S,9aS)-3a,4,4a,8a,9,9a-Hexahydro-9-iodo-5-{[(4-methoxybenzyl)oxy]methyl}-3,8a-dimeth-
ylnaphtho[2,3-b]furan-2(3H)-one ((3aR,4aS,8aR,9S,9aS)-21). Aq. NaHCO3 soln. (0.95 g, 11.3 mmol, 22 ml) was
added to (2S,4aR,8aR)-22 (420 mg, 1.14 mmol) in CH2Cl2 (4 ml). I2 (0.57 g, 2.2 mmol) and KI (1.14 g, 6.8 mmol)
were added, and the mixture was stirred for 2.5 h at r.t. H2O was added, the aq. phase extracted with Et2O, the
combined org. phase dried (MgSO4), and evaporated, and the residue purified by FC (silica gel, pentane/Et2O
1:1): (3aR,4aS,8aR,9S,9aS)-21 (0.53 g, 94%) as a sticky foam. The two diastereoisomers (d.r. 1:1) were carefully
separated by FC (silica gel).
Less-Polar Diastereoisomer: IR (CHCl3): 1761, 1611, 1246. 1H-NMR (CDCl3, 400 MHz): 1.12 (d, J ˆ 7.2,
1 Me); 1.26 (s, 1 Me); 1.52 ± 1.54 (m, 2 HÀC(4)); 2.25 ± 2.30 (m, HÀC(4a)); 2.72 ± 2.76 (m, HÀC(3a)); 2.84 ±
2.87 (m, HÀC(3)); 3.82 (s, MeO); 3.94 (dd, J ˆ 13.4, 0.7, 1 H, CH2ÀC(5)); 4.06 (dd, J ˆ 13.3, 1.1, 1 H,
CH2ÀC(5)); 4.40 (d, J ˆ 11.4, 1 H, ArCH2); 4.50 (d, J ˆ 11.4, 1 H, ArCH2); 4.75 (d, J ˆ 2.5, HÀC(9a)); 4.91 ±
4.92 (m, HÀC(9)); 5.70 ± 5.84 (m, HÀC(6), HÀC(7), HÀC(8)); 6.89 (d, J ˆ 8.2, 2 arom. H); 7.29 (m, 2
arom. H). 13C-NMR (CDCl3, 100 MHz): 8.9; 23.3; 30.7; 34.9; 36.5; 38.0; 41.9; 42.4; 55.2; 71.5; 71.6; 82.0; 113.8
‡
(2 C); 120.0; 122.0; 129.3 (2 C); 130.2; 131.9; 139.3; 159.2; 178.6. MS: 494 (1, M ), 231 (1), 122 (10), 121 (100),
‡
105 (2), 91 (73), 77 (35). HR-MS: 494.0958 (C23H27IO4 ; calc. 494.0954).
1
More-Polar Diastereoisomer: IR (CHCl3): 1761, 1611, 1246. H-NMR (CDCl3, 400 MHz): 1.23 (d, J ˆ 7.3,
1 Me); 1.26 (s, 1 Me); 1.74 ± 1.80 (m, 2 HÀC(4)); 2.29 ± 2.33 (m, HÀC(3a), HÀC(4a)); 2.46 ± 2.50
(m, HÀC(3)); 3.81 (s, MeO); 3.9, 4.04 (2d, each J ˆ 12.9, CH2ÀC(5)); 4.38, 4.48 (2d, each J ˆ 11.5, ArCH2);
4.62 ± 4.64 (m, HÀC(9a)); 4.98 (t, J ˆ 5.1, HÀC(9)); 5.65 (d, J ˆ 9.4, HÀC(8)); 5.79 (dd, J ˆ 9.4, 5.2, HÀC(7));
5.84 (d, J ˆ 5.3, HÀC(6)); 6.89 (d, J ˆ 8.6, 2 arom. H); 7.26 ± 7.31 (m, 2 arom. H). 13C-NMR (CDCl3, 100 MHz):
13.8; 27.2; 29.5; 37.9; 38.1; 38.6; 42.4; 42.9; 55.2; 71.5 (2 C); 80.7; 113.8 (2 C); 120.5; 121.8; 129.3 (2 C); 130.1;
‡
132.3; 138.3; 159.2; 179.0. MS: 494 (1, M ), 231 (1), 122 (10), 121 (100), 105 (2), 91 (73), 77 (35).HR-MS:
‡
494.0958 (C23H27IO4 ; calc. 494.0954).
2-{(2R,4aS,8aS)-1,2,4a,8a-Tetrahydro-8-{[(methoxybenzyl)oxy]methyl}-4a-methylnaphthalen-2-yl}-N,N-di-
methylpropanamide ((2R,4aS,8aS)-20). A mixture of (1R,4aR,8aS)-13b (320 mg, 1.0 mmol) and 2,2-dimethoxy-
N,N-dimethylpropan-1-amine (19; 1.18 g, 8.0 mmol) in xylene (10 ml) was stirred in a sealed tube at 1508 for
12 h under N2. After cooling to r.t., the mixture was evaporated and the residue purified by FC (Et2O/pentane
2 :1): diastereoisomer mixture (2R,4aS,8aS)-20 (387 mg, 98%) (d.r. 1:1). Viscous oil. [a]2D0 ˆ ‡155.0 (c ˆ 0.96,
CHCl3). IR (CHCl3): 2921, 1627, 1507, 1245, 1076. 1H-NMR (CDCl3, 200 MHz): 1.03 (s, Me); 1.04 (d, J ˆ 6.7,
Me); 1.10 (d, J ˆ 6.7, Me); 1.43 ± 1.69 (m, 2 HÀC(1)); 2.06 ± 2.11 (m, HÀC(8a)); 2.25 ± 2.51 (m, HÀC(2),
MeCHCON); 2.93, 2.97, 2.99, 3.03 (4s, Me2N); 3.81 (s, MeO); 3.91 (d, J ˆ 13.1, 1 H); 4.09 and 4.14 (2d, J ˆ 13.1,
1 H); 4.38, 4.39 (2d, J ˆ 11.4, 1 H); 4.50, 4.52 (2d, J ˆ 11.3, 1 H); 5.36 ± 5.41 (m, HÀC(3), HÀC(4)); 5.45 ± 5.55
(m, HÀC(5)); 5.72 ± 5.5.76 (m, HÀC(6)); 5.85 (d, J ˆ 5.0, HÀC(7)); 6.88 (d, J ˆ 8.6, 2 arom. H); 7.27 (d, J ˆ 8.6,
2 arom. H). 13C-NMR (CDCl3, 100 MHz): 13.9; 14.4; 15.2; 25.46; 25.53; 25.7; 27.5; 29.6; 30.3; 35.6; 36.6; 37.3;
37.6; 37.7; 39.6; 40.6; 41.1; 41.3; 55.2; 71.3; 71.4; 71.7; 71.73; 113.7; 118.5; 119.1; 119.2; 119.3; 126.8; 128.8; 129.1;
‡
129.2; 130.5; 130.51; 134.3; 134.5; 134.6; 135.2; 137.6; 175.6; 175.7. MS: 395 (2, M ), 274 (1), 256 (2), 157 (3), 122
‡
(12), 121 (100), 101 (10), 72 (21). HR-MS: 395.2456 (C25H33NO3 ; calc. 395.2460).
(3aS,4aR,8aS,9R,9aR)-3a,4,4a,8a,9,9a-Hexahydro-9-iodo-5-{[(4-methoxybenzyl)oxy]methyl}-3,8a-dimeth-
ylnaphtho[2,3-b]furan-2(3H)-one ((3aS,4aR,8aS,9R,9aR)-21). To a soln. of the diastereoisomer mixture
(2R,4aS,8aS)-20 (80 mg, 0.20 mmol) in THF (4 ml) and H2O (2 ml) was added I2 (200 mg, 0.81 mmol) in one
portion, and the mixture was stirred under N2 for 3 h at r.t. (TLC monitoring). Sat. aq. NaHSO3 soln. was added
after completion of the reaction, the mixture extracted with Et2O, the Et2O layer washed with H2O and brine,
dried (MgSO4), and evaporated, and the residue purified by FC (silica gel; pentane/Et2O 2 :1): (3aS,4aR,8-
aS,9R,9aR)-21 (73 mg, 73%) as a 1 :1 mixture of diastereoisomers. White foamy material. Data: see above.
(3aS,4aS,8aS,9aS)-3a,4,4a,8a,9,9a-Hexahydro-5-{[(4-methoxybenzyl)oxy]methyl}-3,8a-dimethylnaph-
tho[2,3b]furan-2(3H)-one ((3aS,4aS,8aS,9aS)-23). Tributylstannane (1.04 ml, 3.57 mmol) and AIBN (cat.
amount) were added to (3aS,4aR,8aS,9R,9aR)-21 (0.7 g, 1.42 mmol) in dry toluene (15 ml), and the soln. was
refluxed for 8 h. After completion of the reaction, H2O was added, the mixture extracted with Et2O, the org.

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Helvetica Chimica Acta ± Vol. 88 (2005)
layer washed with brine, dried (MgSO4) and evaporated, and the residue purified by FC (silica gel, pentane/
Et2O 1:1): (3aS,4aS,8aS,9aS)-23 (0.48 g, 91%) as a sticky foam (d.r. 1 :1). After intensive chromatographic
separation, a pure sample of each diastereoisomer was obtained.
Less-Polar Diastereoisomer: [a]2D0 ˆ À28.5 (c ˆ 0.61, CHCl3). IR (CHCl3): 2921, 2856, 1763, 1611, 1218.
1H-NMR (CDCl3, 200 MHz): 1.03 (s, 1 Me); 1.24 (d, J ˆ 7.3, 1 Me); 1.26 ± 1.63 (m, 3 H); 1.80 ± 2.05 (m, 2 H):
2.19 ± 2.29 (m, 2 H); 3.81 (s, MeO); 3.88 (d, J ˆ 12.8, 1 H); 4.06 (d, J ˆ 12.7, 1 H); 4.36 (d, J ˆ 11.4, 1 H); 4.48
(d, J ˆ 11.4, 1 H); 4.61 ± 4.65 (m, 1 HÀC(9)); 5.57 ± 5.59 (m, 1 olef. H); 5.77 ± 5.81 (m, 2 olef. H); 6.85 ± 6.94
(m, 2 arom. H); 7.2 ± 7.32 (m, 2 arom. H). 13C-NMR (CDCl3, 100 MHz): 13.9; 26.2; 26.9; 33.3; 38.1; 40.3; 40.6;
43.6; 55.2; 71.2; 71.8; 113.8 (2 C); 120.1; 121.2; 128.6; 129.3 (2 C); 130.3; 136.0; 137.7; 159.2; 180.2. MS: 368 (1,
‡
‡
M ), 157 (2), 143 (5),122 (15), 121 (100), 105 (2), 91 (4), 77 (4). HR-MS: 368.1949 (C23H28O4 ; calc. 368.1988).
More-Polar Diastereoisomer: [a]2D0 ˆ À47.5 (c ˆ 1.5, CHCl3). IR (CHCl3): 2921, 2856, 1763, 1611, 1218.
1H-NMR (CDCl3, 200 MHz): 1.02 (s, Me); 1.11 (d, J ˆ 7.3, Me); 1.14 ± 1.57 (m, 3 H); 1.85 ± 1.89 (m, 1 H); 2.19 ±
2.32 (m, 2 H); 2.72 ± 2.75 (m, 1 H); 3.81 (s, MeO); 3.91 (d, J ˆ 13.0, 1 H); 4.08 (d, J ˆ 13.1, 1 H); 4.37 (d, J ˆ 11.3,
1 H); 4.41 ± 4.43 (m, 1 H); 4.49 (d, J ˆ 11.3, 1 H); 5.61 (d, J ˆ 8.7, 1 olef. H); 5.77 ± 5.82 (m, 2 olef. H); 6.87 ± 6.90
(m, 2 arom. H); 7.2 ± 7.28 (m, 2 arom. H). 13C-NMR (CDCl3, 100 MHz): 9.1; 22.0; 26.4; 33.3; 38.3; 38.5; 40.2;
41.6; 55.2; 71.2; 71.8; 77.3; 113.7 (2 C); 120.1; 121.5; 129.2 (2 C); 130.3; 136.3; 138.2; 159.1; 179.3. MS: 368 (1,
‡
‡
M ), 157 (2), 143 (5), 122 (15), 121 (100), 105 (2), 91 (4), 77 (4). HR-MS: 368.2024 (C23H28O4 ; calc. 368.1988).
(4aS,8aS,9aS)-4a,8a,9,9a-Tetrahydro-5-{[(4-methoxybenzyl)oxy]methyl}-3,8a-dimethylnaphtho[2,3-b]fur-
an-2(4H)-one ((4aS,8aS,9aS)-24) and (3aS,4aS,8aS,9aS)-3a,4,4a,8a,9,9a-Hexahydro-5-{[(4-methoxybenzyl)oxy]-
methyl}-8a-methyl-3-methylenenaphtho[2,3-b]furan-2(3H)-one ((3aS,4aS,8aS,9aS)-25). A soln. of (3aS,4aS,8a-
S,9aS)-23 (0.11 g, 0.3 mmol) in THF (3 ml) was added at À 788 to a freshly prepared LDA soln. (prepared from
iPr2NH2 (0.054 ml, 0.39 mmol) and 1.6m BuLi in hexane (0.24 ml, 0.39 mmol). The resultant soln. was stirred for
1 h. A soln. of phenylselenyl chloride (ˆ benzeneselenenyl chloride; 75 mg, 0.39 mmol) in THF (1 ml) was
added, and the mixture was stirred for 2.5 h before treating with aq. NH4Cl soln. The aq. phase was extracted
with Et2O and the combined org. phase dried (MgSO4) and evaporated. The crude residue was dissolved in
CH2Cl2 (5 ml), and pyridine (0.35 ml, 1.44 mmol) and 30% aq. soln. H2O2 (0.6 ml) were added at r.t. After
stirring for 30 min, the mixture was diluted with Et2O and washed with brine, the org. phase dried (MgSO4) and
evaporated, and the residue purified by FC (silica gel, pentane/Et2O 1:1): (4aS,8aS,9aS)-24 and (3aS,4aS,8a-
S,9aS)-25 (72 mg, 66%) (3 :2 ratio).
Data of (4aS,8aS,9aS)-24: [a]2D0 ˆ ‡220.6 (c ˆ 0.34, CHCl3). IR (CHCl3): 3018, 2926, 2856, 1744, 1514, 1224,
1039. 1H-NMR (CDCl3, 200 MHz): 1.34 (s, Me); 1.50 (t, J ˆ 12.1, 1 HÀC(9)); 1.73 (s, Me); 2.01 (dd, J ˆ 6.3, 12.1,
1 H); 2.56 (dd, J ˆ 6.6, 15.2, 1 HÀC(4)); 2.79 (br. s, HÀC(4a)); 3.23 (dd, J ˆ 2.3, 15.2, 1 HÀC(4)); 3.79 (d, J ˆ
11.9, 1 H); 3.81 (s, MeO); 4.06 (d, J ˆ 12.1, 1 H); 4.33 (d, J ˆ 11.6, 1 H); 4.48 (d, J ˆ 11.6, 1 H); 4.75 (dd, J ˆ 6.3,
11.6, 1 H); 5.54 (d, J ˆ 9.6, HÀC(8)); 5.83 (dd, J ˆ 5.3, 9.6, HÀC(7)); 5.91(br. s, HÀC(6)); 6.91 (d, J ˆ 8.4,
2 arom. H); 7.28 (d, J ˆ 8.4, 2 arom. H). 13C-NMR (CDCl3, 50 MHz): 9.2; 24.5; 25.5; 36.4; 38.0; 43.2; 55.8; 71.9;
‡
72.0; 78.2; 114.4 (2 C); 121.3; 122.4; 124.9; 130.1 (2 C); 130.4; 135.3; 137.6; 159.8; 161.1; 175.2. MS: 366 (M ),
‡
137 (1), 121 (100), 119 (4), 77 (3). HR-MS: 366.1845 (C23H26O4 ; calc. 366.1831).
Data of (3aS,4aS,8aS,9aS)-25: [a]2D0 ˆ À74.8 (c ˆ 0.6, CHCl3). IR (CHCl3): 3008, 2932, 1757, 1670, 1512,
1224, 1039. 1H-NMR (CDCl3, 200 MHz): 1.04 (s, 3 H); 1.43 (t, J ˆ 12.1, 1 H); 1.58 ± 1.79 (m, HÀC(4), HÀC(9));
1.98 (dd, J ˆ 12.9, 2.0, HÀC(4a)); 2.12 (dd, J ˆ 4.8, 15.2, 1 H); 2.80 ± 2.95 (m, HÀC(3a)); 3.81 (s, MeO); 3.90
(d, J ˆ 13.1, 1 H); 4.06 (d, J ˆ 13.4, 1 H); 4.35 (d, J ˆ 11.4, 1 H); 4.48 (d, J ˆ 11.4, 1 H); 4.52 ± 4.54 (m, 1 H); 5.49
(d, J ˆ 1.2, CH2ˆC(3)); 5.57 (br. d, J ˆ 8.8, HÀC(8)); 5.75 ± 5.81 (m, HÀC(6), HÀC(7)); 6.09 (d, J ˆ 1.7, 1 H);
6.88 (d, J ˆ 8.7, 2 arom. H); 7.26 (d, J ˆ 8.6, 2 arom. H). 13C-NMR (CDCl3, 50 MHz): 26.8; 27.8; 33.6; 38.6; 39.6;
40.6; 55.8; 71.8; 72.4; 76.4; 114.3 (2 C); 120.7; 120.8; 121.7; 129.8 (2 C); 130.8; 136.3; 137.7; 141.7; 159.7; 180.0.
‡
‡
MS: 366 (1, M ), 137(1), 122 (10), 121 (100), 119 (2), 91 (3), 77 (4). HR-MS: 366.1829 (C23H26O4 ; calc.
366.1831).
(4aS,8aS,9aS)-4a,8a,9,9a-Tetrahydro-5-(hydroxymethyl)-3,8a-dimethylnaphtho[2,3-b]furan-2(4H)-one
((4aS,8aS,9aS)-26) and (3aS,4aS,8aS,9aS)-3a,4,4a,8a,9,9a-Hexahydro-5-(hydroxymethyl)-8a-methyl-3-methyl-
enenaphtho[2,3-b]furan-2(3H)-one ((3aS,4aS,8aS,9aS)-27). To a stirred soln. of 24/25 (167 mg, 0.46 mmol) in
CH2Cl2 (12 ml) and H2O (0.6 ml), DDQ (124 mg, 0.55 mmol) was added at r.t. (TLC (pentane/Et2O 1:2)
monitoring). After completion of the reaction (ca. 2.5 h), the mixture was diluted with CH2Cl2, the soln. washed
with sat. NaHCO3 soln., dried (MgSO4), and evaporated, and the crude product purified by FC (pentane/Et2O
1:2): 26/27 (90 mg, 80%) as an inseparable mixture (3 :2 ratio). Colorless oil.
(4aS,8aS)-4,4a,8a,9-Tetrahydro-3,8a-dimethylnaphtho[2,3-b]furan-5-methanol ((4aS,8aS)-28). To 26/27
(25 mg, 0.1 mmol) in dry toluene (1 ml) at À 408 was added 1m DIBAL in THF (0.3 ml, 0.3 mmol). Progress
of the reaction was followed by TLC, and excess DIBAL (0.3 ml, 0.3 mmol) was added until TLC showed

Helvetica Chimica Acta ± Vol. 88 (2005)
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complete disappearance of the starting material (after ca. 3 ± 4 h). AcOH (2 ml) was added, and the mixture was
brought to r.t. and stirred for 30 min. Then the mixture was extracted with Et2O, the org. layer washed with a sat.
aq. NaHCO3 soln., H2O, and brine, dried (MgSO4), and evaporated, and the residue subjected to
chromatography (neutral alumina, pentane/Et2O 1:2): (4aS,8aS)-28 (17 mg, 73%). [a]2D0 ˆ ‡58.8 (c ˆ 0.24,
CHCl3). IR (CHCl3): 3444, 3013, 2924, 1665, 1456, 1227, 1102, 1017, 992. 1H-NMR (CDCl3, 400 MHz): 1.15
(s, Me); 1.54 ± 1.78 (br. s, OH); 1.90 (d, J ˆ 1.1, 3 H); 2.18 ± 2.28 (m, 2 HÀC(4)); 2.50 (d, J ˆ 16.7, 1 HÀC(9));
2.54 ± 2.58 (m, HÀC(4a)); 2.60 (d, J ˆ 16.6, 1 HÀC(9)); 4.22 (s, 2 H); 5.56 (d, J ˆ 8.9, HÀC(8)); 5.88 ± 5.93
(m, HÀC(6), HÀC(7)); 7.01 (s, HÀC(2)). 13C-NMR (CDCl3, 100 MHz): 8.0; 23.7; 25.7; 35.0; 35.7; 40.1; 65.4;
‡
118.1; 118.8; 119.0; 123.4; 136.5; 137.5; 142.7; 149.5. MS: 230 (M ), 205 (2), 149 (6), 121 (2), 108 (100), 79 (8), 77
‡
(4), 51 (1). HR-MS: 230.1306 (C15H18O2 ; calc. 230.1295).
(‡)-(4aS,8aS)-15-Acetoxytubipofuran (ˆ(‡)-(4aS,8aS)-4,4a,8a,9-Tetrahydro-3,8a-dimethylnaphtho[2,3-b]-
furan-5-methanol Acetate; (‡)-(S,S)-2). To a soln. of (4aS,8aS)-28 (20 mg, 0.08 mmol), pyridine (0.03 ml,
0.35 mmol), and a catalytic amount of DMAP in dry CH2Cl2 (1.5 ml) at 08 was added Ac2O (0.02 ml,
1.74 mmol). After stirring for 30 min, the mixture was diluted with Et2O, the soln. washed with 5% HCl soln.,
sat. aq. NaHCO3 soln., H2O, and brine, dried (MgSO4), and evaporated, and the residue subjected to FC
(neutral alumina, pentane/Et2O 4 :1): (‡)-(S,S)-2 (22 mg, 93%). Light yellow oil which turned brown (dec.)
after a few days at r.t. [a]2D0 ˆ ‡100.3 (c ˆ 0.29, CHCl3). IR (CHCl3): 3019, 2921, 1730, 1649, 1572, 1376, 1218,
1022. 1H-NMR (CDCl3, 400 MHz): 1.14 (s, 1 Me); 1.91(s, 1 Me); 2.1 (s, 1 Me); 2.14 ± 2.24 (m, 2 HÀC(4)); 2.53
(d, J ˆ 16.4, 1 HÀC(9)); 2.54 ± 2.61(m, HÀC(4a)); 2.66 (d, J ˆ 16.7, 1 HÀC(9)); 4.63 (d, J ˆ 13.2, 1 H,
CH2ÀC(5)); 4.70 (d, J ˆ 13.5, 1 H, CH2ÀC(5)); 5.58 (d, J ˆ 8.6, HÀC(8)); 5.88 ± 5.91 (m, HÀC(6),
HÀC(7)); 7.01 (s, HÀC(2)). 13C-NMR (CDCl3, 100 MHz): 8.1; 20.8; 23.7; 25.7; 35.1; 35.8; 40.2; 66.3; 118.9;
‡
119.0; 120.9; 123.3; 136.5; 137.7; 138.2; 149.4; 170.8. MS: 272 (M ), 205 (2), 165 (0.5), 149 (4), 123 (1), 108 (100),
‡
79 (7), 77 (6), 51 (2). HR-MS: 272.1404 (C17H20O3 ; calc. 272.1412).
(À)-(R,R)-2 was obtained analogously from (3aR,4aS,8aR,9S,9aS)-21. [a]2D0 ˆ À120 (c ˆ 0.64, CHCl3) [9]:
[a]2D0 ˆ ‡10.7 (c ˆ 0.5, CHCl3)). CD: lmax 274 nm ((De À 3) ([9]: lmax 274 (De ‡ 3)).
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Received December 23, 2004