Studies towards Simalikalactone D and Quassimarin: Construction of an Advanced Pentacyclic Intermediate

Article abstract of DOI:10.1002/chem.200305158

An advanced pentacyclic intermediate, amenable to further elaboration into the target molecules simalikalactone D and quassimarin, has been synthesized from (S)-(+)-carvone in 21 steps and with an overall yield of 12%. The synthesis is efficient, stereocontrolled, enantiospecific, and chirality productive, creating eight new chiral centres in pentacycle, and should provide opportunities for rapid access to simalikalactone D analogues and other bioactive quassinoids. The reaction sequence involves a regioselective bishydroxylmethylation, a stereocontrolled epoxidation, an epoxymethano-bridge formation, a 1,3-sigmatropic rearrangement and an intramolecular Diels-Alder reaction as the key steps.

Full text of DOI:10.1002/chem.200305158

FULL PAPER
Studies towards Simalikalactone D and Quassimarin:
Construction of an Advanced Pentacyclic Intermediate**
Tony K. M. Shing,* Xue Y. Zhu, and Yeung Y. Yeung[a]
Abstract: An advanced pentacyclic in-
termediate, amenable to further elabo-
ration into the target molecules simali-
kalactone D and quassimarin, has been
synthesized from (S)-(‡)-carvone in 21
steps and with an overall yield of 12%.
The synthesis is efficient, stereocontrol-
led, enantiospecific, and chirality pro-
ductive, creating eight newchiral centres
in pentacycle, and should provide op-
portunities for rapid access to simalika-
lactone D analogues and other bioactive
quassinoids. The reaction sequence in-
volves a regioselective bishydroxylme-
thylation, a stereocontrolled epoxida-
tion, an epoxymethano-bridge forma-
tion, a 1,3-sigmatropic rearrangement
and an intramolecular Diels Alder re-
action as the key steps.
Keywords:
antitumor agents
¥
lactones ¥ terpenoids ¥ total synthesis
total synthesis of dl-samaderin B, belonging to the C19
picrasane family, has been acheived by the same group.[5a]
Other synthetic accomplishments are contributed from
groups led by Takahashi [(Æ)-amarolide],[13] Murae [relay
synthesis of (À)-bruceantin],[5m] Valenta [(Æ)-quassin],[5k] and
Fuchs [15-deoxy-16b-ethoxybruceantin].[5b] Additional inter-
ests on enantioselective routes to quassinoids began with early
investigations by Dias,[14] Graf,[15] Ziegler,[16] Fukumoto[17] and
Schlessinger[18] and resulted the first total syntheses of (‡)-
picrasin B, (‡)-D2-picrasin B and (‡)-quassin by Watt×s
group[5n,r,s] using the (À)-enantiomer of the Wieland
Miescher ketone as the starting material.
Plant natural products continue to supply clinically useful
antitumor agents, novel structural prototypes for the develop-
ment of analogues, and biochemical tools for the elucidation
of unprecedented mechanism of tumor growth control.[19]
Among the quassinoids, simalikalactone D (1)[20] and quassi-
marin (2)[21] (Scheme 1) are of considerable interest because
they display potent activity in vivo against the P-388
lymphocytic leukemia in mice (PS) and possess differential
solid tumour selectivity.[5i,g, 22] Recent findings have indicated
that 1 and 2 were significantly active against the growth of a
panel of human tumour cell lines (KB, A-549, HCT-8, CAKI-
1, MCF-7, and SK-MEL-2).[23] The antiviral activity of
simalikalactone D (1) has also been demonstrated.[24] Both
compounds share a pentacyclic carbon skeleton 3 (rings A
E) with common stereochemical features, but with different
butyrate esters at C-15. The essential structural requirements
for potent antineoplastic activity could well be the presence of
an epoxymethano bridge (ring E) between C-8 and C-13, an
a,b-enone unit with a free hydroxyl group in ring A, and an
ester group at C-15.[25] The ester group is believed to be
important for the transport of the drug across the cell
Introduction
The quassinoids[1] constitute a diverse and constantly expand-
ing group of terpenoid bitter compounds isolated from
Simaroubaceae,[2] a large botanical family of pantropical
distribution.[3] The discovery of a wide spectrum of biological
properties[1, 4] of quassinoids has attracted the attention of
synthetic chemists in recent years.[5] Continued studies on the
bioactivity profile of quassinoids have reported that these
substances display, amongst other things, antifeedant and
insecticidal,[6] antiprotozoal,[7] antimalarial,[8] and antitumor
activities.[9] The highly oxygenated tetracyclic/pentacyclic
carbon frameworks of the C20 picrasane family, comprising a
number of contiguous stereocenters, pose a formidable
synthetic challenge and therefore have stimulated massive
synthetic efforts from many research teams. The pioneer and
the major contributor in this area of research has been Grieco
and co-workers, producing astute and exquisite total synthe-
ses of a number of tetracyclic and pentacyclic members,
namely (Æ)-quassin,[10] (Æ)-catelanolide,[11] (Æ)-klaineano-
ne,[12, 5t] (Æ)-chaparrinone,[5p] (Æ)-glaucarubolone and (Æ)-
holacanthone,[5j] (‡)-simalikalactone D (1),[5i] (À)-chaparri-
none, (À)-glaucarubolone and (‡)-glaucarubinone,[5e] (Æ)-
bruceantin,[5f] and (‡)-quassimarin (2).[5g] Recently, the first
[a] Prof. T. K. M. Shing, Dr. X. Y. Zhu, Y. Y. Yeung
Department of Chemistry
The Chinese University of Hong Kong
Shatin, NT, Hong Kong (VR China)
Fax: (852)-2603 5057
E-mail: tonyshing@cuhk.edu.hk
[**] Part of this work was published as a preliminary communication:
T. K. M. Shing, X. Y. Zhu, T. C. W. Mak, Chem. Commun. 1996,
2369 2370.
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membranes and to increase the lipophilicity of the mole-
cule.[26] The enone unit may be involved in reactions with
biological nucleophiles and therefore be central to the activity
of these compounds.[27]
This task appeared trivial in principle, but proved trouble-
some in practice. Our first problem was the introduction of a
suitable functional group at C-6 of (S)-(‡)-carvone (10) and
the attachment of different hydroxymethyl equivalents to that
position. Thus, deprotonation of (S)-(‡)-carvone (10) with
LDA followed by addition of methyl chloroformate gave a 1:1
mixture of products, the carbon-alkylated b-ketoester 11 and
the oxygen-alkylated carbonate 12 (Scheme 3). When methyl
cyanoformate, Mander×s reagent,[29] was used instead,
In our own quest for an enantiospecific entry to optically
active quassinoids, we recently reported the total synthesis of
quassin (4) which has the general ABCD ring system with
seven chiral centers common to numerous quassinoids via a
series of regioselective and stereocontrolled reactions from
(S)-(‡)-carvone (10) with one stereogenic center (Sche-
me 2).[28a] Our synthetic strategy for its construction is based
on the C ! ABC ! ABCD ring annulation sequence and the
major hurdle in the synthesis of quassinoids is the stereo-
controlled construction of the angular methyl groups.[28b,c] We
described two solutions to this problem by employing an aldol
reaction [6 (R ˆ CH3) ‡ 7 ! 8] and an intramolecular Diels
Alder (IMDA) reaction (8 ! 9), leading to a trans,anti,trans-
perhydrophenanthrene nucleus 9 (R ˆ CH3) with excellent
stereocontrol.[28d,e]
Scheme 3. Acylation of carvone 10. a) i) LDA, THF; ii) ClCO2Me or
CNCO2Me.
the b-ketoester 11 was isolated in 95% yield as a single
1
diastereomer. The H NMR spectrum of 11 showed that H1
appeared at d 3.51 as a doublet. A large coupling constant of
12 Hz between H1 and H6 provided evidence of their pseudo-
trans-diaxial relationship and suggested that the acylation
took place at the less hindered a face. At this stage, we had
high hopes that b-ketoester 11 would react with aldehyde 7 to
furnish the desired aldol product (8, R ˆ CO2Me) [c.f. the
conversion of 6 (R ˆ Me) ‡ 7 ! 8 (R ˆ Me) in Scheme 2].
Unfortunately, under a variety of basic reaction conditions,
the aldolisation failed to furnish any aldol adducts. Attempts
to stabilize the aldol product by metal chelation,[30] by
conducting Lewis acid (TiCl4 or ZnCl2) catalyzed aldolisation
of silyl enol ether 13 or by reaction with boron enolate,[31] 14
were unsuccessful.
Now, we would like to exploit this approach to synthesise
optically active pentacyclic simalikalactone D (1) and quassi-
marin (2). This paper we describe in detail our effort in the
construction of the advanced pentacyclic intermediate 5
(Scheme 1), which is amenable for further elaboration into
the target molecules.
Selective reduction of the ketone moiety in 11 with sodium
borohydride in methanol in the presence of CeCl3 afforded a
1:1 mixture of diastereomeric alcohols 15 in 88% yield
(Scheme 4). However, aldolisation of the bisanion derived
from b-hydroxyester 15 with aldehydes (benzaldehyde, hexa-
nal or aldehyde 7) also met with failures although the
alkylation of b-hydroxyester has literature precedence.[32]
Scheme 1. Pentacyclic quassinoids.
Results and Discussion
On the basis of the synthetic strategy shown in Scheme 2, we
reasoned that substitution of the methyl group in 6 with a
hydroxymethyl group or a suitable synthetic equivalent and
taking it (6, R ˆ CH2OH) through the same sequence of
reactions as in the preparation of tricycle 9 would allow
formation of the ring E at a later stage.
Scheme 4. Enolisation of carvone derivatives.
Another pathyway aimed at preparing the bisanion was also
attempted. Enolisation of (S)-(‡)-carvone 10 with LDA in
THF/N,N'-dimethylpropyleneurea (DMPU) 3:1 at À788C
followed by addition of gaseous formaldehyde afforded a-
hydroxymethylcarvone 16 in 90% yield as a single diaster-
eomer. The 1H NMR spectrum of the alcohol 16 showed that
H6 appeared at d 2.46 as a ddd (J6,7 or 7' ˆ 3.5, J6,7 or 7' ˆ 7, and
J6,5 ˆ 13 Hz) and H5 appears at d 2.68 also as a ddd (J5,4a ˆ 4.5,
J5,4b ˆ 11, and J5,6 ˆ 13 Hz). The pseudo-trans-diaxial relation-
ship between H6 and H5 was evident from their large coupling
constant of 13 Hz and this suggested that the aldol reaction
occurred at the less hindered a face. However, treatment of
Scheme 2. Synthesis of quassin.
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Simalikalactone D and Quassimarin
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alcohol 16 with 2 4 equivalents of LDA in the presence of
DMPU at À788C followed by addition of aldehydes failed to
give any aldol adduct. Masked hydroxymethyl derivative such
as 6-SEM-carvone 17[33] also failed to enolise under the
conditions as confirmed by deuterium exchange experiments
(Scheme 4).
With the problems of effecting the aldol reaction, we
decided to introduce the hydroxymethyl group at C-6 of (S)-
(‡)-carvone 10 in a later stage of our synthesis and envisaged
that bicycle 8 (R ˆ H) could be synthesized from (S)-(‡)-
carvone 10 and aldehyde 7. We reasoned that kinetic
deprotonation of tricycle 9 (R ˆ H) with LDA followed by
reaction with methanal should give us the desired tricyclic
alcohol 9 (R ˆ CH2OH). Thus aldolisation of the enolized (S)-
(‡)-carvone 10 with aldehyde 7 proceeded smoothly to give
alcohol 18 which was acetylated with acetic anhydride to
furnish ester 19 in an overall yield of 62%. However, the
IMDA reaction of sulfolene 19 gave enone 20 instead
(Scheme 5). Obviously, the acetate group at C-7 was elimi-
nated during the Diels Alder reaction to give the thermo-
dynamically more stable enone product 20.
Scheme 7. Synthesis of keto-aldehyde 31. a) LDA, DMPU, THF, HCHO,
À78 !À 408C then rt, 24 h, 75%; b) DMP, pTsOH, CH2Cl2, rt, 2 h, 96%;
c) tBuOOH, 2n NaOH, MeOH, 458C, 24 h, 94%; d) TFA, EtOH, 508C,
48 h, 85%; e) TBSCl, Et3N, DMAP, CH2Cl2, rt, 48 h, 92%; f) 2-methox-
ypropene, PPTS, CH2Cl2, 08C, 4 h, 96%; g) TBAF, THF, rt, 96%; h) PCC,
CH2Cl2, rt, 70%.
primary alcohols to ring open the epoxide, leading to an
epoxymethano bridge. By analogy with the reactivity of a-
haloketones, the epoxide ring opening is expected to proceed
at the a position regioselectively. However, exposure of enone
24 to alkaline tert-butylhydroperoxide caused a retro-aldol
reaction, hence the primary alcohol units in 24 had to be
protected first. Although the hydroxy groups in 24 could be
protected as THP derivatives under standard conditions, these
alcohols were best and conveniently protected as an aceto-
nide. Thus the diol 24 was isopropylidenated under standard
conditions to give the spiral compound 25. Epoxidation of the
electrophilic alkene in 25 with alkaline tert-butylhydroper-
oxide occurred smoothly at the less hindered a face to give the
a-epoxide 26 in 94% yield. The alternative a-epoxide was not
detectable by NMR or TLC. Acid hydrolysis of the acetonide
protecting group in 26 proceeded with concomitant ring-
opening reaction by the liberated alcohol to form the THF
ring 27. Again there was no other isomer isolable or detected.
The structure 27 was confirmed by X-ray diffraction which
demonstrated the nucleophilic opening of the oxirane 26 did
proceed as anticipated.
Scheme 5. a) LDA, THF/DMPU 3:1, À788C, 1 h, 62 %; b) Ac2O, pyridine,
DMAP, CH2Cl2, rt, 10 h, 100%; c) PhCN, methylene blue, sealed tube,
1908C, 110 h, 40%.
In viewof the failures, we had to revise our synthetic
approach and attempted to construct first an E ring 21 with
reversed polarity so that a nucleophilic diene equivalent could
be introduced in order to set up the IMDA precursor 22
(Scheme 6). Thermolysis of the diene 22 should provide the
Nowthe secondary alcohol moiety in 27 had to be protected
for further synthetic manipulation. This could be achieved by
a selective protection and deprotection sequence. Thus
silylation of the primary alcohol in 27 could be effected
smoothly and selectively to give the silyl ether 28 in 92%
yield. The remaining secondary alcohol was treated with
2-methoxypropene in CH2Cl2, catalyzed by PPTS, affording
the mixed acetal 29 in 96% yield. Removal of the silyl
protecting group with nBu4NF (TBAF) in THF (96% yield)
followed by PCC oxidation of the resulting alcohol 30 gave
aldehyde 31 in 70% yield (Scheme 7). However, aldehyde 31
was unstable even at 08C under N2 due to the acid liability of
the mixed acetal functionality. We circumvented this problem
by choosing an alternative silane protecting group. Thus
selective acylation of the primary alcohol in diol 27 with acetyl
chloride in the presence of diisopropylethylamine according
to the Yamamoto protocol[34] gave the monoacetate 32 in
Scheme 6. Synthetic approach towards ABCE ring system.
trans,anti,trans fused ABC ring system 23. This change of
strategy proved successful and nowwe describe a simple
solution to the synthesis of epoxymethano-bridge in pentacy-
clic quassinoids. Thus reaction of (S)-(‡)-carvone 10 with
LDA followed by an excess of formaldehyde from À788C to
room temperature gave 6,6-bishydroxymethylated carvone 24
in 75% yield (Scheme 7). Enolisation of the intermediate
compound 16 must have occurred at the a position, but it
appeared that this enolate would only react with formalde-
hyde.
We envisaged that formation of an oxirane across the
electrophilic alkene moiety in 24 would allow one of the
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excellent yield (Scheme 8). The silylation of the free secon-
dary alcohol in 32 was best effected with TBS-triflate,
affording the silyl ether 33 in quantitative yield. The ester
methyl-5-bromopenta-1,3-diene, 37a and 37b in a ratio of 3:1.
The attack of the bromide should be at the less hindered
primary carbon. Reaction of bromide 37 with magnesium then
gave the desired Grignard reagent 3-methylpentadienyl-
magnesium bromide 38 (Scheme 10).
Scheme 10. Synthesis of Grignard reagent 38. a) Vinyl magnesium
bromide, THF, 08C to rt, 4 h, 70%; b) PBr3, pyridine, Et2O, À108C,
30 min, 80%; c) Mg, Et2O, À10 !À 58C, 12 h.
First examination of the addition of 3-methylpentadienyl-
magnesium bromide 38 to aldehyde 35 at room temperature
was encouraging, giving a mixture of 1,4-diene 41 (50%), 1,3-
diene 42 (20%), and polyene 43 (5%). After several trials, the
conditions for the chemoselective addition of Grignard
reagent 38 to aldehyde 35 in the presence of a ketone
functionality were optimized. When a dilute solution of
Grignard reagent 38 was used, the addition occurred exclu-
sively at the aldehyde function and afforded 1,4-diene 41 in a
yield of 80% (Scheme 11). Presumably, the addition of the
Scheme 8. Synthesis of keto-aldehyde 35. a) AcCl, iPr2EtN, CH2Cl2, 08C
to rt, 4 h, 97%; b) TBDMSOTf, 2,6-lutidine, CH2Cl2, rt, 2 h, 100%;
c) NaOH, MeOH, THF, rt, 4 h, 96%; d) TPAP, NMO, CH2Cl2, rt, 2 h, 84%.
group in 33 was hydrolysed under basic conditions without
incident to give alcohol 34 that was subjected to a number of
oxidation protocols [PDC, PCC, Swern, tetrapropylammoni-
um perruthenate (TPAP)[35]]. The most efficient transforma-
tion was achieved using TPAP, leading to the aldehyde 35 in
84% yield.
With both an efficient and facile approach to the optically
active aldehyde 35 available, the stage was set for the IMDA
reaction and the installation of the diene unit onto 35 was our
next mission. In our synthetic plan, the required diene unit
might be provided by 3-methyl-pentadienyl carbanion. We
reasoned that the Grignard equivalent of pentadienyllithium
carbanion could be prepared easily on a large scale from
5-bromo-3-methylpenta-1,3-diene. Thus, treatment of a sol-
ution of (E)-pentadienyl alcohol 36a with PBr3 provided a
mixture of (E)- and (Z)-3-methyl-5-bromopenta-1,3-diene[36]
37a and 37b in a ratio of 5:1 (combined yield 83%). (Z)-
Pentadienyl alcohol 36b gave a mixture of (Z)- and (E)-
bromopentadiene 37b and 37a in a ratio of 6:1 (combined
yield 80%). Initially, pentadienyl alcohols 36a and 36b could
be made by partial hydrogenation of trans-3-methyl-2-penten-
4-yn-1-ol and cis-3-methyl-2-penten-4-yn-1-ol with P2Ni as
catalyst, respectively (Scheme 9).[37] Unfortunately, both
Scheme 11. Synthesis of IMDA precursor 44 and 45. a) Grignard reagent
38, Et2O, rt, 5 min, 80%; b) KH, dibenzo-[18]crown-6, THF, rt, 4 h, 85%.
pentadienyl carbanion proceeded through an allylic rear-
rangement via a cyclic six-membered transition state 46,
leading to the exclusive formation of the 1,4-diene product 47
(Scheme 12). Previous report had indicated that the addition
of 3-methylpentadienyllithium to aldehyde gave 1,4-diene as
Scheme 9. Synthesis of Grignard reagent 38. a) PBr3, pyridine, Et2O,
À308C, 30 min, 83% for 37a, 80% for 37b; b) Mg, Et2O, À10 !À 58C,
12 h.
trans-3-methyl-2-penten-4-yn-1-ol and cis-3-methyl-2-penten-
4-yn-1-ol are no longer commercially available and an
alternative route had to be devised for the bromopentadiene
(37a and 37b). After considerable experimentation, a simple
entry was developed. Treatment of ethyl acetate 39 with
vinylmagnesium bromide afforded the divinyl carbinol 40[38]
which with PBr3 furnished a mixture of (E)- and (Z)-3-
Scheme 12. Proposed mechanism for the addition of 3-methylpentadienyl
magnesium bromide to aldehyde.
the minor product.[39] Our results of the addition of 3-meth-
ylpentadienylmagnesium bromide to aldehyde to give 1,4-
diene as the major product was possibly the first example. A
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Simalikalactone D and Quassimarin
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skipped 1,4-diene unit has nowbeen introduced, but in order
to perform the IMDA reaction, transformation into the
corresponding 1,3-diene had to be performed. The conversion
was realized via an anion accelerated [1,3]-sigmatropic shift
(Scheme 13).[40] The effect of cations on the acceleration of
the shift was investigated and potassium salt had a dramatic
Scheme 15. Intramolecular Diels Alder reaction of triene 45. a) Ac2O,
Et3N, CH2Cl2, rt, 24 h, 96%; b) toluene, methylene blue, sealed tube,
1708C, 120 h, 85%.
With an appreciable amount of the tetracyclic ketone 49 at
hand, we initiated the construction of ring D. The trans-
formation of tetracycle 49 into the pentacyclic lactone
required the inversion of the configuration at C-7 into the
desired a-oriented acetate 51. This could be realised via an
oxidation reduction sequence. Thus, acetate 49 was saponi-
fied to alcohol 52 in a yield of 96%. (Scheme 16). Alcohol 52
was oxidized into diketone 53 using several oxidants, such as
Scheme 13. [1,3]-Sigmatropic shift.
acceleration effect. We found that the use of crown ether was
essential for our shift to proceed in a reasonable rate. An
important feature of the [1,3]-sigmatropic shift was that the
geometry of the double bond in the product was exclusively
(E). Thus, triene 41 was treated with KH in the presence of
dibenzo-[18]crown-6 in THF at room temperature. The
rearrangement was completed in 4 h, giving trans-trienes 44
and 45 in a ratio of 12:1 and a combined yield of 85%
(Scheme 11). The stereochemistry of the hydroxy group in the
major product 44 was undesirable whereas that in the minor
45 was correct. This was determined after the IMDA reaction.
Our previous work on quassin synthesis[28b] had shown that
the b-hydroxyketone moiety underwent a retrol-aldol reac-
tion on heating. Thus the major triene 44 was acetylated to the
corresponding acetate 48 which was dissolved in toluene in
sealed tube in the presence of methylene blue. The IMDA
reaction proceeded smoothly, offering tetracyclic acetate 49 in
quantitative yield (Scheme 14). The reaction provided two
newstereocenters at C-5 and C-10, which are founded in most
Scheme 16. Synthesis of a,b-unsaturated lactone 56 a) NaOH, MeOH, rt,
12 h, 96%; b) Dess Martin periodiane, CH2Cl2, rt, 6 h, 96%; c) K-
selectride, THF, rt, 20 min, 97%; d) Ac2O, DMAP, CH2Cl2, rt, 24 h,
100%; e) LDA, toluene/THF 2:1, À308C, 30 min, 87%; f) SOCl2, pyridine,
CH2Cl2, 08C to rt, 12 h, 90%.
PCC, TPAP, and Dess Martin periodinane.[41] The best
conversion was achieved using Dess Martin periodinane[41]
at room temperature, affording ketone 53 in a yield of 96%.
The regio- and stereoselective reduction of the C-7 ketone
group in 53 to the desired a-oriented hydroxy group was
accomplished employing K-selectride as the reducing agent.
The hydride reduction at C-7 proceeded smoothly at room
temperature, resulting in the exclusive formation of the a-
oriented alcohol 54 in 97% yield. The successful reduction of
ketone at C-7 was attributed to the bulky K-selectride and the
shielded environment where the ketone at C-14 was situated.
Initially, acetylation of alcohol 54 was carried out in
refluxing CH2Cl2 with acetic anhydride in the presence of
pyridine and a catalytic amount of DMAP. After seven days,
the acetate 51 was obtained in a 94% yield. It was found that
the amount of DMAP had a dramatic effect on the speed of
the formation of acetate. If ten equivalents of DMAP were
used, the acetylation was complete in 20 min, providing
acetate 51 in a quantitative yield. The constitution of the
acetate was confirmed by an X-ray analysis (see preliminary
communication).
Scheme 14. Intramolecular Diels Alder reaction of triene 44. a) Ac2O,
Et3N, CH2Cl2, rt, 24 h, 100%; b) toluene, methylene blue, sealed tube,
1708C, 120 h, 100%.
tetracyclic and pentacyclic quassinoids. The stereochemistry
of the acetate was determined by the J coupling constant in
the 1H NMR spectrum of 49. The proton resonance at
5.77 ppm, assigned to H-7, was a doublet of doublets with
J7ax,6ax ˆ 12, J7ax,6eq ˆ 4.8 Hz, which indicates that the C-7
acetate was a oriented. The high reaction temperature
(1708C) and long reaction time (120 h) revealed that the
IMDA reaction was simply thermodynamically controlled.
The major drawback of the approach is that inversion of the
configuration at C-7 is required before formation of the
lactone D ring. The minor product 45 of the [1,3]-sigmatropic
shift was also converted into the corresponding acetate 50.
The IMDA reaction of 50 then afforded tetracycle 51 in a
yield of 85%. In the 1H NMR spectrum of 51, the H-7
resonance was a broad single peak (d ˆ 5.40 ppm), thereby
showing that the C-7 acetate was a oriented (Scheme 15).
With an efficient and expeditious route to the tetracyclic
acetate 51 available, we anticipated that the cyclization to
form the pentacyclic carbon framework could be accomplish-
ed via an LDA mediated intramolecular aldol addition.
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However, the initial attempt to afford pentacyclic lactone
failed because the solubility of acetate 51 in THF was poor. To
overcome this problem, we used toluene as a co-solvent.
Treatment of the acetate 51 in toluene/THF 2:1 with LDA
(1.5 equiv) caused the cyclization to complete in 30 min,
giving the pentacyclic lactone 55 in 87% yield. Elimination of
the hydroxy group was realized using SOCl2/pyridine to give
the a,b-unsaturated lactone 56 in 90% yield. The driving force
for this reaction was attributed to the formation of the
thermodynamically more stable conjugated lactone 56
(Scheme 16). The pentacyclic carbon framework 56, which
possesses seven stereocenters at C-5, 7, 8, 9, 10, 12 and 13, in
common in both simalikalactone D 1 and quassimarin 2, has
been constructed successfully.
At this stage, functionalisation of ring D to give an epoxide
across the alkene moiety of the enoate was attempted.
However, several experimental conditions (alkaline perox-
ides) examined failed to effect the desired epoxidation. With
the above failure, the remaining work that could be done was
to introduce 14b-oriented hydrogen (Scheme 17).
Figure 1. X-ray crystal structure of pentacycle 57.
Scheme 18. Allylic oxidation of 57. a) CrO3 ¥ pyridine, CH2Cl2, reflux;
b) CrO3 ¥ pyridine, CH3CN, reflux; c) Cr(CO)6, tBuOOH, CH3CN, reflux.
NaBH4/NiCl2 ¥ 6H2O in methanol which was then immedi-
ately treated with conc. HCl to effect the acetalisation; the
reaction afforded the mixed acetal 59 in an excellent overall
yield. Indeed, the allylic oxidation of ring A in acetal 59 was
feasible without the lactone functionality and the best reagent
was CrO3 ¥ DMP, affording the enone 60 in 81% yield.
Manganese(iii) acetate had been proved to be an efficient
reagent for a-acetoxylation of enones.[42] Thus, enone 60 was
treated with Mn(OAc)3 ¥ 2H2O in dry benzene under reflux
using a Dean and Stark apparatus for separation of the water
of crystallization in manganese acetate, furnishing the a-
acetoxyenone 5 in 80% yield (Scheme 17). The structure and
stereochemistry of the acetate 5 has been confirmed by an
X-ray crystallographic study (Figure 2).
Scheme 17. Synthesis of pentacycle 5. a) NaBH4, NiCl2 ¥ 6H2O, MeOH,
08C to rt, 3 h, 100%; b) Dess Martin periodinane, CH2Cl2, rt; c) i)
NaBH4, NiCl2 ¥ H2O, MeOH, rt, 3 h, ii) conc. HCl, 95%; d) CrO3 ¥ DMP,
CH2Cl2, 08C to rt, 24 h, 81%; e) Mn(OAc)3 ¥ 2H2O, benzene, reflux, 48 h,
80%.
This was realized by a regio- and stereoselective 1,4-
reduction of the conjugated double bond in the unsaturated
lactone 56 with NaBH4/NiCl2 ¥ 6H2O. This protocol had been
used in our previous synthesis of (‡)-quassin 4.[28b] The
reduction occurred at the less hindered convex face, affording
a mixture of saturated lactone 57 and lactol 58 in a ratio of 2:1,
and with the correct stereochemistry at C-14 which was
determined by an X-ray analysis (Figure 1). Lactol 58 could
be oxidized into the saturated lactone 57 by Dess Martin[41]
oxidation.
Functionalisation of ring A was our next objective. The
allylic oxidation of the C-2 methylene in ring A of alkene 57 to
give enone 61 did pose problems and failed to give the desired
enone under a number of different reaction conditions. Our
studies on the synthesis of the tetracyclic quassin had
indicated that the failure was probably due to the instability
of the lactone D ring that could not survive the vigorous
oxidation conditions (Scheme 18).[28a] Hence, the unsaturated
lactone 56 was reduced to the corresponding lactol with
Figure 2. X-ray crystal structure of pentacycle 5.
5494
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 5489 5500

Simalikalactone D and Quassimarin
5489 5500
column chromatography (petroleum ether/Et2O 2:1) yielded the diaster-
Conclusion
iomeric mixture of 15 in a ratio of 1:1 (0.18 g, 88%) as a colourless oil. Rf ˆ
1
0.31 (petroleum ether/Et2O 2:1); H NMR (250 MHz): d (selected) ˆ 5.50
In summary, the advanced pentacyclic intermediate 5, ame-
nable to further elaboration into the target molecules
simalikalactone D (1) and quassimarin (2), has been synthe-
sized from (S)-(‡)-carvone (10) in 21 steps and with an overall
yield of 12%. The synthesis is efficient, stereocontrolled,
enantiospecific, and chirality productive, creating eight new
chiral centres in pentacycle 5, and should provide opportu-
nities for rapid access to simalikalactone D analogues and
other bioactive quassinoids. Research in this direction is
underway.
(brs, 0.5H), 5.56 (brs, 0.5H); IR (neat): nÄ ˆ 3481, 1730 cmÀ1; MS (CI): m/z:
‡
211 [M‡H] ; elemental analysis calcd (%) for C12H18O3: C 68.55, H 8.63;
found: C 68.43, H 8.57.
(S)-(‡)-6a-Hydroxymethylcarvone 16: nBuLi (1.6m in hexane; 2.29 mL,
3.67 mmol) at À788C was added under N2 to a solution of diisopropyl-
amine (0.51 mL, 3.67 mmol) in dry THF (10 mL). After the reaction
mixture was stirred for 20 min at À788C, (S)-(‡)-carvone 10 (0.5 g,
3.34 mmol) in THF (5 mL) containing DMPU (1 mL) was added dropwise.
After the reaction mixture was stirred for 1 h at À788C, a N2 stream
containing gaseous formaldehyde, obtained by thermal decomposition of
paraformaldehyde (2.0 g, dried over P2O5 in vacuo) on heating at 1508C,
was introduced into the reaction mixture. The reaction mixture was stirred
for 5 min at À788C and quenched with saturated aq. NH4Cl. The aqueous
phase was extracted with CH2Cl2 (4 Â ). The combined extracts were
washed with brine (2 Â ), dried (MgSO4), and filtered. Concentration of the
filtrate in vacuo followed by purification through silica gel flash column
chromatography (petroleum ether/Et2O 5:1) yielded the 16 (0.54 g, 90%)
as a colorless oil. Rf ˆ 0.20 (petroleum ether/Et2O 4:1); [a] ˆ ‡13.0 (c ˆ 1.1
in CHCl3); 1H NMR (250 MHz): d ˆ 1.62 (s, 3H), 1.68 (s, 3H), 2.28 (dt, J ˆ
5, 18.5 Hz, 1H), 2.46 (ddd, J ˆ 3.5, 7, 13.7 Hz, 1H), 2.47 2.49 (m, 1H), 2.68
(ddd, J ˆ 4.5, 11, 13 Hz, 1H), 3.20 (brs, 1H), 3.52 3.70 (m, 2H), 4.85 (s,
2H), 6.76 (brs, 1H); IR (neat): nÄ ˆ 3492, 1661 cmÀ1; MS (CI): m/z: 181
Experimental Section
General: Melting points were determined with a Reichert apparatus and
are uncorrected. NMR spectra were recorded on a Bruker WM250
spectrometer at 250.13 MHz (1H) or at 62.89 MHz (13C), on a Bruker
DPX300 spectrometer at 300.13 MHz (1H) or at 75.47 MHz (13C) and
Bruker DPX500 spectrometer at 500.13 MHz (1H) using CDCl3 as solvent
unless otherwise stated. Chemical shift positions were in ppm downfield
from internal tetramethylsilane and coupling constants (J values) are given
in Hz. Peak multiplicities were denoted by s (singlet), brs (broad singlet), d
(doublet), brd (board doublet), dd (doublet of doublets), dt (doublet of
triplets), ddd (doublet of doublet of doublets), t (triplet), q (quartet) and m
‡
[M‡H] ; elemental analysis calcd (%) for C11H16O2: C 73.30, H 8.95;
found: C 72.94, H 9.25.
Silyl ether 17: Prepared using the method described in the previous
experiment from (S)-(‡)-carvone 10 (0.5 g, 3.34 mmol), diisopropylamine
(0.51 mL, 3.67 mmol), nBuLi (1.6m in hexane; 2.29 mL, 3.67 mmol),
2-(trimethylsilyl)ethoxymethyl chloride (0.65 mL, 3.67 mmol) in dry THF
(15 mL) containing DMPU (1 mL). Fractionation through silica gel flash
column chromatography (petroleum ether/Et2O 2:1) yielded the 17 (0.77 g,
82%) as a colorless oil. Rf ˆ 0.48 (petroleum ether/Et2O 3:2); [a] ˆ ‡10.8
(c ˆ 1.0 in CHCl3); 1H NMR (250 MHz): d ˆ 0.01 (s, 9H), 0.88 0.91 (m,
2H), 1.71 (s, 3H), 1.77 (s, 3H), 2.36 2.42 (m, 3H), 2.94 (ddd, J ˆ 5.5, 10,
11.5 Hz, 1H), 3.40 3.43 (m, 3H), 3.88 (dd, J ˆ 3.2, 9 Hz, 1H), 4.82 (brs,
(multiplet). IR spectra were recorded on
a Nicolet 20SXC Fourier
transform spectrometer. Mass spectra were recorded on a VG Micromass
7070F mass spectrometer or on a ThermoFinnigan MAT 95 XL mass
spectrometer. HRMS were recorded at Shanghai Institute of Organic
Chemistry, The Chinese Academy of Sciences, China or on a Thermofin-
nigan MAT 95 XL masss spectrometer. Optical rotations were measured on
a JASCO DIP-300 polarimeter using dichloromethane or chloroform as
solvent. Elemental analyses were carried out at Shanghai Institute of
Organic Chemistry, Academic Sinica, China or at MEDAC Ltd., Depart-
ment of Chemistry, Brunel University, Uxbridge, U.K. All reactions were
monitored by TLC on aluminium percoated with silica gel 60F254 (E.
‡
2H), 6.68 (brs, 1H); IR (neat): nÄ ˆ 1674 cmÀ1; MS (CI): m/z: 281 [M‡H] ;
‡
HRMS calcd for C16H28O2Si: 280.1858; found: 280.1870 [M] .
Keto alcohol 18: nBuLi (1.6m in hexane; 4.63 mL, 7.40 mmol) was added at
À788C under N2 to a solution of diisopropylamine (1.04 mL, 7.40 mmol) in
dry THF (10 mL). After the reaction mixture was stirred for 10 min at
À788C, (S)-(‡)-carvone 10 (0.9 mL, 5.69 mmol) in THF (3 mL) containing
DMPU (2 mL) was added dropwise. The reaction mixture was stirred for
1 h and a solution of the aldehyde 7[25b] (0.90 g, 5.17 mmol) in THF (2 mL)
was added in one portion. The reaction mixture was kept under stirring for
5 min at À788C under N2, and quenched with saturated aq. NH4Cl. The
aqueous phase was extracted with CH2Cl2 (4 Â ) and the combined extracts
were washed with brine (2 Â ), dried (MgSO4), and filtered. Concentration
of the filtrate in vacuo followed by silica gel flash column chromatography
(hexane/Et2O 1:1) yielded 18 (1.04 g, 62%) as a colorless oil. Rf ˆ 0.20
(hexane/Et2O 1:3); 1H NMR (250 MHz): d (selected) ˆ 6.70 (brs, olefin
proton at position 11, 0.5H), 6.80 (brs, olefin proton at position 11, 0.5H);
Merck) and compounds were visualized with
a spray of 5% w/v
dodecamolybdophosphoric acid in EtOH and subsequent heating. Flash
chromatography was perfomed on Merck silica gel (230 400 mesh).
Benzene, toluene, THF and Et2O were freshly distilled from Na/benzo-
phenone under N2. Pyridine, Et3N, N,N'-dimethylpropyleneurea (DMPU)
and diisopropylamine were freshly distilled from calcium hydride.
(S)-(‡)-6a-Methoxycarbonylcarvone 11: nBuLi in hexane (1.6m in hexane;
3.12 mL, 4.67 mmol) was added under N2 at À788C to a solution of
diisopropylamine (0.70 mL, 5.00 mmol) in dry THF (10 mL). After the
reaction mixture was stirred for 20 min at À788C, (S)-(‡)-carvone 10
(0.5 g, 3.34 mmol) in THF (5 mL) containing DMPU (1 mL) was added
dropwise. After the reaction mixture was stirred for 1 h at À788C, methyl
cyanoformate (0.38 mL, 5.00 mmol) was added in one portion. The reaction
mixture was stirred for 5 min at À788C and quenched with saturated aq.
NH4Cl. The aqueous phase was extracted with CH2Cl2 (4 Â ). The
combined extracts were washed with brine (2 Â ), dried (MgSO4), and
filtered. Concentration of the filtrate in vacuo followed by purification
through silica gel flash column chromatography (petroleum ether/Et2O
5:1) yielded the b-ketoester 11 (0.66 g, 95%) as a colorless oil. Rf ˆ 0.46
(petroleum ether/Et2O 5:1); [a] ˆ ‡43.0 (c ˆ 1.2 in CHCl3); 1H NMR
(250 MHz): d ˆ 1.76 (s, 3H), 1.81 (s, 3H), 2.33 2.43 (m, 2H), 3.13 (ddd, J ˆ
5, 11, 13 Hz, 1H), 3.51 (d, J ˆ 13 Hz, 1H), 4.85 4.87 (m, 2H), 6.76 6.77
‡
IR (neat): nÄ ˆ 3501, 1659 cmÀ1; MS (EI): m/z: 325 [M‡H] ; HRMS calcd
‡
for C17H24SO4: 324.1395; found: 324.1373 [M] .
Keto ester 19: Dry pyridine (0.13 mL, 1.6 mmol) and Ac2O (0.20 mL,
1.6 mmol) at room temperature under N2 was added to a solution of 18
(85 mg, 0.40 mmol) in Cl2Cl2 (2.5 mL). The reaction mixture was stirred for
10 h, then H2O was added. Neutralization with saturated aq. NaHCO3 and
extracted with Cl2Cl2 (2 Â ). The combined extracts was washed with brine
(3 Â ), dried (MgSO4) and filtered. Concentration of the filtrate in vacuo
and followed by flash chromatography (hexane/EtOAc 5:1) gave 19 as a
colorless oil (97 mg 90%). Rf ˆ 0.50 (hexane/EtOAc 5:2); [a] ˆ ‡104.8
(m, 1H); IR (neat): nÄ ˆ 1746, 1674 cmÀ1; MS (EI): m/z: 209 [M‡H] ;
‡
‡
HRMS calcd for C12H20NO3: 226.1443; found: 226.1433 [M‡NH4] .
1
Ester 15: NaBH4 (36 mg, 0.96 mmol) was added at 08C in small batches
over 20 min to a stirred solution of 11 (0.2 g, 0.96 mmol) and CeCl3 (0.24 g,
0.96 mmol) in methanol (5 mL). The reaction mixture was stirred for
30 min at 08C and quenched with ice-cold saturated aq. NH4Cl. The
aqueous phase was extracted with CH2Cl2 (4 Â ) and the combined extracts
were washed with brine (2 Â ), dried (MgSO4) and filtered. Concentration
of the filtrate in vacuo followed by purification through silica gel flash
(c ˆ 0.8 in Cl2Cl2); H NMR (250 MHz): d ˆ 1.22 (s, 3H), 1.70 (dd, J ˆ 3.3,
14.2 Hz, 1H), 1.79 (s, 3H), 2.02 (s, 3H), 2.46 (ddd, J ˆ 4.1, 13.7, 14.9 Hz,
1H), 2.71 (dd, J ˆ 4.3, 13.5 Hz, 1H), 4.02 (d, J ˆ 9.0 Hz, 1H), 4.16 (d, J ˆ
11.9 Hz, 1H), 4.29 (d, J ˆ 11.9 Hz, 1H), 4.48 (d, J ˆ 9 Hz, 1H), 4.89 (s, 2H),
5.12 (d, J ˆ 2.9 Hz, 1H); IR (neat): nÄ ˆ 1730, 1630 cmÀ1; MS (EI): m/z: 310
‡
[M] ; elemental analysis calcd (%) for C16H22O6: C 61.92, H 7.15; found: C
61.91, H 7.48.
Chem. Eur. J. 2003, 9, 5489 5500
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5495

T. K. M. Shing et al.
FULL PAPER
Tricycle 20: A solution of the 19 (0.3 g) and methylene blue (1 mg) in dry
benzonitrile (80 mL) was heated under reflux in a sealed tube for 110 h.
After the reaction mixture was cooled to room temperature, the solvent
was removed in vacuo. Purification by silica gel flash column chromatog-
raphy (hexane/Et2O 7:1) afforded 20 (0.12 g, 40%) as a colorless oil. Rf ˆ
0.30 (hexane/Et2O 1:1); 1H NMR (250 MHz): d ˆ 0.74 (s, 3H), 1.20 1.22
(m, 1H), 1.61 (s, 3H), 1.75 (dd, J ˆ 4.5, 13 Hz, 1H), 1.80 (s, 3H), 1.82 2.60
(m, 8H), 5.39 (s, 1H), 6.17 6.18 (m, 1H), 7.03 7.07 (m, 1H); IR (neat):
J ˆ 7.2 Hz, 1H), 2.43 (dt, J ˆ 3.8, 14.2 Hz, 1H), 2.88 (dd, J ˆ 4.6, 13.6 Hz,
1H), 3.55 (dd, J ˆ 7.7, 12.5 Hz, 1H), 3.82 (dd, J ˆ 6.6, 12.3 Hz, 1H), 4.06
(brs, 1H), 4.07 (d, J ˆ 9.0 Hz, 1H), 4.40 (d, J ˆ 8.8 Hz, 1H); 13C NMR
(62.89 MHz): d ˆ 15.3, 22.0, 33.0, 47.9, 55.6, 60.0, 65.1, 78.8, 80.2, 114.8,
143.0, 210.3; IR (film): nÄ ˆ 3430, 3300, 2900, 1770, 1500, 1085 cmÀ1; MS (L-
‡
SIMS); m/z: 227 [M‡H] ; elemental analysis calcd (%) for C12H18O4: C
63.70, H 8.02; found: C 63.41, H 7.84.
Silyl ether 28: Et3N (1 mL), DMAP (100 mg) and tert-butyldimethylsilyl
chloride (1.17 g, 7.7 mmol) were added at room temperature to a solution of
27 (0.7 g, 3.1 mmol) in dry Cl2Cl2 (12 mL). The reaction mixture was stirred
for 48 h, then poured into H2O, extracted with Cl2Cl2 (2 Â ), dried (MgSO4)
and filtered. The solvent was removed under reduced pressure. Flash
chromatography on silica gel (hexane/EtOAc 5:1) gave 28 as a white solid
(0.94 g, 92%). Rf ˆ 0.6 (hexane/EtOAc 2:1); m.p. 70 728C; [a] ˆ ‡67.4
(c ˆ 0.9 in Cl2Cl2); 1H NMR (250 MHz): d ˆ 0.02 (s, 3H), 0.4 (s, 3H), 0.81 (s,
9H), 1.24 (s, 3H), 1.58 (dd, J ˆ 4.3, 14.5 Hz, 1H), 1.74 (s, 3H), 2.38 (dt, J ˆ
3.6, 13.5, 14.5 Hz, 2H), 2.68 (dd, J ˆ 4.4, 13.5 Hz, 1H), 3.44 (d, J ˆ 10.5 Hz,
1H), 3.82 (d, J ˆ 10.5 Hz, 1H), 3.98 (d, J ˆ 3.6 Hz, 1H), 4.19 (d, J ˆ 8.7 Hz,
1H), 4.38 (d, J ˆ 8.7 Hz, 1H), 4.77 (s, 1H), 4.81 (s, 1H); 13C NMR
(62.89 MHz): d ˆ À5.8, À5.7, 15.3, 18.1, 21.5, 25.7, 32.9, 49.3, 55.9, 59.7, 65.5,
78.6, 80.7, 114.3, 143.3, 211.4; IR (neat): nÄ ˆ 3300, 1768 cmÀ1; MS (EI): m/z:
‡
nÄ ˆ 1666 cmÀ1; MS (CI, NH3): m/z: 243 [M‡H] ; HRMS calcd for C17H22O
‡
242.1671; found: 242.1670 [M] .
(S)-(‡)-6,6-Dihydroxymethenylcarvone 24: nBuLi (1.6m in hexane;
30 mL, 45 mmol) was added dropwise under N2 at 08C to a solution of
diisopropylamine (6.3 mL, 45.28 mmol) in dry THF (70 mL). After stirring
for 30 min, the solution was cooled to À788C, followed by dropwise
addition of a solution of (S)-(‡)-carvone 10 (3.84 g, 25.2 mmol) and DMPU
(3 mL, 25.2 mmol) in THF (15 mL). This mixture was kept under stirring
for 1 h at À788C, and then formaldehyde was introduced into the mixture
by decomposition of paraformaldehyde (3.0 g) at 1508C, with smooth
stream of N2, over 2 h. The reaction mixture was allowed to warm up to
À408C, followed by introduction of more formaldehyde (2.0 g). After
finishing the introduction, the reaction mixture was allowed to warm up to
room temperature and stand overnight, quenched with saturated aq. NH4Cl
and extracted with CH2Cl2 (3 Â ). The combined extracts were dried
(MgSO4) and concentrated in vacuo to give an oily residue. Flash
chromatography on silica gel (hexane/EtOAc 8:3) afforded 24 as a white
solid (3.1 g, 75%). Rf ˆ 0.21 (hexane/EtOAc 5:2); m.p. 84 858C; [a] ˆ
‡
340 [M] ; elemental analysis calcd (%) for C18H32SiO4: C 63.48, H 9.47;
found: C 63.51, H 9.85.
Acetal 29: PPTS (10 mg) was added to a solution of 28 (145 mg, 0.42 mmol)
in dry Cl2Cl2 (2 mL). The solution was cooled to 08C, followed by addition
of 2-methoxypropene (0.081 mL, 0.85 mmol). The reaction was stirred for
4 h at 08C and then Et3N (0.07 mL) and H2O were added. The aqueous
layer was extracted with Et2O (2 Â ), dried (MgSO4) and filtered.
Concentration under vacuo and flash chromatography on silica gel
(hexane/Et2O 10:1) gave 29 as a colorless oil (171 mg, 96%). Rf ˆ 0.46
(hexane/Et2O 5:1); [a] ˆ ‡46.0 (c ˆ 1.3 in Cl2Cl2); 1H NMR (250 MHz):
d ˆ 0.01 (s, 3H), 0.03 (s, 3H), 0.81 (s, 9H), 1.18 (s, 3H), 1.28 (s, 3H), 1.29 (s,
3H), 1.68 (dd, J ˆ 4.3, 14.7 Hz, 1H), 1.74 (s, 3H), 2.28 (dt, J ˆ 3.7, 14.2 Hz,
1H), 2.65 (dd, J ˆ 4.3, 13.4 Hz, 1H), 3.12 (s, 3H), 3.45 (d, J ˆ 10.5 Hz, 1H),
3.85 (d, J ˆ 10.5 Hz, 1H), 4.00 (d, J ˆ 2.1Hz, 1H), 4.16 (d, J ˆ 8.1 Hz, 1H),
4.36 (d, J ˆ 8.1 Hz, 1H), 4.74 (s, 1H), 4.79 (s, 1H); 13C NMR (62.89 MHz):
d ˆ À5.7, 15.8, 18.1, 21.3, 24.9, 25.2, 25.7, 31.2, 49.3, 55.1, 59.7, 65.5, 78.2, 79.8,
101.1, 113.9, 143.8, 210.0; IR (neat): nÄ ˆ 1771 cmÀ1; MS (EI): m/z: 381 [M À
1
‡39.1, (c ˆ 1.6 in CH2Cl2); H NMR (250 MHz): d ˆ 1.61 (s, 3H), 1.78 (s,
3H), 2.32 (d, J ˆ 20.4 Hz, 1H), 2.77 (d, J ˆ 20.4 Hz, 1H), 2.98 (dd, J ˆ 3.6,
6.3 Hz, 1H), 3.56 (d, J ˆ 9.9 Hz, 2H), 3.76 3.98 (m, 4H), 4.77 (s, 2H), 6.67
(s, 1H); 13C NMR (62.89 MHz): d ˆ 15.4, 21.6, 18.74, 44.4, 52.6, 64.0, 64.5,
114.4, 134.6, 143.1, 144.7, 204.1; IR (neat): nÄ ˆ 3300, 1630 cmÀ1; MS (EI):
‡
m/z: 192 [M À H2O] ; elemential analysis calcd (%) for C12H18O3: C 68.54,
H 8.62; found: C 68.29, H 8.86.
(S)-(‡)-6,6-(O,O-Isopropylidenebishydroxymethyl)-carvone (25): 2,2-Di-
methoxypropane (3.0 mL, 24.5 mmol) and p-TsOH (25 mg) were added to
a solution of 24 (0.5 g, 23.8 mmol) in CH2Cl2 (4 mL). The reaction mixture
was stirred at room temperature for 2 h. Subsequent purification by flash
chromatography on silica gel (hexane/EtOAc 9:1) gave 25 as a colourless
oil (0.7 g, 96%). Rf ˆ 0.8 (hexane/EtOAc 5:1); [a] ˆ ‡149.7, (c ˆ 1.9 in
‡
MeO] ; elemental analysis calcd (%) for C22H40O5Si: C 64.02, H 9.77;
1
CH2Cl2); H NMR (250 MHz): d ˆ 1.41 (s, 3H), 1.44 (s, 3H), 1.60 (s, 3H),
found: C 64.22, H 9.54.
1.75 (s, 3H), 2.30 (dd, J ˆ 3.6, 14.2 Hz), 1H), 2.90 (dd, J ˆ 3.6, 13.5 Hz, 1H),
3.48 (d, J ˆ 12.2 Hz, 1H), 3.64 3.85 (m, 3H), 4.43 (d, J ˆ 3.3 Hz, 1H), 4.79
(d, J ˆ 8.6 Hz, 2H), 6.61 (s, 1H); 13C NMR (62.89 MHz): d ˆ 15.1, 19.5, 21.1,
25.3, 27.1, 45.2, 48.6, 59.5, 61.9, 63.2, 97.9, 113.8, 144.9, 200.4; IR (neat): nÄ ˆ
Alcohol 30: 1.0m Tetrabutylammonium fluoride in THF (5.0 mL) was
added to a solution of 29 (1.0 g, 2.5 mmol) in dry THF (20 mL) at room
temperature. The reaction mixture was stirred for 0.5 h and poured into
H2O, extracted with Et2O (2 Â ), dried (MgSO4) and filtered. Concentration
under vacuo and flash chromatograhpy on silica gel (hexane/EtOAc 5:1)
gave 30 as a white solid (0.72 g, 96%). Rf ˆ 0.20 (hexane/Et2O 5:2); m.p.
90 928C; [a] ˆ ‡64.8 (c ˆ 0.7 in Cl2Cl2); 1H NMR (250 MHz): d ˆ 1.23 (s,
3H), 1.33 (s, 6H), 1.74 (dd, J ˆ 4.4, 14.2 Hz, 1H), 1.80 (s, 3H), 2.30 (dt, J ˆ
3.6, 14.2 Hz, 1H), 2.83 (dd, J ˆ 3.6, 13.5 Hz, 1H), 3.18 (s, 3H), 3.55 (d, J ˆ
12.2 Hz, 1H), 3.85 (d, J ˆ 12.2 Hz, 1H), 4.04 (d, J ˆ 3.3 Hz, 1H), 4.04 (d,
J ˆ 8.6 Hz, 1H), 4.38 (d, J ˆ 8.6 Hz, 1H), 4.83 4.90 (m, 2H); IR (neat): nÄ ˆ
‡
1662 cmÀ1; MS (EI): m/z: 250 [M] ; elemental analysis calcd (%) for
C15H22O3: C 71.69, H 8.86; found: C 72.02, H 8.74.
Epoxide 26: tert-Butyloxyperoxide (13.9 mL, 101.5 mmol, 70% aq. sol-
ution) and 2n NaOH solution (20 mL) were added to a solution of 25 (5 g,
20.0 mmol) in MeOH (70 mL). The reaction mixture was stirred for 24 h at
458C and then poured into H2O, extracted with Et2O (2 Â ), dried (MgSO4)
and filtered. Concentration under vacuo and flash chromatogaphy on silica
gel (hexane/EtOAc 10:1) gave 26 as a white solid (5 g, 94%). Rf ˆ 0.48
(hexane/EtOAc 5:1); m.p. 68 68.58C; [a] ˆ ‡81.8, (c ˆ 0.88 in CH2Cl2);
1H NMR (250 MHz): d ˆ 1.36 (s, 3H), 1.39 (s, 6H), 1.65 (s, 3H), 1.98 (ddd,
J ˆ 1.8, 4.9, 16.3 Hz, 1H), 2.66 (dd, J ˆ 7.3, 16.3 Hz, 1H), 3.29 (d, J ˆ 7.2 Hz,
1H), 3.46 (d, J ˆ 4.7 Hz, 1H), 3.55(dd, J ˆ 2.1, 12.2 Hz, 1H), 3.81 (d, J ˆ
12.0 Hz, 1H), 4.24 (d, J ˆ 12.2 Hz, 1H), 4.25 (dd, J ˆ 2.1, 12 Hz, 1H), 4.75
(s, 1H), 4.83 (t, J ˆ 1.4 Hz, 1H); 13C NMR (62.89 MHz): d ˆ 15.1, 19.5, 21.1,
25.3, 27.1, 45.2, 48.6, 59.5, 61.9, 63.2, 63.7, 97.9, 113.8, 144.9, 200.4; IR (neat):
‡
1769.6 cmÀ1; MS (EI): m/z: 209 [M À OC(Me)2OMe] ; elemental analysis
calcd (%) for C16H26O5: C 64.40, H 8.78; found: C 64.34, H 9.14.
Keto ester 32: iPr2EtN (129 mg, 1 mmol) and then AcCl (50 mg, 0.6 mmol)
was added dropwise under stirring at 08C under N2 to a solution of 27
(115 mg, 0.5 mmol) in Cl2Cl2 (2 mL). After stirring for a further 4 h at room
temperature, the reaction mixture was purified directly by flash chroma-
tography (hexane/EtOAc 4:1) to afford 32 as colourless crystals (134 mg,
97%). Rf ˆ 0.50 (hexane/EtOAc 1:1); m.p. 130 1318C, [a] ˆ ‡105.0 (c ˆ
1.1 in Cl2Cl2); 1H NMR (250 MHz): d ˆ 1.32 (s, 3H), 1.66 (dd, J ˆ 4.4,
14.8 Hz, 1H), 1.73 (d, J ˆ 4.5 Hz, 1H), 1.79 (s, 3H), 2.00 (s, 3H), 2.45 (dt,
J ˆ 3.9, 14 Hz, 1H), 2.82 (dd, J ˆ 4.5, 13.5 Hz, 1H), 4.03 (d, J ˆ 9.0 Hz, 1H),
4.05 (t, J ˆ 3.8 Hz, 1H), 4.09 (d, J ˆ 11.9 Hz, 1H), 4.22 (d, J ˆ 11.9 Hz, 1H),
4.46 (d, J ˆ 9.0 Hz, 1H), 4.87 (s, 1H), 4.89 (s, 1H); 13C NMR (62.89 MHz):
d ˆ 15.3, 20.5, 21.2, 32.8, 48.9, 53.2, 60.7, 65.1, 78.3, 80.4, 115.1, 142.5, 170.6,
209.4; IR (film): nÄ ˆ 3500, 2950, 1760, 1740, 1250 cmÀ1; MS (L-SIMS): m/z:
‡
nÄ ˆ 1693.4 cmÀ1; MS (EI): m/z: 267 [M‡H] ; elemental analysis calcd (%)
for C15H22O4: C 67.64; H 8.3; found: C 67.26, H 8.3.
Alcohol 27: CF3CO2H (1 mL) was added under stirring at room temper-
ature to a solution of 26 (0.7 g, 2.63 mmol) in EtOH (10 mL). Then the
mixture was stirred for 24 h at 508C. The EtOH was removed in vacuo and
then saturated aq. Na2CO3 was added. The mixture was extracted with
EtOAc (3 Â ). The combined extracts were washed with brine (3 Â ), dried
(MgSO4) and filtered. Concentration of the filtrate in vacuo followed by
flash chromatography (hexane/EtOAc 4:1) afforded 27 as colourless
crystals (0.5 g, 85%). Rf ˆ 0.2 (hexane/EtOAc 1:1); m.p. 150 1538C;
[a] ˆ ‡64.0 (c ˆ 1.0 in CH2Cl2); 1H NMR (500 MHz): d ˆ 1.3 (s, 3H), 1.66
(dd, J ˆ 4.4, 15 Hz, 1H), 1.73 (d, J ˆ 4.3 Hz, 1H), 1.8 (s, 3H), 2.27 (t,
‡
269 [M‡H] ; elemental analysis calcd (%) for C14H20O5: C 62.67, H 7.51;
found: C 62.70, H 7.54.
Silyl ether 33: 2,6-Lutidine (0.45 mL, 3.7 mmol) and TBSOTf (0.64 mL,
2.8 mmol) were sequentially added dropwise under stirring at room
5496
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 5489 5500

Simalikalactone D and Quassimarin
5489 5500
temperature under N2 to a solution of 32 (0.5 g, 1.86 mmol) in Cl2Cl2
(10 mL). After stirring for a further 2 h, the mixture was purified directly by
flash chromatography (hexane/EtOAc 9:1) to give 33 as a white solid
(0.72 g, 100%). Rf ˆ 0.80 (hexane/EtOAc 4:1); m.p. 87.5 888C; [a] ˆ
‡88.0 (c ˆ 1.2 in Cl2Cl2); 1H NMR (500 MHz): d ˆ 0.01 (s, 3H), 0.05 (s,
3H), 0.86 (s, 9H), 1.24 (s, 3H), 1.52 (dd, J ˆ 3.6, 14.8 Hz, 1H), 1.78 (s, 3H),
2.0 (s, 3H), 2.42 (dt, J ˆ 3.5, 13.7 Hz, 1H), 2.75 (dd, J ˆ 4.4, 13.5 Hz, 1H),
3.96 (brs, 1H), 3.99 (d, J ˆ 8.9 Hz, 1H), 4.05 (d, J ˆ 11.9 Hz, 1H), 4.24 (d,
J ˆ 11.9 Hz, 1H), 4.43 (d, J ˆ 9.0 Hz, 1H), 4.84 (s, 1H), 4.85 (s, 1H);
13C NMR (62.89 MHz): d ˆ À5.1, À4.6, 15.8, 17.8, 20.5, 21.3, 25.5, 33.6, 48.5,
52.9, 60.8, 65.3, 78.8, 80.4, 114.9, 143.0, 170.4, 207.5; IR (film): nÄ ˆ 3500,
5-Bromo-3-methylpenta-1,3-diene (37) (from ethyl acetate 39)[38]: Vinyl
bromide (29 mL, 0.42 mol) was added dropwise by condensation with a
cold finger containing dry ice in acetone to a vigorously stirred suspension
of magnesium powder (10 g, 0.42 mol) in dry THF (400 mL) under N2 at
À788C. The suspension was stirred at 08C and 1,2-dibromoethane
(0.04 mL, 0.04 mol) was added as an initiator. When the solution started
to reflux, it was allowed to stirred at 08C for 1 h and then at room
temperature for 2 h. A solution of ethyl acetate 39 (18 mL, 0.19 mol) in
THF (30 mL) was added dropwise to the suspension at 08C over 1 h. The
suspension was allowed to stir at room temperature for 4 h and then
quenched with saturated aq. NH4Cl. The mixture was extracted with Et2O
(3 Â ) and the combined organic extracts were dried (MgSO4) and filtered.
The filtrate was concentrated in vacuo, giving a crude product which was
purified by distillation in vacuo to yield 3-methyl-1,4-pentadien-3-ol (40) as
a colorless liquid (13 g, 70%). B.p. 558C at 40 mmHg; 1H NMR (300 MHz,
C6D6): d ˆ 1.22 (s, 3H), 1.86 (brs, 1H), 4.91 (dd, J ˆ 1.2, 10.5 Hz, 2H), 5.19
(dd, J ˆ 1.2, 17.4 Hz, 2H), 5.83 (dd, J ˆ 10.5, 17.4 Hz, 2H); 13C NMR
(75.47 MHz): d ˆ 27.9, 73.5, 111.9, 144.3.
PBr3 (4 mL, 0.42 mol) was added dropwise under stirring at À108C under
N2 in 10 min to a solution of 3-methyl-1,4-penta-dien-3-ol (40; 10 g,
0.1 mol) in pyridine (400 mg) and Et2O (100 mL). The mixture was stirred
for 30 min and was then quenched with ice water. The mixture was
extracted with Et2O (3 Â ). The combined organic extracts were dried
(MgSO4) and filtered. The filtrate was concentrated in vacuo, giving a crude
product which was purified by distillation in vacuo to yield 5-bromo-3-
methylpenta-1,3-diene (37) (E:Z 3:1, based on NMR analysis) as a pale
yellowliquid (13.1 g, 80%). B.p. 50 8C at 10 mmHg (lit.:[26c] 53 568C,
10 mmHg).
E Isomer 37a: 1H NMR (300 MHz): d ˆ 1.85 (s, 3H), 4.15 (d, J ˆ 8.7 Hz,
2H), 5.12 (d, J ˆ 10.5 Hz, 1H), 5.30 (d, J ˆ 17.4 Hz, 1H), 5.78 (t, J ˆ 8.7 Hz,
1H), 6.38 (dd, J ˆ 10.5, 17.4 Hz, 1H); 13C NMR (75.47 MHz): d ˆ 11.8, 29.3,
115.2, 127.1, 140.2, 140.5; (Z)-isomer 37b: 1H NMR (300 MHz): d ˆ 1.89 (s,
3H), 4.15 (d, J ˆ 8.7 Hz, 2H), 5.30 (d, J ˆ 10.5 Hz, 1H), 5.39 (d, J ˆ 17.4 Hz,
1H), 5.69 (t, J ˆ 8.7 Hz, 1H), 6.80 (dd, J ˆ 10.5, 17.4 Hz, 1H); 13C NMR
(75.47 MHz): d ˆ 20.3, 28.2, 117.5, 125.3, 132.3, 138.6.
3-Methyl-2,4-pentadienyl magnesium bromide (38): A catalytic amount of
I2 was added to a suspension of magnesium powder (900 mg, 37.4 mmol) in
Et2O (40 mL). A solution of 37 (2 g, 12.4 mmol) in Et2O (10 mL) was added
dropwise to the suspension with vigorous stirring at À108C under N2 in 4 h.
After stirring at À108C for 2 h and at room temperature for 2 h, the
Grignard reagent 38 was ready for use.
‡
2950, 1760, 1740, 1250 cmÀ1; MS (EI): m/z: 382 [M] ; elemental analysis
calcd (%) for C20H34O5Si: C 62.79, H 8.96; found: C 63.01, H 9.00.
Keto alcohol 34: Solid NaOH (40 mg, 1 mmol) was added under stirring to
a solution of 33 (200 mg, 0.52 mmol) in MeOH (5 mL). After stirring for 4 h
at room temperature, the mixture was concentrated in vacuo and the
residue was purified by chromatography (hexane/EtOAc 4:1) to give 34 as
a white solid (170 mg, 96%). Rf ˆ 0.60 (hexane/EtOAc 4:1); m.p. 74 758C;
1
[a] ˆ ‡80.0 (c ˆ 1.1 in Cl2Cl2); H NMR (500 MHz): d ˆ 0.01 (s, 3H), 0.06
(s, 3H), 0.86 (s, 9H), 1.24 (s, 3H), 1.53 (ddd, J ˆ 1.6, 4.3, 14.3 Hz, 1H), 1.80
(s, 3H), 2.30 (brs, 1H), 2.38 (dt, J ˆ 1.6, 13.7 Hz, 1H), 2.82 (dd, J ˆ 4.3,
13.4 Hz, 1H), 3.55 (dd, J ˆ 7.7, 12.3 Hz, 1H), 3.80 (dd, J ˆ 6.3, 12.3 Hz, 1H),
3.96 (q, J ˆ 11.8 Hz, 1H), 4.03 (dd, J ˆ 0.8, 8.8 Hz, 1H), 4.36 (d, J ˆ 8.8 Hz,
1
1H), 4.88 (brs, 2H); H NMR (500 MHz, CDCl3‡D2O): d ˆ 0.02 (s, 3H),
0.05 (s, 3H), 0.87 (s, 9H, 1.2 (s, 3H), 1.53 (ddd, J ˆ 1.6, 4.3, 14.3 Hz, 1H),
1.80 (s, 3H), 2.38 (dt, J ˆ 1.6, 13.7 Hz, 1H), 2.82 (dd, J ˆ 4.3, 13.4 Hz, 1H),
3.54 (d, J ˆ 12.3 Hz, 1H), 3.79 (d, J ˆ 12.3 Hz, 1H), 3.96 (brs, 1H), 4.03 (d,
J ˆ 8.8 Hz, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.88 (brs, 2H); 13C NMR
(62.89 MHz): d ˆ À5.1, À4.6, 15.5, 17.8, 22.0, 25.5, 33.6, 47.3, 55.0, 60.0, 65.0,
78.9, 80.2, 114.3, 143.4, 211.6; IR (film): nÄ ˆ 3400, 2950, 2880, 1780, 1260,
‡
1130 cmÀ1; MS (EI): m/z: 339 [M À H] ; elemental analysis calcd (%) for
C18H32O4Si: C 63.33, H 9.45; found: C 63.40, H 9.67.
Keto aldehyde 35: TPAP (15 mg) was added at room temperature to a
mixture of 34 (285 mg, 0.85 mmol), NMO (172 mg, 1.47 mmol) and 4 ä MS
(50 mg) in Cl2Cl2 (4 mL). The mixture was stirred for 2 h and then filtered
through a short silica gel column. Concentration of the filtrate in vacuo
followed by flash chromatography (hexane/EtOAc 9:1) afforded 35 as a
white solid (242 mg, 84%). Rf ˆ 0.70 (hexane/EtOAc 3:1); m.p. 66 678C;
[a] ˆ ‡121.0 (c ˆ 3.0 in Cl2Cl2); 1H NMR (500 MHz): d ˆ 0.001 (s, 6H),
0.83 (s, 9H), 1.16 (s, 3H), 1.66 (s, 1H), 1.71 (ddd, J ˆ 2.9, 4.5, 13.2 Hz, 1H),
2.25 (dt, J ˆ 3.4, 13.4 Hz, 1H), 3.39 (dd, J ˆ 4.4, 13.1 Hz, 1H), 3.90 (brs,
1H), 4.31 (d, J ˆ 9.4 Hz, 1H), 4.43 (d, J ˆ 9.3 Hz, 1H), 4.63 (s, 1H), 4.80
(brs, 1H), 9.64 (brs, 1H); 13C NMR (62.89 MHz): d ˆ À5.1, À4.6, 15.4, 17.8,
21.7, 25.5, 33.4, 47.5, 63.7, 64.2, 78.4, 81.8, 114.1, 142.5, 198.2, 201.7; IR (film):
Triene 41: tert-Butyloxyperoxide (13.9 mL, 101.5 mmol, 70% aq. solution)
and 2n NaOH solution (20 mL) was added to a solution of aldehyde 35
(64 mg, 0.19 mmol) in Et2O (2 mL). After stirring for 5 min, the reaction
was quenched with saturated aq. NH4Cl and extracted with Et2O (3 Â ). The
combined organic extracts was washed with brine (3 Â ), dried (MgSO4)
and filtered. Concentration of the filtrate in vacuo followed by flash
chromatography (hexane/EtOAc 9:1) afforded 41 as a colourless oil
(68 mg, 80%). Rf ˆ 0.80 (hexane/EtOAc 5:1); [a] ˆ À6.5 (c ˆ 2.6 in Cl2Cl2);
1H NMR (500 MHz): d ˆ 0.01 (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H), 1.13 (s,
3H), 1.16 (s, 3H), 1.52 (dd, J ˆ 4.7, 14.0 Hz, 1H), 1.8 (s, 3H), 2.30 (dt, J ˆ
3.5, 14.0 Hz, 1H), 3.30 (dd, J ˆ 4.2, 13.6 Hz, 1H), 3.67 (J ˆ 11.3 Hz, 1H),
3.90 (brs, 1H), 4.07 (d, J ˆ 9.5 Hz, 1H), 4.36 (d, J ˆ 9.8 Hz, 1H), 4.83 (d, J ˆ
11.6 Hz, 1H), 4.93 5.16 (m, 6H), 5.72 (dd, J ˆ 10.7, 17.5 Hz, 1H), 5.91 (dd,
J ˆ 10.9, 17.5 Hz, 1H); 13C NMR (62.89 MHz): d ˆ À5.2, À4.6, 15.9, 17.7,
22.3, 23.0, 25.5, 33.7, 48.6, 50.1, 56.2, 65.9, 78.0, 79.5, 81.1, 112.6, 114.6, 115.1,
141.8, 144.2, 192.5; IR (film) nÄ ˆ 3458, 2932, 1748, 1112 cmÀ1; MS (EI): m/z:
‡
nÄ ˆ 2950, 1698, 1518 cmÀ1; MS (FAB): m/z: 339 [M‡H] ; HRMS calcd for
‡
C19H30O4Si: 339.1986; found: 339.1987 [M‡H] .
(Z)-3-Methyl-5-bromopenta-1,3-diene (37b) (from cis-3-methyl-2-penten-
4-yn-1-ol): NaBH4 (0.8 g, 21 mmol) was added under stirring under H2
atmosphere to a solution of Ni(OAc)2 ¥ 4H2O (5 g, 20 mmol) in EtOH
(150 mL). The resulting black suspension was stirred for 30 min and cis-3-
methyl-2-penten-4-yn-1-ol (11 mL, 0.1 mol) and ethandiamine (2.6 mL)
were added under stirring at room temperature under H2. The mixture
was stirred overnight under H2 at atmospheric pressure and filtered
through a short pad of Celite. The filtrate was concentrated and anhydrous
Et2O was added to the residue. The mixture was filtered through a short
silica gel column. The eluant was concentrated in vacuo, giving a crude
product which was purified by distillation in vacuo to yield (Z)-3-
methylpenta-1,3-dien-5-ol (36b) as a colorless liquid (7.3 g, 86%): b.p.
428C at 1 mmHg.
‡
‡
421 [M‡H] ; HRMS calcd for C24H40O4Si: 420.2695; found: 420.2691 [M] .
Triene 44 and 45: KH (33 mg, 0.83 mmol) was added under stirring at room
temperature under N2 to a solution of triene 41 (30 mg, 0.07 mmol) and
dibenzo-[18]crown-6 (25 mg, 0.07 mmol) in THF (4 mL). The mixture was
stirred for 4 h at room temperature and then quenched with H2O, extracted
with Et2O (2 Â ). The combined extracts were washed with brine (3 Â ),
dried (MgSO4) and filtered. Concentration of the filtrate in vacuo followed
by flash chromatography (hexane/EtOAc 19:1) gave 44 and 45 (44 24 mg
and 45 2 mg, 85%).
PBr3 (2 mL, 21 mmol) was added dropwise under stirring at À308C under
N2 within 10 min to a solution of (Z)-3-methylpenta-1,3-dien-5-ol (36b; 5 g,
51 mmol) in pyridine (200 mg) and Et2O (50 mL). The mixture was
continued for 30 min at À308C, then quenched with ice-water. The organic
layer was separated and the aqueous was extracted with Et2O (2 Â ). The
combined organic extracts were washed with brine (3 Â ), dried (MgSO4)
and filtered. Concentration of filtrate and followed by distillation in vacuo
afforded (Z)-3-methyl-5-bromopenta-1,3-diene (37b), together with
a
Triene 44: white solid; Rf ˆ 0.60 (hexane/EtOAc 5:1); m.p. 90 918C; [a] ˆ
‡38.0 (c ˆ 2.0 in Cl2Cl2); 1H NMR (500 MHz): d ˆ 0.02 (s, 3H), 0.04 (s,
3H), 0.87 (s, 9H), 1.2 (s, 3H), 1.50 (dd, J ˆ 1.6, 4.5 Hz, 1H), 1.72 (s, 3H),
1.85 (s, 3H), 2.26 2.33 (m, 1H), 2.39 (dt, J ˆ 3.5, 13.9 Hz, 1H), 2.50 (dd,
small amount of the (E)-isomer 37a as a pale yellowliquid ( Z:E 6:1,
determined by 1H NMR) (6.8 g, 83%). B.p. 908C at 20 mmHg (lit.:[36c]
528C, 14 mmHg).
Chem. Eur. J. 2003, 9, 5489 5500
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5497

T. K. M. Shing et al.
FULL PAPER
J ˆ 5.8, 15.4 Hz, 1H), 2.8 (d, J ˆ 7.1 Hz, 1H), 3.03 (dd, J ˆ 4.3, 13.5 Hz, 1H),
3.78 3.82 (m, 1H), 3.94 (brs, 1H), 4.04 (d, J ˆ 9.2 Hz, 1H), 4.39 (d, J ˆ
9.1 Hz, 1H), 4.92 (brs, 1H), 4.95 (d, J ˆ 10.7 Hz, 1H), 4.98 (brs, 1H), 5.10
(d, J ˆ 17.4 Hz, 1H), 5.57 (t, J ˆ 7.1Hz, 1H), 6.38 (dd, J ˆ 10.7, 17.4 Hz, 1H);
13C NMR (62.89 MHz): d ˆ À5.2, À4.7, 11.8, 15.6, 17.7, 22.2, 25.4, 31.5, 34.2,
47.8, 57.8, 65.8, 70.7, 78.8, 80.6, 110.8, 114.7, 129.1, 135.6, 141.2, 144.9, 195.5;
3H), À0.04 (s, 3H), 0.71 (s, 3H), 0.84 0.93 (m, 1H), 0.95 (s, 9H), 1.16 1.22
(m, 1H), 1.29 (s, 3H), 1.50 1.58 (m, 5H), 1.75 (brd, J ˆ 14.4 Hz, 1H),
1.83 1.92 (m, 2H), 1.97 2.06 (m, 4H), 2.25 (dd, J ˆ 4.2, 13.4 Hz, 1H), 2.62
(brd, J ˆ 13.4 Hz, 1H), 3.46 (d, J ˆ 8.8 Hz, 1H), 3.86 (brs, 1H), 4.29 (d, J ˆ
8.8 Hz, 1H), 5.27 (brs, 1H), 5.58 (brs, 1H); 13C NMR (62.89 MHz): d ˆ
À5.1, À4.4, 12.7, 15.9, 17.8, 21.2, 21.3, 22.5, 25.5, 27.7, 35.3, 36.4, 40.2, 44.8,
51.5, 68.3, 69.2, 78.3, 79.8, 121.0, 133.7, 170.4, 201.3; IR (film): nÄ ˆ 2954, 2857,
‡
IR (film): nÄ ˆ 3500, 2930, 1758, 1150 cmÀ1; MS (EI): m/z: 419 [M À H] ;
‡
‡
HRMS calcd for C24H40O4Si: 420.2696; found: 420.2691 [M] .
1767, 1745, 1248, 1107 cmÀ1; MS (EI): m/z: 462 [M] ; HRMS calcd for
‡
C26H42O5SiNa: 485.2699; found: 485.2718 [M‡Na] .
Triene 45: colourless oil; Rf ˆ 0.50 (hexane/EtOAc 5:1); [a] ˆ ‡68.0 (c ˆ
1
0.7, in Cl2Cl2); H NMR (500 MHz): d ˆ 0.02 (s, 3H), 0.05 (s, 3H), 0.88 (s,
Tetracycle 51 (from tetracycle 54): DMAP (100 mg) and Ac2O (0.1 mL,
1 mmol) was added to a stirred solution of 54 (40 mg, 0.097 mmol) in Cl2Cl2
(4 mL). The mixture was stirred overnight under N2 and direct flash
chromatography (hexane/EtOAc 19:1) afforded 51 as a white solid (44 mg,
100%). Rf ˆ 0.60 (hexane/EtOAc 6:1); m.p. 145 1478C; [a] ˆ ‡14.2 (c ˆ
1.4 in Cl2Cl2); 1H NMR (500 MHz, C6D6): d ˆ À0.07 (s, 3H), À0.04 (s, 3H),
0.71 (s, 3H), 0.84 0.93 (m, 1H), 0.95 (s, 9H), 1.16 1.22 (m, 1H), 1.29 (s,
3H), 1.50 1.58 (m, 5H), 1.76 (d, J ˆ 14.4 Hz, 1H), 1.88 1.97 (m, 2H),
1.97 2.06 (m, 4H), 2.26 (dd, J ˆ 4.2, 13.4 Hz, 1H), 2.62 (d, J ˆ 13.4 Hz,
1H), 3.46 (d, J ˆ 8.8 Hz, 1H), 3.86 (brs, 1H), 4.29 (d, J ˆ 8.8 Hz, 1H), 5.27
(brs, 1H), 5.58 (brs, 1H); 13C NMR (62.89 MHz): d ˆ À5.1, À4.4, 12.7, 15.9,
17.8, 21.2, 21.3, 22.5, 25.5, 27.7, 35.3, 36.4, 40.2, 44.8, 51.5, 68.3, 69.2, 78.3,
79.8, 121.0, 133.7, 170.4, 201.3; IR (film): nÄ ˆ 2954, 2857, 1767, 1745, 1248,
9H), 1.2 (s, 3H), 1.54 (ddd, J ˆ 1.6, 4.5, 14.4 Hz, 1H), 1.74 (s, 3H), 1.87 (s,
3H), 2.28 2.44 (m, 3H), 2.62 2.72 (m, 1H), 2.94 (dd, J ˆ 4.3, 13.3 Hz,
1H), 3.76 3.80 (m, 1H), 3.94 (brs, 1H), 4.17 (d, J ˆ 9.0 Hz, 1H), 4.44 (d,
J ˆ 9.0 Hz, 1H), 4.89 4.96 (m, 3H), 5.11 (d, J ˆ 17.4 Hz, 1H), 5.56 (t, J ˆ
7.1 Hz, 1H), 6.39 (dd, J ˆ 10.7, 17.4 Hz, 1H); 13C NMR (62.89 MHz): d ˆ
À5.0, À4.5, 11.9, 15.8, 17.8, 22.1, 25.6, 30.7, 34.6, 48.1, 57.7, 66.0, 71, 78.7, 80.8,
111.1, 114.7, 129.3, 136.2, 141.3, 145.4, 196.6; IR (film): nÄ ˆ 3500, 2930, 1758,
‡
1150 cmÀ1; MS (EI): m/z: 419 [M À H] ; HRMS calcd for C24H40O4Si:
‡
420.2696; found: 420.2690 [M] .
Acetate 48: DMAP (10 mg) and Ac2O (0.5 mL, 4.9 mmol) at room
temperature under N2 were added under stirring to a solution of 44
(400 mg, 0.95 mmol) in Cl2Cl2 (10 mL) and Et3N (1 mL, 7.2 mmol). Stirring
was continued overnight. Direct flash chromatography (hexane/EtOAc
19:1) gave acetate 48 as a white solid (440 mg, 100%). Rf ˆ 0.60 (hexane/
EtOAc 5:1); m.p. 80 828C; [a] ˆ ‡54.0 (c ˆ 2.0 in Cl2Cl2); 1H NMR
(500 MHz): d ˆ 0.02 (s, 3H), 0.04 (s, 3H), 0.87 (s, 9H), 1.2 (s, 3H), 1.49 (ddd,
J ˆ 2.6, 8.9, 14.4 Hz, 1H), 1.70 (s, 3H), 1.86 (s, 3H), 1.92 (s, 3H), 2.43 (dt,
J ˆ 2.8, 13.4 Hz, 1H), 2.61 2.70 (m, 2H), 3.04 (dd, J ˆ 4.7, 13.2 Hz, 1H),
3.92 (brs, 1H), 3.99 (d, J ˆ 8.8 Hz, 1H), 4.43 (d, J ˆ 9.0 Hz, 1H), 4.89 4.94
(m, 3H), 5.06 (d, J ˆ 17.7 Hz, 1H), 5.28 (dd, J ˆ 3.5, 9.6 Hz, 1H), 5.39 (t, J ˆ
8.7 Hz, 1H), 6.33 (dd, J ˆ 10.7, 17.4 Hz, 1H); 13C NMR (62.89 MHz): d ˆ
À5.1, À4.7, 11.6, 15.8, 17.8, 20.6, 20.7, 25.5, 29.3, 34.5, 47.6, 56.1, 67.1, 72.2,
78.4, 80.7, 111.0, 115.3, 127.7, 136.3, 141.1, 145.0, 169.6, 200.0; IR (film): nÄ ˆ
‡
1107 cmÀ1; MS (EI): m/z: 462 [M] ; HRMS calcd for C26H42O5SiNa:
‡
485.2699; found: 485.2718 [M‡Na] ; elemental analysis calcd (%) for
C26H42O5Si: C 67.49, H 9.15; found: C 67.86, H 8.94.
Tetracycle 52: Solid NaOH (20 mg, 0.5 mmol) was added under stirring at
room temperature to a solution of 49 (120 mg, 0.26 mmol) in MeOH
(5 mL). The mixture was further stirred at 12 h. Concentration of the
reaction mixture in vacuo followed by flash chromatography (hexane/
EtOAc 19:1) gave 52 as a colourless oil (115 mg, 96%). Rf ˆ 0.35 (hexane/
EtOAc 6:1); [a] ˆ ‡78.0 (c ˆ 2.6 in Cl2Cl2); 1H NMR (500 MHz): d ˆ 0.01
(s, 3H), 0.03 (s, 3H), 0.84 (s, 9H), 0.88 (s, 3H), 1.07 1.10 (m, 1H), 1.14
1.28 (m, 5H), 1.62 1.68 (m, 5H), 2.0 2.27 (m, 6H), 3.97 (brs, 1H), 4.19
4.23 (m, 1H), 4.34 (d, J ˆ 8.6 Hz, 1H), 4.44 (d, J ˆ 8.6 Hz, 1H), 5.32 (brs,
1H); 13C NMR (62.89 MHz): d ˆ À5.1, À4.5, 12.2, 15.6, 17.7, 21.3, 22.4, 25.5,
28.0, 29.6, 34.9, 36.3, 45.8, 49.5, 56.7, 64.1, 67.8, 78.9, 79.2, 120.8, 133.3, 196.9;
‡
2957, 2659, 1767, 1745, 1252, 1231, 1116 cmÀ1; MS (EI): m/z: 462 [M] ;
‡
HRMS calcd for C26H42O5SiNa: 485.2699, found: 485.2735 [M‡Na] .
Tetracycle 49: A solution of 48 (440 mg, 0.95 mmol) and methylene blue
(10 mg) in toluene (5 mL) was refluxed under stirring in a sealed tube for
110 h at 1708C. Direct flash chromatography (hexane/EtOAc 19:1) gave 49
as a colourless oil (440 mg, 100%). Rf ˆ 0.58 (hexane/EtOAc 6:1); [a] ˆ
‡130.0 (c ˆ 0.4 in Cl2Cl2); 1H NMR (500 MHz, C6D6): d ˆ 0.002 (s, 3H),
0.02 (s, 3H), 0.73 (s, 3H), 0.88 1.04 (m, 11H), 1.42 1.67 (m, 12H), 1.73
1.85 (m, 3H), 2.03 (dt, J ˆ 3.3, 13.6 Hz, 1H), 2.29 (ddd, J ˆ 2.6, 4.8, 12.2 Hz,
1H), 3.95 (brs, 1H), 4.49 (dd, J ˆ 9.6 Hz, 2H), 5.2 (brs, 1H), 5.62 (dd, J ˆ
4.9, 12 Hz, 1H); 13C NMR (62.89 MHz): d ˆ À5.1, À4.5, 12.3, 15.7, 17.8,
21.0, 21.3, 22.4, 25.5, 26.7, 28.0, 34.8, 36.2, 45.3, 49.8, 54.6, 64.9, 69.7, 78.7,
79.4, 121.1, 132.9, 169.4, 199.9; IR (film): nÄ ˆ 2955, 2856, 1769, 1742, 1375,
‡
IR (film): nÄ ˆ 3458, 2953, 1766, 1255, 1114 cmÀ1; MS (EI): m/z: 420 [M] ;
‡
HRMS calcd for C24H40O4Si: 420.2696; found: 420.2712 [M] .
Tetracycle 53: Dess Martin periodiane[41] (120 mg, 0.28 mmol) was added
under stirring at room temperature under N2 to a solution of 52 (100 mg,
0.24 mmol) in Cl2Cl2 (10 mL). After stirring for 6 h, the reaction mixture
was filtered through a short silica gel column. Concentrated of the eluant in
vacuo followed by flash chromatography (hexane/EtOAc 97:3) gave 53 as a
white solid (96 mg, 96%). Rf ˆ 0.55 (hexane/EtOAc 6:1); m.p. 133 1358C;
[a] ˆ ‡94.0 (c ˆ 2.1 in Cl2Cl2); 1H NMR (500 MHz): d ˆ 0.03 (s, 3H), 0.04
(s, 3H), 0.89 (s, 9H), 0.91 (s, 3H), 1.10 1.23 (m, 4H), 1.55 (s, 3H), 1.74
1.76 (m, 2H), 2.00 2.12 (m, 4H), 2.31 (dd, J ˆ 9.8, 13.3 Hz, 1H), 2.42 (d,
J ˆ 14.7 Hz, 1H), 2.78 (dd, J ˆ 4.6, 18.1 Hz, 1H), 3.97 (brs, 1H), 4.04 (d, J ˆ
8.2 Hz, 1H), 4.49 (d, J ˆ 8.2 Hz, 1H), 5.39 (brs, 1H); 13C NMR
(62.89 MHz): d ˆ À5.1, À4.5, 12.0, 15.7, 17.7, 20.6, 22.1, 25.5, 27.6, 33.6,
35.1, 40.1, 44.8, 50.4, 64.0, 70.9, 78.4, 81.9, 122.0, 131.9, 201.0, 203.5; IR
‡
1237, 1092 cmÀ1; MS (EI): m/z: 462 [M] ; HRMS calcd for C26H42O5Si:
‡
462.2801; found: 462.2801 [M] .
Acetate 50: DMAP (5 mg) and Ac2O (0.2 mL, 2 mmol) were added under
stirring at room temperature under N2 to a solution of 45 (114 mg,
0.27 mmol) in Cl2Cl2 (4 mL) and Et3N (0.5 mL, 3.6 mmol). Stirring was
continued overnight. Direct flash chromatography (hexane/EtOAc 19:1)
afforded 50 as a colourless oil (120 mg, 96%). Rf ˆ 0.55 (hexane/EtOAc
5:1); [a] ˆ ‡56.0 (c ˆ 3.2 in Cl2Cl2); 1H NMR (500 MHz): d ˆ 0.01 (s, 3H),
0.03 (s, 3H), 0.88 (s, 9H), 1.2 (s, 3H), 1.53 (ddd, J ˆ 1.5, 4.3, 14.4 Hz, 1H),
1.74 (s, 3H), 1.83 (s, 3H), 1.93 (s, 3H), 2.39 2.42 (m, 2H), 2.92 (dd, J ˆ 4.2,
13.1 Hz, 1H), 3.10 (dt, J ˆ 9.6, 14.8 Hz, 1H), 3.93 (brs, 1H), 3.95 (d, J ˆ
9.1Hz, 1H), 4.44 (d, J ˆ 9.2 Hz, 1H), 4.83 (s, 1H), 4.85 (s, 1H), 4.93 (d, J ˆ
10.7 Hz, 1H), 5.08 (d, J ˆ 17.3 Hz, 1H), 5.15 (dd, J ˆ 2.7, 10.1 Hz, 1H), 5.32
(t, J ˆ 7.7 Hz, 1H), 6.30 (dd, J ˆ 10.7, 17.3 Hz, 1H); 13C NMR (62.89 MHz):
d ˆ À5.1, À4.6, 11.8, 15.9, 17.8, 20.6, 21.1, 25.5, 28.5, 34.5, 49.4, 55.9, 65.8,
71.3, 78.7, 80.9, 111.1, 115.3, 127.9, 136.5, 141.2, 143.6, 170.2, 199.8; IR (film):
‡
(film): nÄ ˆ 2959, 2931, 1781, 1728, 1272, 1121 cmÀ1; MS (EI): m/z: 418 [M] ;
‡
HRMS calcd for C24H38O4Si: 418.2539; found: 418.2528 [M] .
Tetracycle 54: K-selectride (0.1 mL, 1m in THF) was added under stirring
by syringe under N2 at room temperature to a solution of 53 (33 mg,
0.078 mmol) in THF (4 mL). After stirring for 20 min, wet Et2O (10 mL)
was added to quench the reaction which was filtered through a short silica
gel. Concentration of the filtrate in vacuo followed by flash chromatog-
raphy (hexane/EtOAc 19:1) afforded 54 as a white solid (32 mg, 97%).
Rf ˆ 0.65 (hexane/EtOAc 6:1); m.p. 105 1078C; [a] ˆ ‡7.5 (c ˆ 2.7 in
Cl2Cl2); 1H NMR (500 MHz): d ˆ 0.01 (s, 6H), 0.83 (s, 9H), 0.89 (s, 3H),
1.18 (s, 3H), 1.16 1.23 (m, 3H), 1.60 1.72 (m, 4H), 2.69 2.74 (d, J ˆ
13.3 Hz, 1H), 3.67 3.71 (d, J ˆ 8.8 Hz, 1H), 3.96 3.98 (t, J ˆ 2.1 Hz, 1H),
4.24 (brs, 1H), 4.50 (d, J ˆ 8.8 Hz, 1H), 5.29 (brs, 1H), 5.32 (d, J ˆ 2.4 Hz,
1H); 1H NMR (500 MHz, CDCl3‡D2O): d0.01(s, 3H), 0.04 (s, 3H), 0.83 (s,
3H), 0.89 (s, 3H), 1.09 1.36 (m, 8H), 1.60 1.72 (m, 4H), 1.92 2.04 (m,
3H), 2.08 2.26 (m, 2H), 2.71 (d, J ˆ 14.2 Hz, 1H), 3.68 (d, J ˆ 8.8 Hz, 1H),
3.97 (brs, 1H), 4.24 (brs, 1H), 4.54 (brs, 1H); 13C NMR (62.89 MHz): d ˆ
À5.1, À4.4, 12.5, 15.6, 17.8, 21.4, 22.5, 25.6, 27.6, 28.5, 35.3, 36.4, 38.8, 45.1,
52.8, 69.1, 79.0, 80.3, 120.5, 134.4, 192.0; IR (film): nÄ ˆ 3496, 2954, 2858,
‡
nÄ ˆ 2954, 2858, 1767, 1743, 1443, 1372, 1233 cmÀ1; MS (EI): m/z: 462 [M] ;
‡
HRMS calcd for C26H43O5Si: 463.2874; found: 463.2862 [M‡H] .
Tetracycle 51 (from Diels Alder reaction): A solution of 50 (120 mg,
0.26 mmol) and methylene blue (10 mg) in toluene (5 mL) was refluxed
under stirring sealed in a tube for 110 h at 1708C. Direct flash chromatog-
raphy (hexane/EtOAc 19:1) gave 51 as a white solid (68 mg, 85%) and
recoveed 50 (40 mg). Rf ˆ 0.55 (hexane/EtOAc 6:1); m.p. 145 1478C;
[a] ˆ ‡14.2 (c ˆ 1.4 in Cl2Cl2); 1H NMR (500 MHz, C6D6): d ˆ À0.07 (s,
5498
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 5489 5500

Simalikalactone D and Quassimarin
5489 5500
‡
1747, 1253, 1108 cmÀ1
C24H40O4Si: 420.2696; found: 420.2675 [M] .
;
MS (EI): m/z: 420 [M] ; HRMS calcd for
71.8, 72.9, 76.0, 81.4, 98.2, 120.7, 134.9; IR (film): nÄ ˆ 2880, 1125, 1080 cmÀ1
;
‡
‡
MS (EI): m/z: 462 [M] ; HRMS calcd for C27H46O4Si: 462.3165; found:
‡
462.3119 [M] .
Pentacycle 55: LDA (0.5 mL, 0.32m, 0.16 mmol) dropwise at À308C w as
added to a stirred solution of 51 (60 mg, 0.13 mmol) in toluene/THF (4 mL,
2:1). The mixture was stirred at À308C for 0.5 h, quenched by 1% aq. HCl,
extracted with Cl2Cl2 (3 Â ). The combined extracts were washed with brine
(3 Â ), dried (MgSO4) and filtered. Concentration of the filtrate in vacuo
followed by flash chromatography (hexane/EtOAc 3:1) gave 55 as a
colourless oil (52 mg, 87%). Rf ˆ 0.30 (hexane/EtOAc 3:1); [a] ˆ ‡45.0
(c ˆ 1.4 in Cl2Cl2); 1H NMR (500 MHz): d ˆ 0.10 (s, 3H), 0.15 (s, 3H), 0.75
(s, 3H), 0.89 (s, 9H), 1.17 1.25 (m, 1H), 1.28 (s, 3H), 1.58 2.04 (m, 11H),
2.21 2.25 (m, 3H), 2.46 2.52 (m, 2H), 2.76 (d, J ˆ 14 Hz, 1H), 3.03 (t, J ˆ
7.5 Hz, 1H), 3.67 (d, J ˆ 9.3 Hz, 1H), 3.82 (s, 1H), 4.36 (d, J ˆ 9.3 Hz, 1H),
4.43 (d, J ˆ 5.3 Hz, 1H), 5.39 (brs, 1H), 5.92 5.93 (d, J ˆ 2.7 Hz, 1H);
13C NMR (62.89 MHz): d ˆ À5.0, À4.7, 12.1, 17.3, 17.7, 21.1, 22.1, 25.6, 27.7,
28.7, 33.6, 33.7, 37.8, 38.8, 41.4, 46.3, 75.2, 78.1, 78.4, 82.7, 121.6, 133.1, 172.8;
IR (film): nÄ ˆ 3389, 2952, 1753, 1260, 1196 cmÀ1; MS (CI): m/z: 463
Pentacycle 60: A solution of 59 (18 mg, 0.04 mmol) in CH2Cl2 (1 mL) was
added dropwise at 08C to a solution of CrO3 (60 mg, 0.6 mmol) and 3,5-
dimethylpyrazole (60 mg, 0.6 mmol) in CH2Cl2 (3 mL). The reaction
mixture was stirred for 24 h and filtered through
a pad of Celite.
Concentration of the filtrate in vacuo followed by flash column chroma-
tography (hexane/Et2O 4:1) afforded 60 (10 mg, 81%) as a colorless oil and
recovered the starting material 59 (6 mg). Rf ˆ 0.31 (hexane/EtOAc 2:1);
[a] ˆ ‡81.5 (c ˆ 0.6 in CHCl3); 1H NMR (300 MHz): d ˆ 0.02 (s, 3H), 0.03
(s, 3H), 0.86 (s, 9H), 0.93 (s, 3H), 1.24 (s, 3H), 1.92 (s, 3H), 1.47 2.56 (m,
9H), 3.09 (d, J ˆ 13.2 Hz, 1H), 3.35 (d, J ˆ 10.2 Hz, 1H), 3.36 (s, 3H), 3.63
(s, 1H), 3.84 (s, 1H), 4.14 (d, J ˆ 8.1 Hz, 1H), 4.83 (d, J ˆ 3 Hz, 1H), 5.89 (s,
1H); 13C NMR (75.47 MHz): d ˆ À4.6, À4.0, 13.9, 18.3, 22.4, 22.8, 26.2,
27.6, 28.4, 28.8, 30.2, 35.7, 40.8, 42.8, 43.8, 45.8, 52.5, 55.2, 71.0, 72.4, 75.2,
82.0, 98.4, 127.0, 164.1, 199.3; IR (film): nÄ ˆ 1697, 1650, 1517, 1459 cmÀ1; MS
‡
‡
‡
(CI): m/z (%): 477 [M‡H] ; HRMS calcd for C27H44O5Si: 477.3020; found:
[M‡H] ; HRMS calcd for C26H43O5Si: 463.2874; found: 463.2867 [M‡H] .
‡
477.3031 [M‡H] .
Pentacycle 56: A solution of 55 (20 mg, 0.043 mmol) in Cl2Cl2 (5 mL) at
08C was added dropwise by syringe under stirring to a solution of pyridine
(0.2 mL) and SOCl2 (0.1 mL) in Cl2Cl2 (10 mL). The mixture was stirred for
12 h at room temperature under N2, quenched with saturated aq. NaHCO3
and extracted with Cl2Cl2 (3 Â ). The combined extracts was washed with
brine (3 Â ), dried (MgSO4) and filtered. Concentration of the filtrate in
vacuo and followed by flash chromatography (Cl2Cl2) provided 56 as a
white solid (14.4 mg, 90%). Rf ˆ 0.48 (hexane/EtOAc 3:1); m.p. 186
1888C; [a] ˆ À38.0 (c ˆ 0.5 in Cl2Cl2); 1H NMR (500 MHz, C6D6): d ˆ
0.01 (s, 3H), 0.02 (s, 3H), 0.72 (s, 3H), 0.92 1.01 (m, 10H), 1.35 (s, 3H),
1.44 1.47 (m, 3H), 1.53 (dd, J ˆ 3.0, 13.7 Hz, 1H), 1.61 (s, 3H), 1.78 2.00
(m, 4H), 2.45 (d, J ˆ 13.2 Hz, 1H), 3.23 (d, J ˆ 8.4 Hz, 1H), 3.80 (brs, 1H),
4.06 (brs, 1H), 4.22 (d, J ˆ 8.37 Hz, 1H), 5.33 (s, 1H), 5.81 (s, 1H); 13C NMR
(62.89 MHz): d ˆ À5.0, À4.4, 11.8, 17.4, 17.8, 21.2, 22.3, 25.6, 27.4, 34.4, 34.7,
40.7, 46.9, 47.1, 72.1, 77.3, 79.0, 82.9, 107.4, 121.3, 133.1, 164.3, 167.1; IR
Pentacycle 5: Mn(OAc)3 ¥ 2H2O (50 mg, 0.2 mmol) was added to a solution
of 60 (20 mg, 0.04 mmol) in dry benzene (10 mL). The reaction mixture was
heated under refluxed with a Dean and Stark trap for 48 h under N2. The
reaction mixture was cooled to room temperature, concentrated in vacuo
and the residue purified by flash column chromatography (hexane/Et2O
4:1) to give 5 (18 mg, 80%) as a white solid. Rf ˆ 0.24 (hexane/EtOAc 9:1);
m.p. 163 1648C; [a] ˆ ‡125.2 (c ˆ 0.6 in CHCl3); 1H NMR (300 MHz):
d ˆ 0.01 (s, 3H), 0.03 (s, 3H), 0.86 (s, 9H), 0.96 (s, 3H), 1.23 (s, 3H), 1.94 (s,
3H), 2.03 (s, 3H), 1.48 2.45 (m, 8H), 3.36 (d, J ˆ 9.9 Hz, 1H), 3.38 (s, 3H),
3.44 (d, J ˆ 12.3 Hz, 1H), 3.60 (d, J ˆ 4.2 Hz, 1H), 3.82 (s, 1H), 4.18 (d, J ˆ
8.1 Hz, 1H), 4.88 (d, J ˆ 3.3 Hz, 1H), 5.07 (s, 1H), 5.86 (t, J ˆ 1.2 Hz, 1H);
13C NMR (75.47 MHz): d ˆ À4.9, À4.1, 12.5, 18.1, 21.5, 22.6, 23.1, 26.3, 27.7,
27.9, 28.0, 28.3, 30.2, 37.6, 43.0, 46.0, 55.2, 70.8, 72.6, 74.4, 75.2, 82.1, 98.4,
124.8, 164.6, 169.3, 193.5; IR (film): nÄ ˆ 1740, 1682, 1540, 1516 cmÀ1; MS
‡
‡
(film): nÄ ˆ 2953, 2856, 1723, 1102 cmÀ1; MS (EI): m/z: 445 [M‡H] ; HRMS
(CI): m/z: 535 [M‡H] ; HRMS calcd for C29H46O7Si: 535.3093; found:
‡
‡
535.3086 [M‡H] .
calcd for C26H40O4Si: 444.2696; found: 444.2683 [M] ; elemental analysis
calcd (%) C26H40O4Si: C 70.23, H 9.07; found: C 70.11, H 9.17.
X-ray analysis: CCDC-194634 (57) and -201545 (5) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: (‡44) 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk).
Pentacycle 57: NaBH4 (32 mg, 0.8 mmol) at 08C was added under stirring
to
a solution of 56 (80 mg, 0.18 mmol) and NiCl2 ¥ 6H2O (10 mg,
0.045 mmol) in MeOH (20 mL). The mixture was stirred for 1 h at 08C
and then room temperature for 2 h, quenched with saturated aq. NH4Cl
and extracted with EtOAc (3 Â ). The combined extracts were washed with
brine (3 Â ), dried (MgSO4) and filtered. Concentration of the filtrate in
vacuo followed by flash chromatography (hexane/EtOAc 17:3) afforded 57
as a white solid (55 mg, 70%) and 58 (25 mg, 30%, which was subsequently
oxidized to 57 by Dess Martin periodinane[41]). Rf ˆ 0.46 (hexane/EtOAc
3:1); m.p. 156 1588C; [a] ˆ ‡28.5 (c ˆ 0.8 in Cl2Cl2); 1H NMR (500 MHz,
C6D6): d ˆ 0.02 (s, 3H), 0.03 (s, 3H), 0.7 (s, 3H), 0.84 1.10 (m, 11H), 1.29
(s, 3H), 1.47 1.60 (m, 6H), 1.70 (dd, J ˆ 4.0, 17.5 Hz, 1H), 1.81 (dt, J ˆ 4.0,
9.5 Hz, 1H), 1.90 (brs, 1H), 2.00 (dt, J ˆ 3.0, 14.5 Hz, 1H), 2.33 (d, J ˆ
13.5 Hz, 1H), 2.56 (dd, J ˆ 6.0, 18.5 Hz, 1H), 3.10 (d, J ˆ 8.5 Hz, 1H), 3.57
(dd, J ˆ 14.0, 18.5 Hz, 1H), 3.71 (d, J ˆ 4.0 Hz, 1H), 4.00 (t, J ˆ 3.0 Hz, 1H),
4.16 (d, J ˆ 8.0 Hz, 1H), 5.33 (s, 1H); 13C NMR (300 MHz): d ˆ À4.6, À4.0,
12.4, 18.3, 21.7, 22.3, 22.8, 26.3, 28.4, 28.7, 29.0, 33.1, 34.6, 35.1, 36.4, 40.8,
43.2, 50.2, 50.3, 73.0, 75.6, 75.7, 81.3, 84.6, 121.7, 133.6, 171.2; IR (film): nÄ ˆ
Acknowledgement
This work was supported by the RGC earmarked grant (ref. no.: CUHK
4185/97P).
[1] a) J. Polonsky, Fortschr. Chem. Org. Naturst. 1985, 47, 221 264; b) J.
Polonsky, Fortschr. Chem. Org. Naturst. 1973, 30, 101 150.
[2] E. S. Fernando, P. A. Gadek, C. Quinn, Am. J. Bot. 1995, 82, 92 103.
[3] Examples of some recently isolated quassinoids, see: a) K. Koike, M.
Yokoh, M. Furukawa, S. Ishii, T. Ohmoto, Phytochemistry 1995, 40,
233 238; b) P. A. Grieco, J. M. VanderRoest, M. M. Pineironunez,
E. E. Campaigne, M. Carmack, Phytochemistry 1995, 38, 1463 1465;
c) Y. Ouyang, K. Mitsunaga, K. Koike, T. Ohmoto, Phytochemistry
1995, 39, 911 913; d) H. Aono, K. Koike, J. Kaneko, T. Ohmoto,
Phytochemistry 1994, 37, 579 584; e) P. A. Grieco, E. D. Moher, M.
Seyer, J. C. Huffman, H. J. Grieco, Phytochemistry 1994, 37, 1451
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‡
2980, 1730, 1200, 1085 cmÀ1; MS (EI): m/z: 446 [M] ; HRMS calcd for
‡
C26H42O4Si: 446.2852; found: 446.2844 [M] .
Pentacycle 59: NaBH4 (20 mg, 0.5 mmol) was added under stirring at room
temperature to a solution of 56 (50 mg, 0.113 mmol) and NiCl2 ¥ 6H2O
(14 mg, 0.06 mmol) in MeOH (10 mL). After stirring for 3 h, concentrated
HCl (36%) was added. The reaction was quenched by saturated aq.
NaHCO3, extracted with EtOAc (3 Â ). The combined extracts were
washed with brine (2 Â ), dried (MgSO4) and filtered. Concentration of the
filtrate in vacuo followed by flash chromatography (hexane/EtOAc 19:1)
gave 59 a colourless oil (49.5 mg, 95%). Rf ˆ 0.73 (hexane/EtOAc 3:1);
[a] ˆ ‡76.7 (c ˆ 1.2 in Cl2Cl2); 1H NMR (500 MHz, C6D6): d ˆ 0.06 (s, 3H),
0.10 (s, 3H), 0.89 (s, 3H), 1.00 1.04 (m, 11H), 1.24 1.29 (m, 2H),
1.47 1.48 (m, 4H), 1.62 1.66 (m, 5H), 1.90 2.21 (m, 6H), 2.62 (dt, J ˆ 4.0,
13.6 Hz, 1H), 2.92 (d, J ˆ 13.5 Hz, 1H), 3.28 3.31 (m, 3H), 3.40 (d,
J ˆ 8.0 Hz, 1H), 3.80 (brs, 1H), 3.85 (brs, 1H), 4.36 (d, J ˆ 8.0 Hz, 1H), 4.84
(brs, 1H), 5.40 (brs, 1H); 13C NMR (62.89 MHz): d ˆ À5.0, À4.3, 12.1,
18.1, 21.6, 22.5, 23.0, 26.0, 28.0, 28.8, 34.8, 35.5, 35.6, 40.9, 44.1, 46.2, 54.3,
Chem. Eur. J. 2003, 9, 5489 5500
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5499

T. K. M. Shing et al.
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Received: May 19, 2003 [F5158]
5500
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 5489 5500