Asymmetric total synthesis of (-)-indicol by a carbene cyclization- cycloaddition cascade strategy

Article abstract of DOI:10.1002/chem.200700838

The first total synthesis of a secodolastane, (-)-indicol, has been accomplished. The key reaction is a rhodium(II)-mediated carbene cyclization-cycloaddition cascade, by which the core bicyclo[5.4.0]undecane skeleton was assembled. In this one-pot reaction, a domino series of transformations resulting in the construction of three o bonds and three stereocenters was realized in good yield.

Full text of DOI:10.1002/chem.200700838

FULL PAPER
DOI: 10.1002/chem.200700838
Asymmetric Total Synthesis of (ꢀ)-Indicol by a Carbene Cyclization–
Cycloaddition Cascade Strategy
Sze Kui Lam and Pauline Chiu*[a]
Abstract: The first total synthesis of a secodolastane, (ꢀ)-indicol, has been accom-
plished. The key reaction is a rhodium(II)-mediated carbene cyclization–cycloaddi-
tion cascade, by which the core bicycloACHTREU[NG 5.4.0]undecane skeleton was assembled. In
this one-pot reaction, a domino series of transformations resulting in the construc-
Keywords: cascade
indicol · rhodium · total synthesis
reactions
·
tion of three s bonds and three stereocenters was realized in good yield.
Introduction
Ahmad et al. reported that the extraction of one kilogram
of dried Dictyota indica yielded 15 mg of indicol (1) plus
minute amounts of other secodolastanes, including linearol
(2) and isolinearol (3). Linearol[15] and isolinearol[16] had
The carbene cyclization–cycloaddition cascade (CCCC) re-
action is a powerful domino process that can construct com-
plex polycyclic structures efficiently.[1] In this one-step reac-
tion catalyzed by metal complexes, three distinct s bonds
are forged, resulting in the creation of up to four new ste-
reocenters. By todayꢀs standards in which synthetic efficien-
cy and atom economy is as important as successfully synthe-
sizing the targets themselves, the CCCC reaction represents
a useful synthetic methodology to access systems bearing
multiple rings. The utility of this reaction in the construction
of complex molecular architectures has been clearly demon-
strated by its application in the formal and total syntheses
of complex natural products, including (ꢁ)-aspidophytine,[2]
(ꢁ)-illudin M,[3] (ꢁ)-vallesamidine,[4] (ꢁ)-lycopodine,[5] (ꢁ)-
epoxysorbicillinol,[6] (ꢁ)-nemorensic acid,[7] (+)-zaragozic
acids A[8] and C,[9] (ꢀ)-polygalolides A and B,[10] (ꢀ)-colchi-
cine,[11] and (ꢀ)-pseudolaric acid A.[12] The application of
this cascade reaction in total synthesis has already led to a
greater understanding of its scope and has led to further de-
velopment of this reaction as a tool for synthesis.[13]
also been previously isolated from the related Dictyota cer-
vicornis and Dictyota linearis, respectively. Secodolastanes
have recently been demonstrated to have antifeedant effects
on herbivores. Experiments showed that when ulva was
spiked with secodolastanes, its consumption by the marine
gastropod, Astraea latispina, was significantly inhibited.[17]
Indicol (1) is a secodolastane diterpenoid isolated from
the brown alga, Dictyota indica, from the Arabian Sea.[14]
The
secodolastanes
have
characteristic
bicyclo-
AHCTRE[UNG 5.4.0]undecane carbon frameworks, which is further con-
[a] S. K. Lam, Prof. Dr. P. Chiu
stricted through a transannular cyclization by a tertiary alco-
hol to form a hemiacetal functionality, so that the carbobicy-
clic skeleton is not an extended platform but is folded back
as a more compact scaffold. Each secodolastane has a cyclo-
hexane ring A bearing an exocyclic methylene group, fused
with a cycloheptane ring B, the latter being geminally substi-
tuted by an ethylene isopropyl ketone moiety and a methyl
group. The members of the secodolastane family are various
Department of Chemistry, and Open Laboratory
of Chemical Biology of the Institute of Molecular Technology
for Drug Discovery and Synthesis
University of Hong Kong
Pokfulam Road, Hong Kong (P. R. China)
Fax : (+852)2857-1586
E-mail: pchiu@hku.hk
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2007, 13, 9589 – 9599
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oxygenated derivatives of this basic carboskeleton, and indi-
col appears to be the simplest member of this family yet dis-
covered, although it nonetheless harbors in its congested
core two pairs of vicinal stereocenters, of which two are qua-
ternary.
The absolute configuration of indicol is assumed to be the
same as that of linearol, the structure of which was deduced
from chemical correlation with its biogenetic dolastane pre-
cursor of known absolute stereochemistry, isoamijiol (4).[18]
Amijiol (5), the precursor of isolinearol, has also been iso-
lated, whereas the corresponding parent dolastane of indicol
has not yet been reported.[18] The dolastanes are tricyclic
natural products isolated from the same algal species, and
are characterized by the presence of an additional cyclopen-
tane ring C fused to the AB rings of the secodolastanes. The
dolastanes have been reported to show a wide range of bio-
logical activities, including cytotoxicity, histamine antago-
nism, antifungal, and antibiotic effects.[18–21] Interestingly,
they are structural relatives of the potent antibiotic, guana-
castepene A.[22]
Several dolastanes, such as isoamijiol (4), dolastatrienol 6,
and 14-deoxyisoamijiol, have been successfully synthesized
as racemates and as the unnatural antipodes.[23–27] Coinciden-
tally, all but one of these total syntheses are based on ap-
pending ring A last,[27] that is, a BC!ABC strategy, proba-
bly due to the ubiquity of perhydroazulene systems in natu-
ral products, and the myriad of methodologies available to
gain access to the final six-membered ring. While the syn-
theses of the more adorned dolastanes have been reported,
the total synthesis of any secodolastane has yet to appear in
the literature, although there have been synthetic studies.[28]
Insofar as the secodolastanes are the likely metabolites of
the dolastanes in nature, a direct chemoselective oxidative
conversion of a dolastane into a secodolastane in the labora-
tory is not straightforward due to the presence of competing
olefin functionalities that necessitates additional protection
and manipulations.
The successful total synthesis of indicol would provide an
independent confirmation of its absolute configuration,
which would have stereochemical implications for the other
members of the secodolastane family as well. Furthermore,
the route toward indicol would serve as a basis for the syn-
thesis of the more complex secodolastanes, as well as a
novel entry into the dolastane skeleton by an unexplored
AB!ABC strategy. Moreover, the bioactivity profile of in-
dicol has not been reported. All these considerations moti-
vated us to synthesize this natural product in an enantiose-
lective and stereocontrolled manner. To us, the oxatricyclic
structure of indicol seems to be ideally suited for showcasing
the assembly of polycyclic frameworks by using the carbene
cyclization–cycloaddition cascade reaction.[29,30]
Scheme 1. Retrosynthetic analysis of indicol.
in 7 should be accessible from ketone 8. The key oxatricyclic
framework in 8 is a CCCC cycloadduct obtained from the
reaction of chiral a-diazoketone 9, in which the stereochem-
ically defined protected hydroxyl substituent could confer
stereoselectivity in this domino reaction, as our previous
studies indicated.[12] The precursor of 9 is carboxylic acid 10,
which in turn could be obtained from the homologation of
aldehyde 11. There are various strategies to acquire this
chiral intermediate, and we elected to use the commercially
available TBS-protected glycidol 12 as the starting material.
Results and Discussion
Synthesis of the diazoketone for CCCC reaction: The com-
mercially available chiral oxirane (S)-12 was ring-opened at
the less-hindered site in high yield by 3-methylbut-3-enyl
magnesium bromide in the presence of copper(I) cyanide.
This provided alcohol 13 bearing the stereochemical ele-
ment that would direct the entire synthesis. This key hydrox-
yl stereocenter was secured by protection using TBDPSCl.
The elaboration of the other terminus was initiated by de-
protection of the TBS group to reveal alcohol 14, followed
by oxidation under Swern conditions to yield aldehyde 15.
Treatment of 15 by using Normantꢀs Grignard reagent[31]
provided the desired diol 16 exclusively in high yield, with-
out any interfering silyl group migrations.
To avoid the formation of intermediary lactol or lactone
species that would result in the premature arrest of the de-
sired bisoxidation, a second Swern oxidation was employed
to convert diol 16 to g-ketoaldehyde 17 exclusively. Subse-
quently, a Lindgren oxidation[32] smoothly converted the ke-
toaldehyde 17 to ketoacid 18. Activation of the acid by iso-
butyl chloroformate[33] and treatment with excess diazome-
thane afforded a-diazoketone 19, accompanied by some
methyl ester 20 which could be recycled for use by reduction
(Scheme 2).
Synthetic plan: Our retrosynthetic analysis of indicol (1)
based on the CCCC strategy is outlined in Scheme 1. We en-
visioned that the hemiacetal functionality in 1 could be de-
rived from the reductive ring opening of oxygen-bridged
ketone 7. The required bis-a-substitution and methylenation
CCCC reaction of diazoketone 19: With a-diazoketone 19
in hand, we proceeded to examine the pivotal RhII-mediated
CCCC reaction to construct the carbocyclic platform of indi-
col. When 19 was treated with a catalytic amount of rho-
dium(II) catalyst, the anticipated CCCC reaction proceeded
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Total Synthesis of (ꢀ)-Indicol
FULL PAPER
21 was unambiguously confirmed by X-ray crystallographic
analysis (Figure 1). Thus in one step, the advanced inter-
mediate 21 containing the nucleus of indicol and essentially
Scheme 2. a) CH
3A
b) TBDPSCl, imidazole, DMF, overnight, RT; c) PPTS, MeOH, 4 d, RT,
84% for 2 steps; d) DMSO, (COCl)2, CH2Cl2; iPr2NEt, 10 min, ꢀ788C,
93%; e) ClMgCH2CH2CH2OMgCl, THF, 2 h, ꢀ788C, 91%; f) DMSO,
(COCl)2, CH2Cl2; iPr2NEt, 10 min, ꢀ788C, 90%; g) NaClO2, NaH2PO4,
2-methyl-2-butene, tBuOH, H2O, RT, 88 %; h) iBuOCOCl, NEt3, THF,
Et2O, 2 h, RT; CH2N2, Et2O, 6 h, 0 8C 66% 19 and 20% 20; i) 1m
DIBAL-H, CH2Cl2, ꢀ408C to RT, 4 h, 70%. TBDPSCl=tert-butyldime-
thylsilyl chloride; PPTS=pyridinium p-toluenesulfonate; DIBAL-H=dii-
sobutylaluminium hydride.
Figure 1. ORTEP of cycloadduct (ꢁ)-21.
three out of the four stereocenters in the target molecule
was obtained through the CCCC reaction of acyclic 19.
The minor diastereomer 22 also obtained in the CCCC re-
action was deduced by 2D NMR spectroscopic analysis to
have the stereochemical structure as shown (Scheme 3). Nu-
clear Overhauser effects were observed between the bridge-
head methyl group at C5 and the phenyl groups of the
TBDPS group, but no correlations were found with protons
at C1 or C7. The structure of 22 was additionally confirmed
by a three-step chemical conversion to ketone (ꢀ)-24, which
showed an equal and opposite rotation compared to (+)-24
obtained through the same series of reactions starting from
21 (Scheme 4). Incidentally, the unnatural antipode of indi-
col could be obtained via 22, starting from the same chiral
precursor, (S)-12.
to give as products a major cycloadduct 21 and a minor dia-
stereomeric cycloadduct 22, generally in a ratio of about 3:1
(Scheme 3).
When we analyzed very carefully the product mixture
from the CCCC reaction, we isolated and characterized a
Scheme 3. Diastereomeric cycloadducts from the CCCC reaction of 19.
The major diastereomer 21 is the cycloadduct containing
the desired stereochemistry at the fused rings, and its struc-
ture was deduced by 2D NOE NMR spectroscopic analysis
(Scheme 3). The bridgehead methyl group at C5 showed a
strong NOE with the proton at C1, revealing that they are
on the same face of cyclohexane ring. No NOE correlations
were observed between the bridgehead methyl group with
the TBDPS group or with the proton at C7. The structure of
Scheme 4. For 22: a) TMSCH2CH2OTMS, TMSOTf, CH2Cl2, overnight,
RT, 93 %; b) 1 m TBAF, THF, 40 h, reflux; c) DMSO, (COCl)2, CH2Cl2;
NEt3, 10 min, ꢀ788C, 82% for 2 steps. For 21: a) TMSOCH2CH2OTMS,
TMSOTf, CH2Cl2, overnight, RT; b) 1m TBAF, 64 h, RT, 99% over
2 steps; c) DMSO, (COCl)2, CH2Cl2; NEt3, 10 min, ꢀ788C, 98%. TMS=
trimethylsilyl; OTf=triflate; TBAF=tetrabutylammonium fluoride.
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P. Chiu and S. K. Lam
Table 1. CCCC reaction mediated by achiral RhII catalysts.
trace amount of a third diastereomeric cycloadduct 23, pro-
duced in <5% yield. Analysis by 2D NMR spectroscopy
showed NOE correlations between the methyl group at C5
with both the protons at C1 and at C7. However, for the
bridgehead substituent to be proximate to the protons at C1
and C7, this is possible only if cycloadduct 23 has the struc-
ture as shown (Scheme 3). We were rather surprised to iso-
late this diastereomer which has the oxygen bridge and the
bridgehead methyl group syn to each other, thus necessitat-
ing the tetrahydrofuran to be trans-fused with respect to
ring A. This is an adduct which has never been documented
before as a product of the CCCC reaction, and tends to de-
compose on standing for prolonged periods.
Entry Catalyst[a]
Solvent
T
Yield (21+22)
dr
(21:22)
[8C]
[%]
1
2
3
4
5
6
7
8
C
G
CH2Cl2 RT
CH2Cl2
77
81
74
60
50
64
65
65
2.7:1
3.1:1
3.1:1
3.6:1
3.5:1
3.3:1
3.1:1
2.3:1
n.d.[b]
n.d.
0
CH2Cl2 ꢀ15
hexane
CF3Ph
0
0
CH2Cl2 RT
CH2Cl2
The diastereomeric cycloadducts are rationalized to be
0
formed through transition states as shown in Scheme 5.[34]
CH2Cl2 ꢀ15
9
10
11
hexane
CF3Ph
0
0
0
<15
<15
<15
n.d.
[a] Oct=octanoate. [b] n.d.=not determined.
reoselectivity. Importantly, (ꢀ)-21 thus prepared was found
to have 99% ee by chiral HPLC analysis, compared with
(ꢁ)-21 prepared by the same route starting from (ꢁ)-12.
This verified that racemization did not occur in the course
of the reactions.
In an effort to improve the diastereoselectivity of the
CCCC reaction, chiral rhodium(II) catalysts were screened
in the reaction of chiral diazoketone 19 to evaluate the
extent of reagent control (Table 2). However, for the cata-
Table 2. CCCC reaction mediated by chiral RhII catalysts.
Scheme 5. Proposed transition states of the cycloaddition of the carbonyl
ylide.
The major cycloadduct 21 is generated from transition-state
A in which the tether adopts a chair conformation, with the
bulky siloxy group residing in an equatorial position. The
minor diastereomer 22 is formed from transition state B the
tether of which is in a less-stable boat conformation. The
least stable diastereomer 23 may be derived from transition-
state C, which is destabilized due to the impending forma-
tion of a trans-fused five-membered ring ether.
After screening a number of reaction parameters in the
CCCC reaction of 19 (Table 1), the use of dichloromethane
as the solvent was found to promote the highest yields. Al-
though the less-polar solvents hexane and trifluorotoluene
appeared to give a slightly higher ratio of the desired diaste-
reomer, this less than compensates for the corresponding de-
crease in the overall yield of the cycloadducts. Dirhodiu-
m(II) octanoate was found to be the best catalyst. Thus at
08C, the CCCC reaction of 19 proceeded in 81% yield in
anhydrous dichloromethane to 21 and 22 in 61 and 20%
yields, respectively (Table 1, entry 2). Further decreasing the
temperature did not lead to any improvement in the diaste-
Entry
Catalyst[a]
[Rh2{(R)-dosp}4]
[Rh2{(S)-dosp}4]
[Rh2{(S)-ntpa}4]
[Rh2{(S)-nttl}4]
[Rh2{(S)-npv}4]
[Rh2{(S)-bptv}4]
t [h]
Yield (21+22) [%]
dr (21:22)
1
2
3
4
5
6
G
3
3
48
3
3
3
82
58
78
68
68
52
2.3:1
2.9:1
3.1:1
3.5:1
3.3:1
2.7:1
AHCTREUNG
A
AHCTREUNG
R
C
[a] For catalysts see ref. [36]. dosp=(N-dodecylbenzenesulfonyl)proli-
nate; ntpa=1,8-naphthdioyl phenylalaninate; nttl=1,8-naphthdioyl tert-
leucinate; npv=1,8-naphthdioyl valinate; bptv=N-benzene-fused phtha-
loyl valinate.
lysts that were tried, only a limited or negligible change in
the ratio of 21/22 was observed. In our previous studies, the
CCCC reaction of cycloaddition substrates, such as 25,
which has a three-carbon tether, had been more responsive
to the effect of solvent, temperature, and chiral catalysts,[12]
for example, the diastereoselectivity could change 5–6-fold
on varying the rhodium catalysts (Scheme 6). We surmise
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Total Synthesis of (ꢀ)-Indicol
FULL PAPER
Scheme 6. CCCC reaction of 25 containing a three-carbon tether.
that because the cycloaddition of 19, which has a four-
carbon (C1 to C4) tether between the dienophile and the
carbonyl ylide, was slower,[35] the rhodium catalyst may have
only a weak association with, or may have even dissociated
fully from the carbonyl ylide during the cycloaddition event.
Thus the chirality of the catalysts did not exert a great influ-
ence on the cycloaddition; as a consequence, the diastereo-
meric ratio between cycloadducts 21 and 22 in the CCCC re-
action with chiral or achiral catalysts remained at about 3:1
(Table 2).
Scheme 7. a) Ph3PCH3Br, 1.6m nBuLi, THF, 2 h, RT, then, 3m HCl, over-
night, reflux, 95%; b) LDA, THF, 1 h, ꢀ788C; NCCO2Me, 2 h, ꢀ788C,
0.005m, 88%; c) NaH, THF, 1 h, RT; MeI, 2 h, RT, 0.005m, 81%;
d) SmI2, MeOH, THF, 1 h, 08C, 0.002m, 91%; e) MOMCl, iPr2NEt,
CH2Cl2, 156 h, RT, 92%; f) LAH, Et2O, 4 h, RT; g) DMSO, (COCl)2,
CH2Cl2; Et3N, 10 min, ꢀ788C; h) NaH, dimethyl(3-methyl-2-oxobutyl)-
phosphonate, THF, overnight, RT, 90% over 3 steps from 36; i) [Ph3P-
AHCTRE(UNG CuH)]6, THF, H2O, 24 h, RT; then 12m HCl, MeOH, 48 h, RT, 98%.
MOM=methoxymethyl.
Total synthesis of indicol (1): To complete the total synthesis
of indicol, further functionalizations of 21 including the in-
stallation of the two substituents a to the carbonyl group,
olefination at C1, and the formation of hemiacetal remain
to be accomplished.
The direct alkylation of the enolate of 21 with various
alkyl halides was attempted under many reaction conditions,
but the use of various bases, as well as variation of tempera-
ture, solvents, and additives failed to produce the desired
monoalkylated product. Even when 21 was converted to the
less sterically demanding TBS-protected 26 or MOM-pro-
tected 27 (Scheme 3), the alkylation of these ketones still
met with failure. Both the ketones and the alkyl halides
could largely be recovered.
Thus the transformations were resequenced to first con-
vert the protected hydroxyl group at C1 to the less sterically
demanding exocyclic methylene group. To this end, it was
necessary to temporarily protect the ketone at C8 to avoid
competitive reaction at a later stage. After 21 was protected
as the ketal, desilylation and oxidation afforded ketone (+)-
24 (Scheme 4). Treatment of 24 under typical Wittig condi-
tions, followed by a relatively vigorous acid workup, induced
both methylenation and deketalization in the same pot to
furnish ketone 28 in high yield (Scheme 7). No isomeriza-
tion of the exocyclic olefin was observed.
Even though 28 is less hindered than 21, alkylation of 28
via its enolate remained disappointingly problematic and af-
forded low yields of alkylation product. Ultimately, a-dia-
lkylation was indirectly accomplished by the intermediacy of
ketoester 29 (Scheme 7). Reaction of 28 with Manderꢀs re-
agent under dilute conditions (ꢂ0.005m) led to an 88%
yield of ketoester 29, which was predominantly in the enol
form. At typical reaction concentrations (ꢂ0.3m), however,
the methoxycarbonylation of 28 proceeded to give 29 with
diminished yields of ꢂ60%. Subsequently, methylation of
29 proceeded readily with predictably high syn selectivity
with respect to the oxygen bridge, to install the final quater-
nary stereocenter at C12, affording b-ketoester 30 as a
single diastereomer.
Reductive cleavage of ketoester 30 proceeded by treat-
ment with freshly prepared SmI2 in THF at 08C to give a hy-
droxyketone that spontaneously underwent transannular
cyclization to hemiacetal 31 (Scheme 7). In this reaction, a
dilute reaction concentration (ꢂ0.002m) ensured a reprodu-
cibly clean reaction and high yield of product. At this stage,
we found it beneficial to protect 31. Even though this in-
creased the overall number of steps in the synthetic route,
the subsequent transformations occurred in near quantita-
tive yields and were found to be much cleaner than by di-
rectly using hemiacetal 31 as substrate. Protection by
MOMCl required a rather long time for complete reaction,
attesting to the hindrance of the structure of 31. Mixed
acetal 32 thus obtained was subjected to reduction, then oxi-
dation to afford aldehyde 33 (Scheme 7). Then 33 under-
went a smooth Horner–Emmons reaction to afford enone
34. The yield over these three steps was 90%. Finally enone
34 was chemoselectively reduced by a Stryker reduction,[37]
and after an acidic workup that also accomplished the de-
protection of the MOM in the same pot, 386 mg of (ꢀ)-indi-
col (1) was furnished in excellent yield. The spectral data
(Table 3) and optical rotation of synthetic (ꢀ)-indicol (1)
thus obtained were in full accordance with literature values
in all respects,[14] and confirms by chemical synthesis the pre-
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P. Chiu and S. K. Lam
Table 3. Comparison of the 13C NMR (CDCl3) data reported for (ꢀ)-in-
dicol (1) and that reported in this work.
were dried and distilled. Flash chromatography was performed with E.
Merck silica gel 60 (230–400 mesh ASTM). Components were visualized
by illumination with a short-wavelength UV-light and/or staining. Proton
(1H) and carbon (13C) nuclear magnetic resonance spectra were obtained
in CDCl3 unless otherwise indicated, with tetramethylsilane as internal
standard at ambient temperature on Bruker DPX 300 and 500, Bruker
Avance 400, and 600 spectrometers. Splitting patterns are designated as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet and, br,
broad. IR absorption spectra were recorded on a Bio-Rad FTS 165 spec-
trometer as a solution in CH2Cl2 from 4000 to 400 cmꢀ1, with subtraction
for solvent. Mass spectra (MS) were recorded on a Finnigan MAT 95
mass spectrometer at both low and high resolutions, with accurate mass
reported for the molecular ion (M+) or the next largest fragment ion
thereof. Optical rotations were recorded on a Perkin–Elmer 343 Polarim-
eter.
Number
lit.[14]
Exptl
d [ppm] (75 MHz)
d [ppm] (125 MHz)
C1
C2
C3
C4
C5
C6
C7
C8
148.7
34.4
32.7
23.3
37.0
32.6
30.0
104.8
215.0
28.7
36.2
44.1
40.7
84.1
108.4
21.5
41.0
18.35
18.38
23.0
148.5
34.4
32.6
23.2
37.0
32.5
29.9
104.7
214.8
28.6
36.2
44.1
40.7
84.0
108.2
21.5
40.9
18.3
18.4
22.9
Compound 13: Magnesium (3.79 g, 156.31 mmol) was added to a solution
of 1,2-dibromethane (0.10 mL, 1.16 mmol) in THF (50 mL) at room tem-
perature. The mixture was heated to reflux for 5 min. 4-Bromo-2-methyl-
1-butene (15.89 g, 106.63 mmol) in THF (350 mL) was added by cannula.
The mixture was heated to reflux for 1 h. The Grignard reagent was
transferred by cannula to a round-bottomed flask containing CuCN
(0.59 g, 6.70 mmol) at room temperature. The mixture was cooled to
ꢀ788C. Epoxide (ꢀ)-12 (10.72 g, 57.56 mmol) in THF (100 mL) was
added slowly. The resulting mixture was stirred for 4 h at ꢀ788C. The re-
action was quenched with saturated NH4Cl and extracted with Et2O. The
combined organic layers were dried over anhydrous MgSO4. The solvent
was removed in vacuo and the residue was purified by flash chromatogra-
phy by using 5–8% EtOAc in hexane to afford alcohol 13 (13.80 g, 93%)
as a colorless oil. Rf: 0.50 (10% EtOAc in hexane); [a]2D0 =+3.38 (c=
2.90 in CHCl3); 1H NMR (400 MHz, CDCl3): d=4.62 (s, 1H), 4.60 (s,
1H), 3.58–3.52 (m, 2H), 3.35 (dd, J=9.6, 7.1 Hz, 1H), 2.54 (d, J=2.4 Hz,
1H), 1.96 (t, J=7.8 Hz, 2H), 1.64 (s, 3H), 1.56–1.50 (m, 1H), 1.43–1.31
(m, 3H), 0.84 (s, 9H), 0.01 ppm (d, J=3.0 Hz, 6H); 13C NMR (100 MHz,
CDCl3): d=145.2, 109.9, 71.5, 67.2, 37.6, 32.3, 25.7, 23.4, 22.1, 18.1, ꢀ5.4,
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18[a]
C19[a]
C20
[a] Assignments may be reversed.
ꢀ
ꢀ5.5 ppm; IR (CH2Cl2): n˜ =3566 (O H), 3074, 2955, 2931, 2858,
1647 cmꢀ1 (C=C); LRMS (EI): m/z: 258 [M]+ (1), 201 (22), 183 (4), 133
(4), 131 (6), 109 (100), 105 (23); HRMS (EI): calcd for C14H30O2Si:
258.2015; found: 258.2014.
viously proposed absolute stereochemistry of natural indi-
col.
Compound 14: Imidazole (5.39 g, 79.31 mmol) and TBDPSCl (16.6 mL,
63.8 mmol) were added to a solution of alcohol 13 (13.80 g, 53.48 mmol)
in DMF (10 mL) at room temperature. The resulting mixture was stirred
overnight at room temperature. The reaction was quenched with MeOH.
Water was added. The mixture was extracted with 20% Et2O in hexane.
The combined organic layers were dried over anhydrous MgSO4. The sol-
vent was removed in vacuo to give the crude product as a pale-yellow oil,
which was used in the next step without further purification.
Conclusion
The asymmetric total synthesis of (ꢀ)-indicol (1) has been
successfully accomplished through a 21-step reaction se-
quence by starting from an optically-active, commercially-
available glycidol derivative. The CCCC reaction was the
key strategy for efficiently accessing the bicyclo-
The residue thus obtained was dissolved in MeOH (125 mL). PPTS
(4.03 g, 16.03 mmol) was added at room temperature. The resulting mix-
ture was stirred for 4 d at room temperature. Then H2O was added and
the reaction mixture was extracted with Et2O. The combined organic
layers were dried over anhydrous MgSO4. The solvent was removed in
vacuo and the residue was purified by flash chromatography by using 5–
10% EtOAc in hexane to afford 14 (17.15 g, 84% yield over 2 steps) as a
pale-yellow oil. Rf: 0.32 (10% EtOAc/hexane); [a]2D0 =+12.3 (c=2.02 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.83–7.78 (m, 4H), 7.49–7.45
(m, 6H), 4.73 (s, 1H), 4.65 (s, 1H), 3.90 (m, 1H), 3.60 (m, 2H), 2.15 (brs,
1H), 1.93 (t, J=7.3 Hz, 2H), 1.71 (s, 3H), 1.62–1.41 (m, 4H), 1.19 ppm
(s, 9H); 13C NMR (75 MHz, CDCl3): d=145.2, 135.8, 135.6, 134.0, 133.8,
129.67, 129.66, 127.6, 127.5, 109.9, 73.9, 65.9, 37.5, 33.1, 27.0, 23.0, 22.2,
ACHTREUNG[5.4.0]undecane skeleton and setting up the stereocenters at
C5, and C14, and essentially at C8 as well. Moreover, the bi-
cyclic adduct in this CCCC reaction provided the required
functional groups and the facial bias to enable the stereose-
lective dialkylation to create the final stereocenter at C12.
The reactions in this route have been optimized to furnish 1
in an overall yield of 10.2% starting from the commercially
available oxirane (S)-12. This first total synthesis of (ꢀ)-in-
dicol provides a basis for the preparation of other secodolas-
tanes, as well as a novel entry into the dolastanes. Research
in these directions is in progress.
ꢀ
19.3 ppm; IR (CH2Cl2): n˜ =3588 (O H), 3074, 2934, 2860, 1648 (C=C),
1472, 1463, 1428 cmꢀ1; LRMS (EI): m/z: 325 [MꢀC4H9]+ (100), 200 (8),
199 (45), 139 (9), 109 (55); HRMS (EI): m/z: calcd for C20H25O2Si:
325.1638 [MꢀC4H9]+; found: 325.1624.
Compound 15: DMSO (6.6 mL, 93.0 mmol) was added to a solution of
oxalyl chloride (6.1 mL, 69.9 mmol) in CH2Cl2 (700 mL) at ꢀ788C. The
mixture was stirred for 15 min. Alcohol 14 (17.79 g, 46.49 mmol) in
CH2Cl2 (200 mL) was added at ꢀ788C. The mixture was stirred for
30 min. iPr2NEt (50.0 mL, 287.0 mmol) was added at ꢀ788C. The result-
Experimental Section
General methods: All anhydrous reactions were performed in oven-dried
glassware under a positive pressure of dry argon. All reaction solvents
9594
www.chemeurj.org
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9589 – 9599

Total Synthesis of (ꢀ)-Indicol
FULL PAPER
ing mixture was stirred for 10 min at ꢀ788C. Finally, the reaction was
quenched with phosphate buffer (pH 7) and extracted with Et2O. The
combined organic layers were dried over anhydrous MgSO4. The solvent
was removed in vacuo and the residue was purified by flash chromatogra-
phy by using 3% EtOAc in hexane to afford aldehyde 15 (16.45 g, 93%)
as a pale-yellow oil. Rf: 0.64 (10% EtOAc in hexane); [a]2D0 =ꢀ6.43 (c=
resulting mixture was stirred overnight at room temperature and then
brine was added. The mixture was acidified to pH 4 by dilute HCl and
extracted with EtOAc. The combined organic layers were dried over an-
hydrous MgSO4. The solvent was removed in vacuo and the residue was
purified by flash chromatography, eluting with 0.1% AcOH in 10–30%
EtOAc/hexane to afford acid 18 (14.16 g, 88%) as a pale-yellow oil. Rf:
1
0.30 (20% EtOAc in hexane); [a]2D0 =ꢀ10.2 (c=6.65 in CHCl3); H NMR
1
3.92 in CHCl3); H NMR (400 MHz, CDCl3): d=9.60 (d, J=1.6 Hz, 1H),
(400 MHz, CDCl3): d=7.65–7.60 (m, 4H), 7.45–7.36 (m, 6H), 4.65 (s,
1H), 4.56 (s,1H), 4.22 (t, J=5.8 Hz, 1H), 2.84 (dt, J=19.4, 6.5 Hz, 1H),
2.72 (dt, J=19.1, 6.5 Hz, 1H), 2.56–2.38 (m, 2H), 1.84 (t, J=7.5 Hz, 2H),
1.62 (s, 3H), 1.58–1.18 (m, 4H), 1.13 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=210.9, 178.6, 145.1, 135.85, 135.83, 133.5, 132.9, 130.0, 129.9,
127.8, 127.7, 110.2, 78.9, 37.4, 34.4, 32.8, 27.3, 27.0, 22.2, 22.1, 19.4 ppm;
7.68–7.64 (m, 4H), 7.47–7.36 (m, 6H), 4.69 (s, 1H), 4.61 (s, 1H), 4.06 (dt,
J=5.7, 1.6 Hz, 1H), 1.92 (t, J=7.4 Hz, 2H), 1.66 (s, 3H), 1.63–1.40 (m,
4H), 1.14 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=203.5, 144.9,
135.8, 135.7, 133.2, 133.1, 130.0, 129.9, 127.78, 127.75, 110.3, 78.0, 37.5,
32.3, 27.0, 22.2, 22.0, 19.3 ppm; IR (CH2Cl2): n˜ =3076, 3058, 2938, 2865,
1735 (C=O), 1649 (C=C), 1590, 1466, 1431 cmꢀ1; LRMS (EI): m/z: 380
[M]+ (2), 323 (53), 305 (14), 267 (15), 245 (24), 229 (18), 199 (100), 139
(38), 107 (69); HRMS (EI): m/z: calcd for C24H32O2Si: 380.2172; found:
380.2167.
ꢀ
IR (CH2Cl2): n˜ =3503 (acid O H), 3073, 2933, 2860, 1751 (acid C=O),
1713 (ketone C=O), 1648 (C=C), 1589, 1472, 1463 cmꢀ1; LRMS (EI): m/
z: 395 [MꢀC4H9]+ (11), 377 (3), 349 (18), 317 (15), 299 (24), 261 (11),
223 (23), 199 (100), 179 (68), 161 (60); HRMS (EI): m/z: calcd for
C23H27O4Si: 395.1679 [MꢀC4H9]+; found: 395.1665.
Compound 16 from 15: ClMgACHTREU(NG CH2)3OMgCl (300 mL, 90.0 mmol, 0.3m in
THF) was added to a solution of aldehyde 15 (16.45 g, 43.31 mmol) in
THF (150 mL) at ꢀ788C.[31] The resulting mixture was stirred for 2 h at
ꢀ788C. The reaction was quenched with saturated NH4Cl and extracted
with Et2O. The combined organic layers were dried over anhydrous
MgSO4. The solvent was removed in vacuo and the residue was purified
by flash chromatography by using 20–40% EtOAc in hexane to afford
diol 16 (17.30 g, 91%) in the form of a pale-yellow oil as a mixture of
diastereomers.
Compounds 19 and 20: NEt3 (0.235 mL, 1.69 mmol) and iBuOCOCl
(0.220 mL, 1.69 mmol) were added to a solution of acid 18 (0.3850 g,
0.8480 mmol) in THF (10 mL) and Et2O (10 mL). The mixture was
stirred for 2 h at room temperature and filtered through sintered glass by
cannula under Ar. CH2N2 in Et2O (15 mL, 6.0 mmol) was added at 08C.
The resulting mixture was stirred for 6 h at 08C. The solvent was re-
moved in vacuo and the residue was purified by flash chromatography by
using 10–20% EtOAc in hexane to afford diazoketone 19 (0.2670 g,
66%) as a pale-yellow oil and ester 20 (0.0992 g, 20%) as a pale-yellow
oil.
Compound 16 from 20: DIBAL-H (1m in hexane, 11.8 mL, 11.8 mmol)
was added to a solution of 20 (1.67 g, 3.58 mmol) in CH2Cl2 (15 mL) at
ꢀ408C. The resulting mixture was stirred for 4 h from ꢀ408C to room
temperature. The reaction was quenched with H2O at ꢀ788C slowly and
extracted with EtOAc. The combined organic layers were dried over an-
hydrous MgSO4. The solvent was removed in vacuo and the residue was
purified by flash chromatography by using 20–40% EtOAc in hexane to
afford a pale-yellow oil 16 (1.10 g, 70%) as a mixture of diastereomers.
Rf: 0.31 (35% EtOAc in hexane); 1H NMR (300 MHz, CDCl3): m/z: d=
7.70–7.66 (m, 4H), 7.44–7.26 (m, 6H), 4.62–4.51 (m, 2H), 3.61–3.56 (m,
4H), 2.55 (brs, 2H), 1.85–1.65 (m, 2H), 1.65–1.15 (m, 11H), 1.08 ppm (s,
9H); 13C NMR (75 MHz, CDCl3): d=145.5, 135.97, 135.93, 135.8, 133.8,
133.77, 133.74, 133.4, 129.8, 129.7, 127.7, 127.6, 127.5, 76.6, 76.5, 74.7,
73.2, 62.9, 62.8, 37.6, 37.5, 32.6, 30.9, 30.3, 29.5, 29.4, 28.7, 27.0, 23.4, 22.9,
Compound 19: Rf: 0.50 (20% EtOAc in hexane); [a]2D0 =ꢀ21.8 (c=5.34
1
in CHCl3); H NMR (600 MHz, CDCl3): d=7.64–7.60 (m, 4H), 7.44–7.40
(m, 2H), 7.38–7.35CAHTRE(UNG m, 4H), 5.21 (brs, 1H), 4.65 (s, 1H), 4.56 (s, 1H),
4.21 (t, J=5.9 Hz, 1H), 2.84 (dt, J=19.0, 6.5 Hz, 1H), 2.77 (dt, J=19.0,
6.6 Hz, 1H), 2.43 (brs, 1H), 2.39 (brs, 1H), 1.85 (t, J=7.9 Hz, 2H), 1.62
(s, 3H), 1.64–1.51 (m, 2H), 1.47–1.40 (m, 1H), 1.35–1.31 (m, 1H),
1.11 ppm (s, 9H); 13C NMR (150 MHz, CDCl3): d=211.1, 193.2, 145.1,
135.8, 135.7, 133.4, 133.0, 129.9, 127.7, 127.6, 110.1, 78.9, 54.3 (br), 37.4,
34.4, 33.5, 32.8, 27.0, 22.2, 22.1, 19.3 ppm; IR (CH2Cl2): n˜ = 3073, 2932,
ꢃ
2108 (N N), 1734 (diazoketone C=O), 1717 (ketone C=O), 1646 (C=C),
1559, 1472 cmꢀ1; LRMS (EI): m/z: 419 [M+ꢀC4H9] (6), 393 (26), 392
(88), 389 (26), 200 (17), 199 (100), 157 (11); HRMS (EI): m/z: calcd for
C24H27N2O3Si: 419.1791 [MꢀC4H9]+; found: 419.1780.
ꢀ
ꢀ
22.2, 22.1, 19.4, 19.3 ppm; IR (CH2Cl2): n˜ =3614 (O H), 3430 (O H),
3073, 2933, 2859, 1648 (C=C), 1488, 1472 cmꢀ1; LRMS (EI): m/z: 383
[MꢀC4H9]+ (4), 365 (24), 305 (22), 199 (54), 167 (15), 150 (13); HRMS
(EI): m/z: calcd for C23H31O3Si: 383.2042 [MꢀC4H9]+; found: 383.2031.
Compound 20: Rf (10% EtOAc in hexane): 0.53; [a]2D0 =ꢀ8.95 (c=2.48,
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.66–7.60 (m, 4H), 7.40–7.37
(m, 6H), 4.65 (s, 1H), 4.57 (s, 1H), 4.21 (t, J=5.8 Hz, 1H), 3.65 (s, 3H),
2.90–2.72 (m, 2H), 2.51–2.35 (m, 2H), 1.85 (t, J=7.4 Hz, 2H), 1.62 (s,
3H), 1.66–1.25 (m, 4H), 1.12 ppm (s, 9H); 13C NMR (75 MHz, CDCl3):
d=210.9, 173.1, 145.2, 135.88, 135.83, 133.5, 133.0, 129.98, 129.95, 127.8,
127.7, 110.2, 79.0, 51.7, 37.4, 34.3, 33.1, 27.2, 27.0, 22.2, 22.1, 19.4 ppm; IR
(CH2Cl2): n˜ =3073, 2954, 2933, 2859, 1735 (ester C=O), 1718 (ketone C=
Compound 17: DMSO (13.0 mL, 183.1 mmol) was added to a solution of
oxalyl chloride (12.0 mL, 137.5 mmol) in CH2Cl2 (700 mL) at ꢀ788C. The
mixture was stirred for 15 min. Diol 16 (17.30 g, 39.43 mmol) in CH2Cl2
(200 mL) was added at ꢀ788C. The mixture was stirred for 30 min.
iPr2NEt (90.0 mL, 516.7 mmol) was added at ꢀ788C. The resulting mix-
ture was stirred for 10 min at ꢀ788C. The reaction was quenched with
phosphate buffer (pH 7) and extracted with Et2O. The combined organic
layers were dried over anhydrous MgSO4. The solvent was removed in
vacuo and the residue was purified by flash chromatography by using 5–
10% EtOAc in hexane to afford ketoaldehyde 17 (15.49 g, 90%) as a
pale-yellow oil. Rf: 0.83 (35% EtOAc in hexane); [a]2D0 =ꢀ8.01 (c=11.0
in CHCl3); 1H NMR (300 MHz, CDCl3): d=9.70 (s, 1H), 7.65–7.61 (m,
4H), 7.42–7.26 (m, 6H), 4.66 (s, 1H), 4.58 (s, 1H), 4.23 (app.t, J=5.9 Hz,
1H), 2.88–2.47 (m, 4H), 1.87 (t, J=7.3 Hz, 2H), 1.63 (s, 3H), 1.61–1.32
(m, 4H), 1.13 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=210.8, 200.4,
145.2, 135.88, 135.84, 133.4, 133.0, 130.0, 129.9, 127.8, 127.7, 110.2, 79.0,
37.4, 36.9, 34.4, 30.7, 27.0, 22.2, 22.1, 19.4 ppm; IR (CH2Cl2): n˜ =3074,
3044, 2934, 1715 (ketone, aldehyde C=O), 1650 (C=C), 1589, 1472,
1428 cmꢀ1; LRMS (EI): m/z: 436 [M]+ (2), 379 (25), 361 (31), 301 (39),
285 (30), 279 (22), 245 (17), 199 (100), 163 (58), 145 (74), 139 (35);
HRMS (EI): m/z: calcd for C27H36O3Si: 436.2434; found: 436.2428.
O), 1648 (C=C), 1589, 1472, 1463 cmꢀ1
; LRMS (EI): m/z: 409
[MꢀC4H9]+ (16), 391 (8), 353 (8), 331 (6), 279 (5), 237 (11), 199 (12), 193
(35), 179 (13), 161 (100); HRMS (EI): m/z: calcd for C24H29O4Si:
409.1835 [MꢀC4H9]+; found: 409.1835.
Compounds 21 to 23: To
a solution of diazoketone 19 (0.4980 g,
1.046 mmol) in CH2Cl2 (105 mL) was added powdered, predried 4 Š mo-
lecular sieves (0.4906 g). The mixture was stirred for 5 min at 08C. [Rh2-
AHCTRE(UNG Oct)4] (0.0047 g, 0.006 mmol) was added. The resulting mixture was
stirred for 3 h at 08C and filtered through sintered glass. The solvent was
removed in vacuo and the residue was purified by flash chromatography
by using 2–4% EtOAc in hexane to afford ketone 21 (0.2859 g, 61%) as
a white solid, ketone 22 (0.0936 g, 20%) as a white solid, and 23
(0.0234 g, 5%) as a colorless oil.
Compound 21: Rf: 0.30 (10% EtOAc in hexane); m.p. 109–1128C; [a]D20
=
1
ꢀ27.8 (c=2.40 in CHCl3); H NMR (400 MHz, CDCl3): d=7.74–7.72 (m,
4H), 7.45–7.36 (m, 6H), 4.33 (dd, J=9.3, 3.5 Hz, 1H), 3.62 (dd, J=11.7,
4.9 Hz, 1H), 2.68–2.54 (m, 2H), 2.30 (m, 1H), 2.07 (dd, J=13.2, 9.4 Hz,
1H), 1.75 (qd, J=12.6, 3.4 Hz, 1H), 1.63–1.48 (m, 4H), 1.43–1.35 (m,
1H), 1.23 (m, 1H), 1.15–1.05 (m, 1H), 1.05 (s, 9H), 0.97 ppm (s, 3H);
Compound 18: 2-Methyl-2-butene (20.0 mL, 188.7 mmol) and NaH2PO4
(21.00 g, 134.66 mmol) were added to a solution of aldehyde 17 (15.49 g,
35.33 mmol) in tBuOH (75 mL) and H2O (75 mL). The mixture was
stirred for 5 min at 08C. NaClO2 (12.00 g, 132.73 mmol) was added. The
Chem. Eur. J. 2007, 13, 9589 – 9599
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9595

P. Chiu and S. K. Lam
13C NMR (75 MHz, CDCl3): d=211.5, 135.9, 135.7, 134.3, 133.5, 129.7,
129.5, 127.6, 127.3, 84.6, 78.4, 74.2, 45.0, 43.7, 38.2, 32.8, 30.8, 27.0, 23.1,
21.0, 19.7, 19.4 ppm; IR (CH2Cl2): n˜ =2960, 2860, 1731 (ketone C=O),
1472, 1428, 1308 cmꢀ1; LRMS (EI): m/z: 391 [MꢀC4H9]+ (100), 373 (10),
363 (6), 313 (22), 199 (29), 147 (19); HRMS (EI): m/z: calcd for
C24H27O3Si: 391.1729 [MꢀC4H9]+; found: 391.1728; 99% ee which was
determined by using an OD chiralcel column, eluting with 3% isopropa-
(EI): m/z: 492 [M]+ (13), 435 (65), 393 (69), 313 (38), 305 (34), 219 (35),
199 (100), 197 (35), 193 (41), 135 (41); HRMS (EI): m/z: calcd for
C30H40O4Si: 492.2695; found: 492.2691.
TBAF (1m, 17.0 mL, 17.0 mmol) was added to a solution of this ketal
(0.8339 g, 1.692 mmol) in THF (3 mL). The resulting mixture was re-
fluxed for 40 h. Brine was added. The mixture was acidified to pH 5 by
dilute HCl and extracted with EtOAc. The combined organic layers were
washed with H2O twice and dried over anhydrous MgSO4. The solvent
was removed in vacuo to give the crude product as a pale-yellow oil,
which was used in the next reaction without further purification.
nol in hexane at 0.5 mLminꢀ1
.
X-ray crystallography: Data were recorded by using a MAR diffractome-
ter with a 300 mm image plate detector by using graphite monochromat-
ized MoKa radiation (l=0.71073 Š). The crystal was mounted on a glass
capillary. The structure was solved by direct methods employing SIR-97
program on PC. Most non-H atoms were located according to the direct
methods and successive least-square Fourier cycles. Positions of other
non-hydrogen atoms were found after successful refinement by full-
matrix least-squares by using program SHELXL-97 on PC.
DMSO (0.60 mL, 8.45 mmol) was added to a solution of oxalyl chloride
(0.50 mL, 5.73 mmol) in CH2Cl2 (25 mL) at ꢀ788C. The mixture was
stirred for 15 min. The crude product in CH2Cl2 (10 mL) was added at
ꢀ788C. The mixture was stirred for 30 min. NEt3 (2.0 mL, 14.3 mmol)
was added at ꢀ788C. The resulting mixture was stirred at ꢀ788C for
10 min. The reaction was quenched with H2O and extracted with Et2O.
The combined organic layers were dried over anhydrous MgSO4. The sol-
vent was removed in vacuo and the residue was purified by flash chroma-
tography by using 35% EtOAc in hexane to afford ketone (ꢀ)-24.
(0.3479 g, 82% yield over 2 steps) as a white solid. Rf: 0.39 (35% EtOAc
in hexane); m.p. 59–628C; [a]2D0 =ꢀ9.76 (c=3.72 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=4.06 (dt, J=8.0, 1.9 Hz, 1H), 3.98–3.75 (m, 4H),
2.67 (ddd, J=13.7, 9.9, 6.4 Hz, 1H), 2.11 (dtd, J=13.7, 5.1, 1.1 Hz, 1H),
1.97–1.71 (m, 7H), 1.66–1.52 (m, 2H), 1.41–1.34 (m, 1H), 1.03 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=210.5, 106.2, 85.8, 78.5, 64.7, 64.6,
50.4, 43.1, 40.2, 38.0, 27.2, 24.3, 23.0, 20.4 ppm; IR (CH2Cl2): n˜ =3061,
2962, 2889, 1714 (ketone C=O), 1447 cmꢀ1; LRMS (EI): m/z: 252 [M]+
(4), 237 (5), 225 (1), 224 (13), 211 (1), 210 (13), 209 (100), 165 (1);
HRMS (EI): m/z: calcd for C14H20O4: 252.1361; found: 252.1368.
X-ray crystallographic data for (ꢁ)-21: C28H36O3 Si; Fw: 448.66 gmolꢀ1
;
crystal size: 0.50”0.40”0.20 mm; monoclinic; P21/n (#14); a=10.376(2),
b=7.990(2), c=30.543(6) Š; b=93.91(3)8; V=2526.3(9) Š3, Z=4, 1calcd
=
1.180 gcmꢀ3; m(MoKa)=0.119 mmꢀ1; F
A
ACHTREUNG
tions collected; 2206 independent reflections; 1212 reflections with F0 >
4s(F0); 2qmax =50.60o; 293 variable parameters by full-matrix least-
squares refinement on F2 reaches to R1 =0.0375 and wR2 =0.0746; S=
ꢀ3
0.779, largest diff. peak and hole: 0.137/ꢀ0.153e Š
.
CCDC-645998 contains the supplementary crystallographic data for (ꢁ)-
21. These data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif/.
Compound 22: Rf: 0.33 (10% EtOAc in hexane); m.p. 119–1228C; [a]D20
=
1
+8.48 (c=0.33 in CHCl3); H NMR (500 MHz, CDCl3): d=7.68–7.64 (m,
4H), 7.46–7.41 (m, 2H), 7.40–7.35 (m, 4H), 4.14 (dd, J=9.1, 3.2 Hz, 1H),
3.89 (t, J=2.6 Hz, 1H), 2.41–2.31 (m, 2H), 2.29–2.24 (m, 1H), 2.06 (dd,
J=13.4, 9.1 Hz, 1H), 1.93–1.88 (m, 1H), 1.76–1.69 (m, 1H), 1.61–1.53 (m,
3H), 1.50 (m, 2H), 1.43 (s, 3H), 1.33–1.29 (m, 1H), 1.09 ppm (s, 9H);
13C NMR (125 MHz, CDCl3): d=209.5, 136.2, 136.1, 134.0, 133.1, 129.8,
129.7, 127.7, 127.5, 82.7, 78.9, 74.2, 45.1, 42.8, 39.4, 31.9, 29.3, 29.2, 27.2,
21.4, 19.5, 16.9 ppm; IR (CH2Cl2): n˜ =2935, 2859, 1732 (ketone C=O),
1472, 1427, 1274, 1265, 1255 cmꢀ1; LRMS (EI): m/z: 391 [MꢀC4H9]+
(100), 373 (14), 313 (15), 253 (5), 200 (10), 199 (69), 147 (16), 139 (13);
HRMS (EI): m/z: calcd for C24H27O3Si: 391.1729 [MꢀC4H9]+; found:
391.1727.
Compounds 26 and 27: TBAF (1m, 3.2 mL, 3.2 mmol) was added to a so-
lution of ketone 21 (0.4800 g, 1.071 mmol) in THF (6 mL). The resulting
mixture was stirred overnight at room temperature. Brine was added.
The mixture was acidified to pH 5 by dilute HCl and extracted with
EtOAc. The combined organic layers were dried over anhydrous MgSO4.
The solvent was removed in vacuo and the residue was purified by flash
chromatography by using 30–50% EtOAc in hexane to afford the desired
alcohol (0.2016 g, 90%) as a white solid. Rf: 0.39 (50% EtOAc in
hexane); m.p. 88–908C; [a]2D0 =ꢀ22.6 (c=1.02 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=4.13 (dd, J=9.2, 3.2 Hz, 1H), 3.38 (dd, J=11.3,
5.1 Hz, 1H), 2.73 (brs, 1H), 2.55–2.47 (m, 1H), 2.41–2.25 (m, 2H), 2.02
(dd, J=13.3, 9.2 Hz, 1H), 1.78–1.66 (m, 2H), 1.54–1.38 (m, 4H), 1.32–
1.24 (m, 2H), 1.05 ppm (s, 3H); 13C NMR (100 MHz, CDCl3) d 209.8,
Compound 23: Rf: 0.33 (10% EtOAc in hexane); [a]2D0 =+31.8 (c=2.54
1
in CHCl3); H NMR (500 MHz, CDCl3): d=7.78–7.70 (m, 4H), 7.44–7.35
84.3, 78.3, 71.5, 44.3, 44.0, 38.6, 32.2, 30.9, 23.8, 20.9, 19.9 ppm; IR
(m, 6H), 4.29 (dd, J=8.9, 5.0 Hz, 1H), 4.24 (dd, J=11.0, 5.3 Hz, 1H),
2.75–2.60 (m, 2H), 2.29 (dd, J=16.4, 5.9 Hz, 1H), 1.95 (dd, J=12.7,
8.9 Hz, 1H), 1.60–1.46 (m, 5H), 1.42–1.35 (m, 2H), 1.31–1.23 (m, 1H),
1.07 (s, 9H), 0.82 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=212.5,
136.2, 135.8, 134.9, 133.5, 129.6, 129.5, 127.5, 127.4, 84.9, 78.1, 71.9, 45.7,
40.6, 33.9, 31.4, 30.0, 26.9, 22.4, 20.2, 19.4, 19.3 ppm; IR (CH2Cl2): n˜ =
2959, 2859, 1731 (ketone C=O), 1473, 1428, 1274, 1266, 1255 cmꢀ1; LRMS
(EI): m/z: 391 [MꢀC4H9]+ (100), 373 (16), 313 (30), 253 (10), 199 (47),
183 (12), 175 (18), 139 (13); HRMS (EI): m/z: calcd for C24H27O3Si:
391.1729 [MꢀC4H9]+; found: 391.1732.
Compound (ꢀ)-24: 1,2-Bistrimethylsiloxyethane (1.0 mL, 4.0 mmol) was
added to a solution of ketone 22 (0.2946 g, 0.6189 mmol) in CH2Cl2
(10 mL) at room temperature. TMSOTf (0.010 mL, 0.055 mmol) was
added. The resulting mixture was stirred overnight at room temperature.
The reaction was quenched with saturated NaHCO3 and extracted with
Et2O. The combined organic layers were dried over anhydrous MgSO4.
The solvent was removed in vacuo and the residue was purified by flash
chromatography by using 10% EtOAc in hexane to afford the desired
ketal (0.2849 g, 93%) as a colorless oil. Rf: 0.46 (20% EtOAc in hexane);
[a]2D0 =ꢀ0.06 (c=8.30 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.70–
7.67 (m, 4H), 7.43–7.34 (m, 6H), 4.00–3.82 (m, 6H), 2.41–2.33 (m, 1H),
2.05–1.96 (m, 1H), 1.85–1.62 (m, 4H), 1.54–1.41 (m, 5H), 1.37 (s, 3H),
1.21–1.16 (m, 1H), 1.10 ppm (s, 9H); 13C NMR (125 MHz, CDCl3): d=
136.2, 136.1, 134.5, 133.3, 129.6, 129.5, 127.5, 127.3, 106.9, 82.2, 75.8, 74.4,
64.8, 64.6, 44.8, 42.2, 40.9, 30.9, 29.0, 27.8, 27.2, 21.2, 19.5, 16.8 ppm; IR
(CH2Cl2): n˜ =2935, 2895, 2859, 1589, 1473, 1464, 1450, 1429 cmꢀ1; LRMS
ꢀ1
ꢀ
(CH2Cl2): n˜ =3580 (O H), 2063, 2942, 2866, 1732 cm (ketone C=O);
LRMS (EI): m/z: 210 [M]+ (54), 182 (70), 167 (55), 166 (61), 136 (26),
111 (100), 107 (50), 93 (61); HRMS (EI): m/z: calcd for C12H18O3:
210.1255; found: 210.1255.
Imidazole (0.7788, 11.43 mmol) and TBSCl (0.8615 g, 5.715 mmol) were
added to a solution of this deprotected alcohol (0.2016 g, 0.9600 mmol) in
DMF (0.500 mL). The resulting mixture was stirred for 64 h at room tem-
perature. The reaction was quenched with H2O and extracted with Et2O.
The combined organic layers were dried over anhydrous MgSO4. The sol-
vent was removed in vacuo and the residue was purified by flash chroma-
tography by using 7% EtOAc in hexane to afford ketone 26 (0.2697 g,
87%) as a white solid. Rf: 0.30 (10% EtOAc in hexane); m.p. 65–668C;
[a]2D0 =ꢀ36.7 (c=2.76 in CHCl3); 1H NMR (500 MHz, CDCl3): d=4.29
(dd, J=9.3, 3.6 Hz, 1H), 3.63 (dd, J=9.0, 7.5 Hz, 1H), 2.56 (dt, J=16.3,
8.6 Hz, 1H), 2.43–2.38 (m, 1H), 2.30 (ddd, J=16.3, 6.7, 4.4 Hz, 1H), 2.09
(dd, J=13.3, 9.4 Hz, 1H), 1.76–1.66 (m, 3H), 1.61–1.53 (m, 3H), 1.44–
1.37 (m, 1H), 1.34–1.30 (m, 1H), 1.14 (s, 3H), 0.91 (s, 9H), 0.10 ppm (d,
J=2.4 Hz, 6H); 13C NMR (125 MHz, CDCl3): d=211.3, 84.4, 78.3, 73.1,
44.9, 43.8, 38.2, 32.8, 30.9, 25.9, 23.2, 21.1, 19.7, 18.1, ꢀ3.6, ꢀ5.0 ppm; IR
(CH2Cl2): n˜ =2958, 2932, 2858, 1732 (ketone C=O), 1472, 1276,
1254 cmꢀ1; LRMS (EI): m/z: 309 [MꢀCH3]+ (3), 268 (23), 267 (100), 249
(20), 239 (17), 169 (9), 147 (29), 129 (15), 123 (12), 105 (12); HRMS (EI):
m/z: calcd for C17H29O3Si: 309.1886 [MꢀCH3]+; found: 309.1884.
To a solution of the deprotected alcohol (0.0650 g, 0.3091 mmol) in
CH2Cl2 (5 mL) was added iPr2NEt (0.60 mL, 3.43 mmol) and MOMCl
9596
www.chemeurj.org
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9589 – 9599

Total Synthesis of (ꢀ)-Indicol
FULL PAPER
(0.200 mL, 2.633 mmol). The resulting mixture was stirred overnight at
room temperature. The reaction was quenched with H2O and extracted
with EtOAc. The combined organic layers were dried over anhydrous
MgSO4. The solvent was removed in vacuo and the residue was purified
by flash chromatography by using 30% EtOAc in hexane to afford
ketone 27 (0.0738 g, 94%) as a white solid. Rf: 0.55 (50% EtOAc in
hexane); m.p. 42–458C; [a]2D0 =ꢀ7.98 (c=5.75 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=4.83 (d, J=7.1 Hz, 1H), 4.65 (d, J=7.1 Hz, 1H),
4.30 (dd, J=9.3, 3.4 Hz, 1H), 3.53 (dd, J=11.6, 5.0 Hz, 1H), 3.41 (s, 3H),
2.59–2.52 (m, 1H), 2.48–2.42 (m, 1H), 2.40–2.34 (m, 1H), 2.12 (dd, J=
13.3, 9.3 Hz, 1H), 1.96–1.91 (m, 1H), 1.82–1.76 (dt, J=13.7, 7.4 Hz, 1H),
1.70–1.55 (m, 4H), 1.43–1.34 (m, 2H), 1.17 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=210.3, 96.0, 83.8, 79.0, 77.5, 56.0, 45.3, 44.0, 38.6,
32.7, 27.4, 23.9, 20.9, 20.0 ppm; IR (CH2Cl2): n˜ =3055, 2946, 2892, 1732
(ketone C=O), 1472, 1455 cmꢀ1; LRMS (EI): m/z: 254 [M]+ (14), 210
(56), 191 (100), 165 (28), 149 (23), 137 (10), 119 (28); HRMS (EI): m/z:
calcd for C14H22O4: 254.1518; found: 254.1517.
112.4, 84.5, 80.0, 46.0, 44.1, 39.9, 32.2, 31.3, 28.8, 22.5, 21.5 ppm; IR
(CH2Cl2): n˜ =3060, 2939, 2858, 1730 (ketone C=O), 1641 (C=C),
1445 cmꢀ1; LRMS (EI): m/z: 206 [M]+ (34), 191 (12), 188 (6), 164 (10),
163 (73), 162 (100), 161 (5), 135 (6), 134 (8); HRMS (EI): m/z: calcd for
C13H18O2: 206.1306; found: 206.1306.
Compound 29: Ketone 28 (0.4406 g, 2.138 mmol) in THF (20 mL) was
added to a solution of LDA (8.5 mmol) in THF (400 mL) at ꢀ788C. The
mixture was stirred for 1 h at ꢀ788C. Manderꢀs reagent (0.850 mL,
10.7 mmol) was added at ꢀ788C. The resulting mixture was stirred for
2 h at ꢀ788C. The reaction was quenched with saturated NH4Cl and ex-
tracted with Et2O. The combined organic layers were dried over anhy-
drous MgSO4. The solvent was removed in vacuo and the residue was pu-
rified by flash chromatography by using 3% EtOAc in hexane to afford
ester 29 (0.4986 g, 88%) as a colorless oil. Rf: 0.30 (4% EtOAc in
hexane); [a]2D0 =ꢀ32.5 (c=2.20 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=11.58 (brs, 1H), 4.97 (s, 1H), 4.95 (s, 1H), 4.38 (d, J=7.3 Hz, 1H),
3.76 (s, 3H), 2.57–2.43 (m, 3H), 2.19–2.13 (m, 2H), 1.92 (d, J=12.4 Hz,
1H), 1.85–1.70 (m, 1H), 1.65–1.50 (m, 1H), 1.37–1.16 (m, 2H), 1.07 ppm
(s, 3H); 13C NMR (75 MHz, CDCl3): d=173.8, 172.1, 149.1, 110.8, 93.1,
86.1, 73.7, 51.5, 46.5, 46.0, 38.1, 29.3, 28.4, 25.1, 18.7 ppm; IR (CH2Cl2):
n˜ =3090, 2954, 2920, 2871, 1750 (ester C=O), 1730, 1667, 1645 (C=C),
1626, 1444 cmꢀ1; LRMS (EI): m/z: 264 [M]+ (17), 246 (12), 231 (5), 141
(5), 125 (9), 124 (100), 109 (15); HRMS (EI): m/z: calcd for C15H20O4:
264.1361; found: 264.1356.
Compound (+)-24: To a solution of ketone 21 (2.41 g, 5.08 mmol) in
CH2Cl2 (22 mL) was added 1,2-bistrimethylsiloxyethane (2.7 mL,
11.0 mmol) at room temperature. TMSOTf (0.020 mL, 0.110 mmol) was
added. The resulting mixture was stirred overnight at room temperature.
The reaction was quenched with saturated NaHCO3 and extracted with
Et2O. The combined organic layers were dried over anhydrous MgSO4.
The solvent was removed in vacuo to give the crude product as a pale-
yellow oil, which was used in the next reaction without further purifica-
tion.
Compound 30: Ester 29 (0.2739 g, 1.0375 mmol) in THF (50 mL) was
added to a solution of NaH (0.1605 g, 6.6875 mmol) in THF (150 mL) at
room temperature. The mixture was stirred for 1 h at room temperature.
MeI(1.5 mL, 23.8 mmol) was added. The resulting mixture was stirred
for 2 h at room temperature. The reaction was quenched with H2O and
extracted with Et2O. The combined organic layers were dried over anhy-
drous MgSO4. The solvent was removed in vacuo and the residue was pu-
rified by flash chromatography by using 5% EtOAc in hexane to afford
ester 30 (0.2336 g, 81%) as a colorless oil. Rf: 0.38 (10% EtOAc in
hexane); [a]2D0 =+44.6 (c=0.92 in CHCl3); 1H NMR (500 MHz, CDCl3):
d=5.10 (s, 1H), 4.97 (s, 1H), 4.45 (dd, J=9.1, 3.7 Hz, 1H), 3.74 (s, 3H),
2.55 (d, J=14.7, 1H), 2.51–2.45 (m, 1H), 2.27 (d, J=14.7 Hz, 1H), 2.19
(dt, J=13.1, 4.1 Hz, 1H), 2.12 (dd, J=13.2, 9.2 Hz, 1H), 1.84 (dd, J=
13.2, 3.7 Hz, 1H), 1.71–1.65 (m, 2H), 1.55 (s, 3H), 1.55–1.46 (m, 1H),
1.41–1.37 (m, 1H), 1.10 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
207.2, 173.4, 148.3, 112.4, 84.6, 78.8, 52.8, 52.7, 46.9, 42.0, 39.0, 34.7, 32.0,
26.0, 23.8, 19.5 ppm; IR (CH2Cl2): n˜ =3093, 2996, 2940, 2865, 1745 (ester
C=O), 1726 (ketone C=O), 1643 cmꢀ1 (C=C); LRMS (EI): m/z: 278 [M]+
(26), 235 (8), 207 (13), 206 (21), 175 (20), 150 (24), 148 (13), 147 (100),
124 (16), 122 (11), 107 (10); HRMS (EI): m/z: calcd for C16H22O4:
278.1518; found: 278.1513.
The residue was dissolved in TBAF (1m, 42.0 mL, 42.0 mmol). The re-
sulting mixture was stirred for 64 h at room temperature. Brine was
added and the mixture was acidified to pH 5 by dilute HCl and extracted
with EtOAc. The combined organic layers were dried over anhydrous
MgSO4. The solvent was removed in vacuo and the residue was purified
by flash chromatography by using 50–90% EtOAc in hexane to afford
the desired alcohol (1.27 g, 99%) as a white solid. Rf: 0.50 (EtOAc); m.p.
96–988C; [a]2D0 =ꢀ4.83 (c=6.35 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=4.04–3.77 (m, 5H), 3.31 (dd, J=11.2, 5.0 Hz, 1H), 2.51 (td, J=13.8,
7.2 Hz, 1H), 2.22 (brs, 1H), 2.00–1.61 (m, 5H), 1.51–1.20 (m, 6H),
1.08 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=106.6, 84.0, 76.3, 71.9,
64.9, 64.7, 44.2, 44.0, 40.8, 31.4, 27.5, 26.5, 21.2, 20.3 ppm; IR (CH2Cl2):
n˜ =3576 (O H), 3469 (O H), 2942, 2892, 1479, 1452 cmꢀ1; LRMS (EI):
m/z: 254 [M]+ (8), 209 (34), 155 (100), 153 (23), 136 (12), 111 (31), 109
(28); HRMS (EI): m/z: calcd for C14H22O4: 254.1518; found: 254.1516.
ꢀ
ꢀ
DMSO (0.100 mL, 1.409 mmol) was added to a solution of oxalyl chlo-
ride (0.080 mL, 0.917 mmol) in CH2Cl2 (10 mL) at ꢀ788C. The mixture
was stirred for 15 min. The alcohol (0.0880 g, 0.3464 mmol) in CH2Cl2
(10 mL) was added at ꢀ788C. The mixture was stirred for 30 min. NEt3
(0.30 mL, 2.15 mmol) was added at ꢀ788C. The resulting mixture was
stirred for 10 min at ꢀ788C. The reaction was quenched with H2O and
extracted with Et2O. The combined organic layers were dried over anhy-
drous MgSO4. The solvent was removed in vacuo and the residue was pu-
rified by flash chromatography by using 35% EtOAc in hexane to afford
ketone (+)-24 (0.0853 g, 98%) as a white solid. All characterizations
were identical to (ꢀ)-24 except [a]2D0 = +0.07 (c=9.52 in CHCl3).
Compound 28: To a mixture of methyltriphenylphosphonium bromide
(6.46 g, 18.10 mmol) in THF (100 mL) was added nBuLi (1.6m, 9.4 mL,
15.0 mmol) at 08C. The mixture was stirred for 30 min at room tempera-
ture. Ketone (+)-24 (0.6899 g, 2.738 mmol) in THF (10 mL) was added.
The resulting mixture was stirred for 5 h at room temperature. The reac-
tion was quenched with H2O (5 mL) and then HCl (3m, 10 mL) was
added. The resulting mixture was refluxed overnight. The mixture was
basicified to pH 6 by saturated NaHCO3 and extracted with Et2O. The
combined organic layers were dried over anhydrous MgSO4. The solvent
was removed in vacuo and the residue was purified by flash chromatogra-
phy by using 7.5% EtOAc in hexane to afford ketone 28 (0.5580 g, 95%)
Compound 31: SmI2 in THF (0.1m 200.0 mL, 20.0 mmol) was added
quickly in one portion at 08C to
a solution of ester 30 (0.4570 g,
1.6438 mmol) in THF (600 mL) by using an addition funnel. The mixture
was stirred for 1 h at 08C. The reaction was quenched with 0.5m HCl and
extracted with Et2O. The combined organic layers were dried over anhy-
drous MgSO4. The solvent was removed in vacuo and the residue was pu-
rified by flash chromatography by using 15% EtOAc in hexane to afford
hemiacetal 31 (0.4185 g, 91%) as a pale-yellow solid. Rf: 0.28 (20%
EtOAc in hexane); m.p. 63–668C; [a]2D0 =+26.0 (c=2.63 in CHCl3);
1H NMR (500 MHz, CDCl3): d=4.88 (s, 1H), 4.70 (s, 1H), 3.74 (s, 3H),
2.80 (d, J=13.7 Hz, 1H), 2.49 (td, J=13.0, 5.5 Hz, 1H), 2.32 (td, J=13.6,
6.5 Hz, 1H), 2.14–2.11 (m, 1H), 1.99 (td, J=13.6, 6.5 Hz, 1H), 1.91 (d,
J=13.7 Hz, 1H), 1.77 (ddd, J=13.7, 6.0, 1.4 Hz, 1H), 1.68–1.52 (m, 3H),
1.34 (s, 3H), 1.31 (ddd, J=14.5, 6.5, 1.3 Hz, 1H), 1.01 (m, 1H), 0.77 ppm
(s, 3H); 13C NMR (125 MHz, CDCl3): d=175.0, 148.2, 108.8, 103.4, 84.6,
53.5, 52.2, 37.8, 37.2, 33.4, 32.6, 32.3, 30.9, 23.8, 23.2, 21.6 ppm; IR
ꢀ1
ꢀ
(CH2Cl2): n˜ =3414 (O H), 2944, 2871, 1727 (ester C=O), 1648 cm (C=
C); LRMS (EI): m/z: 280 [M]+ (3), 262 (4), 234 (14), 207 (75), 175 (16),
151 (14), 148 (24), 147 (100); HRMS (EI): m/z: calcd for C16H24O4:
280.1670; found: 280.1674.
as a white solid. Rf: 0.19 (10% EtOAc in hexane); m.p. 69–728C; [a]D20
=
+20.0 (c=1.00 in CHCl3); 1H NMR (400 MHz, CDCl3): d=5.01 (s, 1H),
4.93 (s, 1H), 4.26 (d, J=8.8 Hz, 1H), 2.58–2.48 (m, 1H), 2.44–2.37 (m,
2H), 2.32–2.24 (m, 1H), 2.20–2.14 (m, 3H), 1.75–1.56 (m, 3H), 1.50–1.35
(m, 2H), 1.13 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=208.1, 148.0,
Compound 32: iPr2NEt (15 mL, 85.8 mmol) and MOMCl (6.0 mL,
78.9 mmol) were added to
a solution of hemiacetal 31 (0.4185 g,
1.4946 mmol) in CH2Cl2 (7 mL). The resulting mixture was stirred for
Chem. Eur. J. 2007, 13, 9589 – 9599
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9597

P. Chiu and S. K. Lam
156 h at room temperature. The reaction was quenched with H2O and ex-
tracted with Et2O. The combined organic layers were dried over anhy-
drous MgSO4. The solvent was removed in vacuo and the residue was pu-
rified by flash chromatography by using 5% EtOAc in hexane to afford
ester 32 (0.4461 g, 92%) as a pale-yellow oil. Rf: 0.70 (20% EtOAc in
hexane); [a]2D0 =ꢀ119 (c=1.64 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=5.13 (d, J=6.8 Hz, 1H), 4.83 (s, 1H), 4.73 (d, J=6.8 Hz, 1H), 4.67 (s,
1H), 3.70 (s, 3H), 3.40 (s, 3H), 2.75 (d, J=13.6 Hz, 1H), 2.45 (td, J=
12.7, 5.7 Hz, 1H), 2.31–2.18 (m, 2H), 2.12–2.07 (m, 1H), 1.87 (d, J=
13.6 Hz, 1H), 1.77–1.47 (m, 4H), 1.29 (s, 3H), 1.30–1.23 (m, 1H), 0.99–
0.94 (m, 1H), 0.74 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=175.5,
148.3, 108.6, 106.1, 91.6, 85.6, 55.3, 55.2, 52.0, 38.3, 37.3, 33.5, 32.7, 32.3,
28.3, 24.7, 23.2, 21.7 ppm; IR (CH2Cl2): n˜ =2947, 1726 (ester C=O),
1651 cmꢀ1 (C=C); LRMS (EI): m/z: 324 [M]+ (19), 279 (48), 261 (34),
229 (34), 219 (72), 207 (76), 201 (44), 161 (31), 147 (100); HRMS (EI):
m/z: calcd for C18H28O5: 324.1936; found: 324.1926.
4.67 (s, 1H), 2.75 (s, 1H), 2.65–2.57 (m, 2H), 2.53–2.31 (m, 2H), 2.35 (td,
J=13.2, 4.9 Hz, 1H), 2.13–2.10 (m, 1H), 1.95–1.90 (m, 1H), 1.87 (d, J=
13.3 Hz, 1H), 1.81–1.52 (m, 7H), 1.39 (dd, J=14.3, 6.1 Hz, 1H), 1.11 (d,
J=6.9 Hz, 3H), 1.10 (d, J=6.9 Hz, 3H), 1.03–0.97 (m, 1H), 1.00 (s, 3H),
ꢀ
0.71 ppm (s, 3H); IR (CH2Cl2): n˜ =3585 (O H), 2971, 2943, 1708 (C=O),
1647 cmꢀ1 (C=C); LRMS (EI): m/z: 320 [M]+ (3), 302 (4), 292 (4), 277
(5), 259 (6), 248 (3), 247 (9), 235 (12), 229 (37), 221 (39), 203 (11);
HRMS (EI): m/z: calcd for C20H32O3: 320.2351; found: 320.2350.
Acknowledgements
This research was supported by the Research Grants Council of Hong
Kong SAR (HKU 7017/04P), and the Areas of Excellence Scheme estab-
lished under the University Grants Committee of the Hong Kong Special
Administrative Region, China (Project no. AoE/P-10/01), and the Uni-
versity of Hong Kong. S.K.L. thanks the CRCG for a conference grant.
Compound 33: To a solution of ester 32 (0.4461 g, 1.3768 mmol) in Et2O
(20 mL) was added LAH (0.3262 g, 8.5842 mmol) at room temperature.
The resulting mixture was stirred for 4 h at room temperature. The reac-
tion was quenched with H2O at ꢀ788C, slowly warmed to room tempera-
ture, and extracted with Et2O. The combined organic layers were dried
over anhydrous MgSO4. The solvent was removed in vacuo and the resi-
due was used in the next step without further purification.
[1] Reviews of the CCCC reaction: a) A. Padwa, Helv. Chim. Acta
2005, 88, 1357–1374; b) M. P. Doyle, Chem. Rev. 1986, 86, 919–939;
c) A. Padwa, Acc. Chem. Res. 1991, 24, 22–28; d) A. Padwa, D. J.
Austin, Angew. Chem. 1994, 106, 1881–1899; Angew. Chem. Int. Ed.
Engl. 1994, 33, 1797–1815; e) G. Mehta, S. Muthusamy, Tetrahedron
2002, 58, 9477–9504.
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62, 1317–1325.
To
a solution of oxalyl chloride (0.500 mL, 5.731 mmol) in CH2Cl2
(100 mL) at ꢀ788C was added DMSO (0.500 mL, 7.045 mmol). The mix-
ture was stirred for 15 min. The crude product in CH2Cl2 (50 mL) was
added at ꢀ788C. The mixture was stirred for 30 min. NEt3 (2.0 mL,
14.3 mmol) was added at ꢀ788C. The resulting mixture was stirred for
10 min at ꢀ788C. The reaction was quenched with H2O and extracted
with Et2O. The combined organic layers were dried over anhydrous
MgSO4. The solvent was removed in vacuo to give the crude product as a
pale-yellow oil, and the residue was used in the next step without further
purification.
[4] A. Padwa, S. R. Harring, M. A. Semones, J. Org. Chem. 1998, 63,
44–54.
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Chem. 1997, 62, 78–87.
Compound 34: 60% NaH (0.2858 g, 7.145 mmol) was added to a solution
of dimethyl (3-methyl-2-oxobutyl)phosphonate (1.45 g, 7.51 mmol) in
THF (20 mL) at room temperature. The mixture was stirred for 30 min at
room temperature. Crude 33 in THF (20 mL) was added. The resulting
mixture was stirred overnight at room temperature. The reaction was
quenched with H2O and extracted with Et2O. The combined organic
layers were dried over anhydrous MgSO4. The solvent was removed in
vacuo and the residue was purified by flash chromatography by using
5% EtOAc in hexane to afford ketone 34 (0.4475 g, 90% yield over
3 steps) as a colorless oil. Rf: 0.50 (10% EtOAc in hexane); [a]2D0 =ꢀ88.1
[6] J. L. Wood, B. D. Thompson, N. Yusuff, D. A. Pflum, M. S. P. Mat-
thäus, J. Am. Chem. Soc. 2001, 123, 2097–2098.
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8898–8925.
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2006, 118, 6682–6685; Angew. Chem. Int. Ed. 2006, 45, 6532–6535.
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1526; b) T. Graening, V. Bette, J. Neudçrfl, J. Lex, H.-G. Schmalz,
Org. Lett. 2005, 7, 4317–4320.
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1
(c=1.71 in CHCl3); H NMR (300 MHz, CDCl3): d=7.05 (d, J=16.0 Hz,
1H), 6.28 (d, J=16.0 Hz, 1H), 5.11 (d, J=6.7 Hz, 1H), 4.85 (s, 1H), 4.69
(d, J=6.7 Hz, 1H), 4.68 (s, 1H), 3.38 (s, 3H), 2.84 (septet, J=6.8 Hz,
1H), 2.49 (td, J=12.0, 5.9 Hz, 1H), 2.32–2.18 (m, 2H), 2.15–2.09 (m,
2H), 1.93 (d, J=13.3 Hz, 1H), 1.66–1.43 (m, 4H), 1.34–1.26 (m, 1H),
1.13 (s, 3H), 1.12 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H), 1.05–6.97
(m, 1H), 0.72 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=203.8, 149.4,
148.3, 126.9, 108.4, 107.1, 91.8, 86.0, 55.6, 50.1, 39.4, 38.7, 37.1, 33.5, 32.7,
32.4, 28.0, 25.8, 23.2, 21.7, 18.5, 18.4 ppm; IR (CH2Cl2): n˜ =3085, 2973,
1693 (enone C=O), 1668 (C=C), 1654 cmꢀ1 (C=C); LRMS (EI): m/z: 362
[M]+ (4), 317 (37), 299 (100), 281 (21), 259 (15), 245 (43), 229 (45);
HRMS (EI): m/z: calcd for C22H34O4: 362.2457; found: 362.2443.
(ꢀ)-Indicol (1): Ketone 34 (0.4475 g, 1.2361 mmol) in THF (40 mL) was
added to a solution of [Ph3PACHTRE(UNG CuH)]6 (1.0569 g, 0.5403 mmol) in THF
(10 mL) and H2O (0.200 mL, 11.111 mmol) at room temperature. The
mixture was stirred for 24 h at room temperature. The reaction was
quenched with saturated NH4Cl. HCl (12m, 4 mL) in MeOH (20 mL)
was added. The resulting mixture was stirred for 48 h at room tempera-
ture. The reaction was quenched with saturated NaHCO3 and extracted
with Et2O. The combined organic layers were dried over anhydrous
MgSO4. The solvent was removed in vacuo and the residue was purified
by flash chromatography by using 15% EtOAc in hexane to afford indi-
col (1) (0.3868 g, 98%) as a white solid. Rf: 0.40 (20% EtOAc in
[17] R. C. Pereira, M. D. Pinheiro, V. L. Teixeira, B. A. D. Gama, Braz. J.
Biol. 2002, 62, 33–40.
[18] M. Ochi, M. Watanabe, Chem. Lett. 1980, 1229–1232.
hexane); m.p. 63–658C; [a]2D0 =ꢀ43.5 (c=1.50 in CHCl3), lit:[14] [a]2D0
=
1
ꢀ44.0 (c=0.426 in CHCl3); H NMR (500 MHz, CDCl3): d=4.84 (s, 1H),
9598
www.chemeurj.org
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9589 – 9599

Total Synthesis of (ꢀ)-Indicol
FULL PAPER
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Received: June 3, 2007
Published online: August 31, 2007
Chem. Eur. J. 2007, 13, 9589 – 9599
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9599