Synthesis of new allocolchicinoids with seven- and eight-membered B-rings by enyne ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.200800595

Total syntheses of allocolchicines 4 and 5, with the ester functionality in the C-ring at the C10 or C11 positions, is reported. An asymmetric synthesis of (7S)-allocolchicine 5 is also described. The main features included the elaboration of a common int

Full text of DOI:10.1002/ejoc.200800595

FULL PAPER
DOI: 10.1002/ejoc.200800595
Synthesis of New Allocolchicinoids with Seven- and Eight-Membered B-Rings
by Enyne Ring-Closing Metathesis
François-Didier Boyer[a] and Issam Hanna*[b]
Keywords: Allocolchicines / Enyne / Ring-closing metathesis / Cycloheptenes / Cyclooctenes / Diels–Alder reactions
Total syntheses of allocolchicines 4 and 5, with the ester func-
tionality in the C-ring at the C10 or C11 positions, is reported.
An asymmetric synthesis of (7S)-allocolchicine 5 is also de-
scribed. The main features included the elaboration of a com-
mon intermediate, the AB bicyclic ring system, in which the
construction of the seven-membered ring was achieved by
an enyne ring-closing metathesis (RCM) reaction. A subse-
quent Diels–Alder/aromatization sequence afforded the set
of functionalized ring-C allocolchicinoids with high regiose-
lectivity. This strategy was also applied for the synthesis of
allocolchicine 6, containing an eight-membered B-ring.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
the seven-membered ring by an intramolecular biaryl coup-
ling reaction (AC Ǟ ABC approach), a different route was
developed by Wulff and co-workers, distinguished by the
construction of the aromatic C-ring through a Diels–Alder
reaction of a suitably substituted diene containing the
seven-membered ring (AB Ǟ ABC approach).[5a] In all
these approaches, the allocolchicinoids described bear func-
tionalities at the C9 position in the C-ring.[6]
In the course of our study of the application of metathe-
sis reactions of enynes to the synthesis of polycyclic com-
pounds containing seven-membered rings,[7] we recently de-
scribed the synthesis of the new allocolchicines 4 and 5
(Figure 1),[8] analogues of 2 containing the ester group at
positions C10 and C11, respectively.[7c] Here we report a
full account of this work and also describe an asymmetric
synthesis of (7S)-allocolchicine 5, together with the synthe-
sis of a new allocolchicinoid 6, an analogue of 5 in which
the seven-membered B-ring is replaced by an eight-mem-
bered ring.
Our route was based on a conceptually similar approach
to Wulff’s one. The construction of the allocolchicine tricy-
clic core was planned to be through a Diels–Alder reaction
with a suitably substituted diene containing either a seven-
or an eight-membered ring fused to the aromatic A-ring
(AB Ǟ ABC approach). As shown in the retrosynthetic
analysis (Scheme 1), target compounds 4, 5, and 6 were to
be obtained by direct reductive amination of ketones 7, 8,
and 9, respectively. These ketones could be prepared by a
Diels–Alder/aromatization sequence from intermediate
dienes 10 (n = 1 or 2), which can be traced back to 11 (R
= TBS). Our initial plan involved the preparation of 11 by
ring-closing metathesis (RCM) of enyne 12.[9] This precur-
sor was to be obtained from the cheap and commercially
available acid 13.
Introduction
Colchicine (1), present as the major alkaloid in Colchi-
cum autumnale, is an old drug used in medicine in acute
gout attacks and in familial Mediterranean fever. It has
long been known for its remarkable antimitotic activity, the
result of its specific binding to tubulin, preventing microtu-
bule assembly, spindle formation, and consequently cell di-
vision.[1,2] Colchicine has also been studied as an anticancer
agent, but therapeutic effects are only observed at toxic or
nearly toxic doses. A significant development in cancer che-
motherapy was the discovery that allocolchicinoids, pos-
sessing a benzene ring in place of the tropolone ring, also
arrest mitosis by inhibiting tubulin polymerization. Natural
allocolchicine (2) binds to tubulin more strongly than col-
chicine itself.[3] Recently, colchicine-type antimicrotubule
agents found a second wind with the discovery that N-ace-
tylcolchinol (3), in the form of its water-soluble phosphate,
selectively induces tumor vascular damage and tumor ne-
crosis at well-tolerated doses; it is currently undergoing clin-
ical trials.[4]
For a long time allocolchicinoids were obtained by trans-
formation of colchicine itself, thus limiting the range of
structural variations. Recently, total syntheses of 2 and 3
have been reported, and a number of syntheses of various
allocolchicinoids have also been described.[5] Whereas most
approaches involve a strategy based on the construction of
[a] Institut de Chimie des Substances Naturelles, INRA, CNRS
UPR 2301,
91198 Gif sur Yvette, France
[b] Laboratoire de Synthèse Organique, CNRS UMR 7652, Ecole
Polytechnique,
91128 Palaiseau, France
E-mail: hanna@poly.polytechnique.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Allocolchicinoids with Seven- and Eight-Membered B-Rings
enynes were then subjected to RCM conditions. Unfortu-
nately, when these compounds were treated with the sec-
ond-generation Grubbs catalyst (17),[11] either in CH2Cl2 at
reflux or in toluene at 80 °C, no ring-closing product such
as 11 was isolated. When this reaction was carried out on
diene 12c under ethylene gas[12] in CH2Cl2 at reflux for 22 h,
however, compound 18 was obtained as the sole product in
70% yield (Scheme 3). We were therefore intrigued by the
potential application of Hoye’s relay RCM strategy[13] for
delivering the catalyst onto the alkene. To this end, dienyne
12e was prepared[14] and subjected to various sets of RCM
conditions in the presence of catalyst 17. In all cases none
of the desired product was formed. These data suggested
that, in the absence of ethylene, the terminal alkene in 12c
reacts more readily with the (alkylidene)Ru unit to afford
the chelated complex 12d, which sequesters the active Ru
system, inhibiting cyclization to 11.[15]
Figure 1. Colchicine and allocolchicines.
Scheme 2. Preparation of enyne 12 (n = 1).
In view of the above result, we turned to another strategy
starting from enyne 20, in which the formation of a seven-
membered ring by RCM would be followed by an oxidative
rearrangement of allylic alcohol 19 to furnish ketone 10
(Scheme 4). It was already known that, contrary to 12c, en-
yne 20 would easily undergo the ring-closing metathesis re-
action.[16]
The RCM precursor 20 was prepared from aldehyde 14
as indicated in Scheme 5. Compound 14 was alkynylated
with lithiated trimethylsilylacetylene, and the resulting pro-
pargylic alcohol was converted into its tert-butyldimethylsi-
Scheme 1. Initial retrosynthesis of allocolchicines.
Results and Discussion
According to this strategy, the synthesis commenced with lyl-protected derivative 21 under standard conditions. To
the conversion of the acid functionality of 13 into the elaborate the “upper” carbon chain, ester 21 was reduced
methyl ester and subsequent formylation with dichlo- with LiAlH4, and the resulting primary alcohol was treated
romethyl methyl ether in the presence of SnCl4 to afford with PDC to furnish aldehyde 22. Conversion of 22 into
aldehyde 14 (Scheme 2).[10] A Wittig reaction converted this enyne 20 was accomplished by a Wittig reaction followed
aldehyde into ester 15. Reduction of 15 with LiAlH4 and by selective desilylation with K2CO3 in MeOH. Treatment
subsequent oxidation of the resulting primary alcohol led of 20 with the second-generation Grubbs catalyst (2.5%) in
to aldehyde 16. Treatment of 16 with ethynylmagnesium dichloromethane at reflux for 5 h smoothly afforded diene
bromide afforded propargylic alcohol 12a, which was con- 23 in 98% yield. Complete deprotection of the secondary
verted either into acetate 12b or into silyl ether 12c. These alcohol was achieved by stirring 23 with tetrabutylammo-
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Scheme 3. Attempted RCM of enyne 12c.
Scheme 4. Revised approach to the bicyclic ring system.
nium fluoride (TBAF, 1 ) solution in THF at room tem-
perature for 2 d, leading to alcohol 19.
With the bicyclic conjugated diene 19 to hand, we next
turned to the construction of the aromatic ring. To place
the C-ring in its correct position through a Diels–Alder re-
action, rearrangement of the allylic alcohol moiety would
have to be achieved at this stage. To this end, treatment of
19 under Dauben’s tertiary allylic rearrangement conditions
was considered.[17a] When a solution of 19 in dichlorometh-
ane was stirred with 2 equiv. of pyridinium chlorochromate
(PCC) at room temperature for 1 h, dienone 10 was ob-
tained as the sole product in 55% yield.[17b] Sequential re-
duction of 10 under Luche’s conditions[18] and protection
of the resulting alcohol as its tert-butyldimethylsilyl ether
Scheme 5. Synthesis of the common intermediate 10.
under standard conditions led to 24 in high yield for this total regiocontrol. Deprotection with TBAF led to
(Scheme 6). alcohol 26, which was oxidized with Dess–Martin
A Diels–Alder reaction of diene 24 was first performed periodinane[19] to give ketone 7 as a white solid (m.p. 147–
with methyl propiolate. When a mixture of 24 and an excess 148 °C). It is worthy of note that alcohol 26 existed as a
of this dienophile was heated in toluene at 115 °C for 24 h, mixture of two atropoisomers. In these compounds the bar-
only one regioisomer was obtained, as indicated by NMR rier of the rotation about the aryl bond is so high that the
spectroscopic data. The regioselectivity of this cycload- individual isomers can be separated at room temperature
dition was confirmed in the next step: DDQ aromatization by silica gel column chromatography.[20]
of the crude cycloadduct afforded the protected allocolchic-
In order to shorten the synthesis, the Diels–Alder reac-
inoid 25 as only one isomer. It is likely that electronic fac- tion with methyl propiolate was attempted directly with di-
tors prevail over steric interactions in 24 and are responsible enone 10. We were pleased to observe that this reaction
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Allocolchicinoids with Seven- and Eight-Membered B-Rings
(27;[22] Scheme 7) should provide the opposite regiochemis-
try to that obtained with methyl propiolate in a Diels–Alder
reaction with diene 10. Indeed, 27 readily reacted with diene
10 at room temperature, affording cycloadduct 28 in 97%
yield. NMR spectroscopy revealed that 28 was a mixture
of two stereoisomers (4:1 ratio) confirming the complete
regioselectivity of this reaction.[23] The elimination of ni-
trous acid by treatment with DBU and subsequent aromati-
zation with DDQ furnished ketone 8 as the sole product
in 50% overall yield. As in the case of ketone 7, reductive
amination of compound 6, followed by N-acylation of the
resulting amino ester, produced rac-5 (m.p. 181–183 °C) in
1
57% yield as a 2:1 mixture of rotamers as shown by H
NMR spectroscopy.
Scheme 6. Synthesis of rac-4.
occurred readily under the same conditions, affording only
one regioisomer as in the case of diene 24. Treatment of the
crude cycloadduct with DDQ led to 7 in 85% overall yield
(Scheme 6). In this way, the synthesis of allocolchicinoid 7
was achieved in two steps from ketone 10 instead of six for
the previous sequence.
Scheme 7. Synthesis of rac-5.
Reductive amination of ketone 7 with ammonium acetate
and sodium cyanoborohydride,[21] followed by N-acylation
of the resulting amino ester, produced rac-4 (m.p. 206–
In order to gain some indication of their ability to func-
209 °C) in 69% yield as a 2:1 mixture of atropoisomers as tion as antimitotic agents, racemic allocolchicines 4 and 5
1
shown by H NMR spectroscopy.
described above were subjected to a tubulin binding as-
We next turned to the synthesis of allocolchicinoids with say.[24] While rac-4 was inactive, allocolchicine rac-5 was
functionality at C-10. On the basis of the regioselectivity found to be as active as colchicine. This result prompted us
observed above, we reasoned that methyl β-nitroacrylate to consider the enantioselective synthesis of 5.
Scheme 8. Synthesis of (7S)-allocolchicine (5).
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F.-D. Boyer, I. Hanna
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This synthesis was based on the introduction of the ste-
reogenic center at C7 by asymmetric reduction of the ketone
8. In their synthesis of the natural (–)-(7S)-allocolchicine
(2a), Wulff and co-workers reported[5a] that the procedure
developed by Singaram and co-workers for the enantioselec-
tive reduction of ketones with (+)-TarB-NO2 (29)[25] had
been found to give the best yields of the (7R)-alcohol.[26]
When ketone 8 was treated with 2 equiv. of (+)-TarB-NO2
and 2.1 equiv. of NaBH4, alcohol (7R)-30 was obtained in
86% yield and 90% ee (Scheme 8). Inversion of stereochem-
istry at C7 with concomitant introduction of a nitrogen func-
tionality was achieved by a two-step procedure, to afford
(7S)-31 in 71% overall yield. The reduction of the azide 31
to the corresponding amine was achieved by heterogeneous
hydrogenation in the presence of 5% Pd/CaCO3/3.5% Pb,
affording (–)-(7S)-allocolchicine (5) in 58% yield after acety-
lation. The enantiomeric purity of 5, determined by chiral
HPLC, was 94% after a single recrystallization.
Synthesis of Allocolchicinoids Containing an Eight-
Membered B-Ring
The antimitotic activity of allocolchicine (5) made us in-
terested in hitherto unknown allocolchicinoids containing
an eight-membered B-ring. Such compounds belong to lig-
nan derivatives possessing the dibenzocyclooctadiene skel-
eton and, like allocolchicinoids, they are characterized by
an atropoisomeric biaryl unit.[20] A number of these prod-
ucts display a wide variety of biological activities. Naturally
occurring steganacin (Figure 2), for example, binds to the
colchicine site in tubulin and shows antitumor activity in
vivo.[27] The syntheses of all dibenzocyclooctadiene lignan
derivatives described to date, including aza and oxa ana-
logues of steganacin, have involved inter- or intramolecular
biaryl coupling reactions (AC Ǟ ABC approaches).[27,28] As
in the cases of allocolchicines 4 and 5, we planned the con-
struction of the tricyclic core of the lignan derivatives by the
AB Ǟ ABC approach. The AB part containing the eight-
membered ring fused to the aromatic A-ring would thus
have to be built by means of a ring-closing metathesis reac-
tion of a suitably substituted enyne (Scheme 9).[29]
Scheme 9. Synthesis of allocolchicinoids containing an eight-mem-
bered B-ring.
ester 32 was reduced with LiAlH4, and the resulting pri-
mary alcohol was treated with PDC to furnish aldehyde
33. One-carbon homologation was achieved in a two-step
sequence transforming 33 into 34 as shown in Scheme 9,
and the resulting aldehyde 34 was converted into enyne 35
by a Wittig reaction.
When enyne 35 was treated with the Grubbs second-gen-
eration catalyst (10%) in dichloromethane at reflux for 4 h,
the RCM reaction took place smoothly to afford, after desi-
lylation, the bicyclic conjugated diene 36 in 84% overall
yield. Obviously, this process was facilitated by the presence
of the pre-existing aromatic ring bearing the alkene and al-
kyne moieties at adjacent positions.[30]
The introduction of the C-ring was achieved as in the
case of the synthesis of allocolchicine 5. Oxidation of
alcohol 36 with pyridinium chlorochromate (PCC) at room
temperature for 1.5 h afforded dienone 37 as the sole prod-
Figure 2. Dibenzocyclooctadiene lignans.
The synthesis commenced with the previously described uct in 76% yield. As in the case of dienone 11, 37 readily
aldehyde 14 (Scheme 9). Addition of ethynylmagnesium reacted with β-nitroacrylate 27 at room temperature to af-
bromide to 14, followed by protection of the resulting pro- ford cycloadduct 38 in a near quantitative yield as a mixture
pargylic alcohol, afforded tert-butyldimethylsilyl ether 32 in of diastereomers. Unexpectedly, treatment of 38 with DBU
high overall yield. To elaborate the “upper” carbon chain, at room temperature for 4 h achieved both elimination of
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Allocolchicinoids with Seven- and Eight-Membered B-Rings
purified by chromatography on silica gel (cyclohexane/EtOAc, 4:1)
nitrous acid and aromatization, leading to a mixture of
ketone 9 and alcohol 39 (1:1 ratio) in 90% combined yield.
Oxidation of 39 with Dess–Martin periodinane reagent gave
ketone 9 in 96% yield. It is worth noting that alcohol 39
to give 14 (27 g, 95.7 mmol, 85%) as a white solid. Rf = 0.4 (cyclo-
1
hexane/EtOAc, 4:1). M.p. 54–55 °C. H NMR: δ = 10.36 (s, 1 H),
6.58 (s, 1 H), 3.97 (s, 3 H), 3.91 (s, 3 H), 3.86 (s, 3 H), 3.65 (s, 3
H), 3.22 (t, J = 7.5 Hz, 2 H), 2.61 (t, J = 7.5 Hz, 2 H) ppm. 13C
NMR: δ = 190.6 (CH), 173.4 (C), 158.6 (C), 157.9 (C), 140.2 (C),
140.1 (C), 120.0 (C), 110.2 (CH), 62.3 (CH3), 60.8 (CH3), 56.0
1
was isolated as a single isomer as shown by H NMR spec-
troscopy. Assignment of the relative configuration (aS,8R)
of this compound was based on the X-ray crystallographic
analysis.[31] For this diastereoisomer the two aryl rings are
twisted out of plane with a torsion angle of about 61°.
(CH ), 51.4 (CH ), 35.0 (CH ), 29.6 (CH ) ppm. IR (neat): ν =
˜
max
3
3
2
2
2946, 2850, 1735, 1678, 1590 cm–1. MS (CI, NH3): m/z (%) = 283
[M + 1]+· (100), 300 [M + 18]+· (5). HMRS (EI): m/z calcd. for
Reductive amination of ketone 9, followed by N-acyl- C14H18O6 282.1103; found 282.1105.
ation of the resulting amino ester, produced allocochicinoid
Alkyne 21: n-Butyllithium (4.4 mL, 7.04 mmol, 1.6  solution in
6 (m.p. 156–158 °C) in 44% yield as a 2:1 mixture of atro-
hexane) was added dropwise under argon at –70 °C to a solution
of ethynyltrimethylsilane (0.99 mL, 7 mmol) in dry THF (28 mL).
The resulting mixture was stirred at –70 °C for 15 min, and this
solution (27 mL) was added dropwise under argon at –70 °C to a
solution of aldehyde 14 (1.58 g, 5.60 mmol) in dry THF (30 mL).
The reaction mixture was stirred at –70 °C for 1.5 h, saturated am-
monium chloride solution (20 mL) was added, and the mixture was
diluted with Et2O (100 mL). The biphasic mixture was allowed to
warm to room temperature, was separated, and the aqueous phase
was extracted with Et2O (2ϫ100 mL). The combined organic ex-
tracts were washed with brine (100 mL), dried (MgSO4), and con-
centrated under reduced pressure to give crude propargylic alcohol
(2.09 g). This crude propargylic alcohol (2.09 g) was immediately
dissolved in dry DMF (5 mL). Imidazole (1.156 g, 17 mmol) and
tert-butyldimethylsilyl chloride (2.56 g, 17 mmol) were added at
room temperature under argon, and the mixture was stirred for
18 h. The reaction mixture was diluted with Et2O (100 mL), washed
with HCl solution (1 , 50 mL), H2O (50 mL), and brine (50 mL),
dried (MgSO4), and concentrated under reduced pressure. The resi-
due was purified by chromatography on silica gel (cyclohexane/
EtOAc, 9:1) to give alkyne 21 (2.30 g 4.65 mmol, 83%) as a color-
1
poisomers as shown by H NMR (Scheme 10).
Scheme 10. Reductive amination of ketone 39.
Conclusions
Total syntheses of (Ϯ)-allocolchicines 4 and 5 were
achieved by use of the enyne ring-closing metathesis (RCM)
reaction for the construction of the seven-membered ring
and a Diels–Alder/aromatization sequence for the elabora-
tion of the aromatic C-ring. An asymmetric synthesis of
(–)-(7S)-allocolchicine (5) was also accomplished. The same
1
less oil. Rf = 0.6 (cyclohexane/EtOAc, 7:3). H NMR: δ = 6.57 (s,
strategy was applied for the synthesis of allocolchicine 6, 1 H), 6.02 (s, 1 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.82 (s, 3 H), 3.68
(s, 3 H), 3.34 (t, J = 8.4 Hz, 2 H), 2.74 (t, J = 8.4 Hz, 2 H), 0.90
(s, 9 H), 0.19 (s, 3 H), 0.12 (s, 9 H), 0.09 (s, 3 H) ppm. 13C NMR:
δ = 173.8 (C), 152.8 (C), 150.6 (C), 139.9 (C), 136.9 (C), 125.9 (C),
109.7 (CH), 107.5 (C), 89.3 (C), 61.6 (CH3), 60.7 (CH3), 57.9 (CH),
55.8 (CH3), 51.3 (CH3), 36.1 (CH2), 27.7 (CH2), 25.8 (CH3), 18.1
containing an eight-membered B-ring. These new allocol-
chicines will be subjected to tubulin binding assay in order
to gain some indication of their potential as antimitotic
agents; the results will be reported in due course.
(C), –0.4 (CH ), –4.7 (CH ), –4.9 (CH ) ppm. IR (neat): ν =
˜
max
3
3
3
2954, 2856, 2169, 1739 cm–1. HMRS (EI): m/z calcd. for
Experimental Section
C25H42O6Si2 494.2520; found 494.2538.
Aldehyde 14: A solution of 3-(3,4,5-trimethoxyphenyl)propionic
acid (13, 25 g, 111.6 mmol) in MeOH (265 mL) and concentrated
HCl (37%, 1.75 mL) was stirred at room temperature for 24 h. The
reaction mixture was neutralized with saturated sodium hydrogen
carbonate solution, and MeOH was evaporated off under reduced
pressure. The residue was extracted with EtOAc (3ϫ30 mL), and
the combined organic extracts were washed with brine (200 mL),
dried (MgSO4), and concentrated under reduced pressure to fur-
nish the crude methyl ester as a slightly yellow solid (25.8 g,
101.6 mmol, 91%). α,α-Dichloromethyl methyl ether (27.43 mL,
304.8 mmol) was added at room temperature under argon to a solu-
Aldehyde 22: A solution of LiAlH4 (336 mg, 8.84 mmol) in THF
(9 mL) was added dropwise under argon to a solution of aldehyde
21 (2.30 g, 4.65 mmol) in anhydrous THF (74 mL). The reaction
mixture was stirred at –10 °C for 30 min and quenched by success-
ive addition of H2O (336 µL), NaOH solution (15%, 336 µL), and
H2O (1020 µL). The solution was filtered, and the granular inor-
ganic precipitate was rinsed with Et2O (200 mL). The combined
organic layers were concentrated under reduced pressure to give
the crude alcohol (2.17 g), which was used in the next step without
further purification. This crude alcohol (2.17 g, 4.65 mmol) was
tion of the methyl ester (25.8 g, 101.6 mmol) in CH2Cl2 (254 mL). dissolved in dry CH2Cl2 (65 mL). PDC (5.25 g, 13.95 mmol) was
This mixture was cooled to –70 °C, and neat SnCl4 (11.68 mL,
101.6 mmol) was added dropwise. The resulting yellow reaction
mixture was warmed slowly to 0 °C (2 h), and water was added
dropwise. The mixture was diluted with CH2Cl2 (500 mL) and neu-
tralized with aqueous saturated sodium hydrogen carbonate solu-
tion and solid NaHCO3. The phases were separated, and the aque-
ous layer was extracted with CH2Cl2 (2ϫ500 mL). The combined
organic extracts were washed with brine (500 mL), dried (MgSO4),
and concentrated under reduced pressure. The crude product was
added at room temperature under argon, and the mixture was
stirred for 18 h. The reaction mixture was diluted with Et2O
(300 mL), filtered through Florisil®, and eluted with Et2O. The
combined organic phases were concentrated under reduced pres-
sure, and the residue was purified by chromatography on silica gel
(cyclohexane/EtOAc, 4:1) to give aldehyde 22 (1.48 g, 3.18 mmol,
68%) as a colorless oil. Rf = 0.3 (cyclohexane/EtOAc, 9:1). 1H
NMR: δ = 9.83 (t, J = 1.5 Hz, 1 H), 6.53 (s, 1 H), 6.03 (s, 1 H),
3.84 (s, 3 H), 3.83 (s, 3 H), 3.82 (s, 3 H), 3.38–3.32 (m, 2 H), 2.88–
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2.83 (m, 2 H), 0.89 (s, 9 H), 0.19 (s, 3 H), 0.12 (s, 9 H), 0.09 (s, 3
H) ppm. 13C NMR: δ = 202.1 (C), 152.8 (C), 150.6 (C), 139.9 (C),
136.6 (C), 125.7 (C), 109.6 (CH), 107.4 (C), 89.3 (C), 61.6 (CH3),
The reaction mixture was stirred at room temperature for 48 h, di-
luted with Et2O (200 mL), washed with saturated aqueous ammo-
nium chloride solution (50 mL) and brine (50 mL), dried with
60.7 (CH3), 57.8 (CH), 55.7 (CH3), 45.9 (CH2), 25.7 (CH3), 24.8 MgSO4, and concentrated under reduced pressure. The residue was
(CH2), 18.1 (C), –0.4 (CH3), –4.8 (CH3), –5.0 (CH3) ppm. IR purified by chromatography on silica gel (cyclohexane/EtOAc, 9:1 to
(neat): ν
= 2955, 2857, 2712, 2169, 1725 cm–1. HMRS (EI): m/z 7:3) to give alcohol 19 (1.1 g, 3.98 mmol, 95%) as a slightly yellow
˜
max
1
calcd. for C24H40O5Si2 464.2414; found 464.2427.
solid. Rf = 0.3 (cyclohexane/EtOAc, 7:3). M.p. 59–60 °C. H NMR:
δ = 6.53 (s, 1 H), 6.36 (dd, J = 17.7, 10.8 Hz, 1 H), 6.06 (s, 1 H),
5.84–5.81 (m, 1 H), 5.48 (d, J = 17.7 Hz, 1 H), 5.05 (d, J = 10.8 Hz,
1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.81 (s, 3 H), 2.67–2.29 (m, 5 H)
ppm. 13C NMR: δ = 152.6 (C), 151.2 (C), 140.9 (CH), 140.1 (C),
138.0 (C), 137.9 (C), 135.7 (CH), 126.9 (C), 110.0 (CH2), 109.0 (CH),
62.0 (CH3), 61.4 (CH), 60.8 (CH3), 55.9 (CH3), 31.4 (CH2), 29.9
Enyne 20: n-Butyllithium (8 mL, 12.8 mmol, 1.6  solution in hex-
ane) was added dropwise under argon at room temperature to a
solution of methyltriphenylphosphonium bromide (4.585 g,
12.85 mmol) in dry THF (30 mL). The resulting yellow-orange
solution was stirred at room temperature for 45 min and cooled to
15 °C, and a solution of aldehyde 22 (1.48 g, 3.189 mmol) in dry
THF (30 mL) was added dropwise under argon to the resulting
ylide solution, which was maintained at 15 °C. The reaction mix-
ture was stirred at room temperature for 30 min, and water (30 mL)
was added. The biphasic mixture was separated, and the aqueous
phase was extracted with Et2O (3ϫ100 mL). The combined or-
ganic extracts were washed with brine (100 mL), dried (MgSO4),
and concentrated under reduced pressure. The residue was dis-
solved in pentane (300 mL), filtered, and concentrated under re-
duced pressure to give the crude alkene (1.6 g) as a yellow oil,
which was used in the next step without further purification. The
crude alkene (1.6 g) was dissolved in MeOH (22 mL), and K2CO3
(216 mg, 1.56 mmol) was added. The reaction mixture was stirred
at room temperature for 4 h, and MeOH was evaporated under
reduced pressure without warming. The residue was dissolved in
CH2Cl2 (100 mL), and the organic phase was washed with water
(50 mL) and brine (50 mL), dried (MgSO4), and concentrated un-
der reduced pressure. The residue was purified by chromatography
on silica gel (cyclohexane/EtOAc, 95:5) to give enyne 20 (1.08 g,
2.77 mmol, 86%) as a colorless oil. Rf = 0.6 (cyclohexane/EtOAc,
9:1). 1H NMR: δ = 6.59 (s, 1 H), 6.07–6.03 (m, 1 H), 6.03–5.90 (m,
1 H), 5.15–5.08 (m, 1 H), 5.04–4.99 (m, 1 H), 3.89 (s, 3 H), 3.86 (s,
6 H), 3.20–2.97 (m, 2 H), 2.50–2.41 (m, 2 H), 0.91 (s, 9 H), 0.21 (s,
3 H), 0.09 (s, 3 H) ppm. 13C NMR: δ = 152.7 (C), 150.5 (C), 139.7
(C), 138.7 (CH), 137.9 (C), 125.4 (C), 114.3 (CH2), 109.5 (CH),
85.4 (C), 72.4 (CH), 61.5 (CH3), 60.6 (CH3), 57.3 (CH), 55.7 (CH3),
35.4 (CH2), 31.6 (CH2), 25.7 (CH3), 18.1 (C), –4.9 (CH3), –5.1
(CH ) ppm. IR (neat): ν
= 3477, 2929, 2852, 1638, 1597 cm–1.
˜
2
max
HMRS (EI): m/z calcd. for C16H20O4 273.1362; found 273.1353.
Representative Procedure for the Oxidative Rearrangement of
Alcohol 19. Ketone 10: A solution of 19 (364 mg, 1.31 mmol) in dry
CH2Cl2 (9 mL) was added dropwise at room temperature under
argon to a suspension of PCC (560 mg, 2.74 mmol) and silica gel
(560 mg) in dry CH2Cl2 (9 mL). The reaction mixture was stirred
for 1 h and filtered through Florisil® with elution with Et2O to give
ketone 10 (200 mg, 0.73 mmol, 55%) as a yellow solid. Rf = 0.37
1
(cyclohexane/EtOAc, 8:2). M.p. 74–75 °C. H NMR: δ = 7.64 (s, 1
H), 6.86 (dd, J = 17.3, 10.8 Hz, 1 H), 6.58 (s, 1 H), 5.63 (dd, J =
17.3, 1.3 Hz, 1 H), 5.22 (dd, J = 10.8, 1.3 Hz, 1 H), 3.93 (s, 3 H),
3.91 (s, 3 H), 3.87 (s, 3 H), 2.91–2.87 (m, 2 H), 2.83–2.79 (m, 2 H)
ppm. 13C NMR: δ = 200.8 (C), 154.4 (C), 153.9 (C), 140.6 (C),
138.6 (C), 135.6 (C), 135.3 (CH), 131.6 (CH), 121.6 (C), 115.2
(CH2), 107.5 (CH), 61.8 (CH3), 61.0 (CH3), 56.1 (CH3), 44.4 (CH2),
29.8 (CH ) ppm. IR (CHCl ): νmax = 2938, 2838, 1663, 1590 cm–1.
˜
2
3
HMRS (EI): m/z calcd. for C16H18O4 274.1205; found 274.1211.
Tricyclic Ketone 7: A solution of methyl propiolate (90 µL, 1 mmol)
and ketone 10 (30 mg, 0.109 mmol) in toluene (400 µL) was heated
in a sealed tube at 115 °C for 22 h. The volatiles were removed by
evaporation under reduced pressure, and the residue was dissolved
in dry CH2Cl2 (1 mL). DDQ (28 mg, 0.123 mmol) was added, and
the mixture was stirred for 20 h. The solvent was then evaporated
under reduced pressure, and the residue was filtered through a layer
of Al2O3 with EtOAc in petroleum ether (25%) as eluent to give
ketone 7 (33 mg, 0.092 mmol, 85%, 2 steps) as a white solid. Rf =
(CH ) ppm. IR (neat): νmax = 3284, 2930, 2855, 2111 cm–1. HMRS
˜
3
(EI): m/z calcd. for C22H34O4Si 390.2226; found 390.2224.
1
0.5 (EtOAc/petroleum ether, 1:2). M.p. 147–148 °C. H NMR: δ =
Metathesis of Enyne 20. Diene 23: Grubbs catalyst II (17, 30 mg,
2.5 mol-%) was added under nitrogen to a degassed solution of
enyne 20 (552 mg, 1.415 mmol) in dry CH2Cl2 (30 mL). The mix-
ture was heated at reflux for 5 h and allowed to cool to room tem-
perature. The solvent was removed, and the residue was subjected
to flash chromatography on silica gel (EtOAc/petroleum ether,
2.5:97.5) to give the diene 23 (540 mg, 1.385 mmol, 98%) as a col-
8.01 (dd, J = 7.6, 1.4 Hz, 1 H), 7.60 (dd, J = 7.6, 1.4 Hz, 1 H), 7.46
(t, J = 7.6 Hz, 1 H), 6.62 (s, 1 H), 3.91 (s, 3 H), 3.84 (s, 3 H), 3.70
(s, 3 H), 3.34 (s, 3 H), 3.19 (td, J = 13.2, 5.2 Hz, 1 H), 3.03–2.86
(m, 2 H), 2.71 (dt, J = 13.6, 3.6 Hz, 1 H) ppm. 13C NMR: δ =
206.7 (C), 168.2 (C), 153.5 (C), 151.9 (C), 141.4 (C), 141.1 (C),
134.4 (C), 134.1 (C), 132.5 (C), 132.4 (CH), 130.2 (CH), 127.6
(CH), 123.2 (C), 106.9 (CH), 61.1 (CH3), 60.6 (CH3), 56.0 (CH3),
1
orless oil. Rf = 0.2 (cyclohexane/EtOAc, 95:5). H NMR: δ = 6.50
52.1 (CH ), 48.6 (CH ), 30.0 (CH ) ppm. IR (CHCl ): νmax = 2937,
˜
3 2 2 3
(s, 1 H), 6.31 (dd, J = 17.1, 10.8 Hz, 1 H), 5.97 (s, 1 H), 5.69 (t, J 2860, 1730, 1692, 1589 cm–1. MS (CI, NH3): m/z (%) = 325 (40),
= 4.2 Hz, 1 H), 5.39 (d, J = 17.1 Hz, 1 H), 4.99 (d, J = 10.8 Hz, 1 357 [M + 1]+· (100), 374 [M + 18]+· (50). HMRS (EI): m/z calcd.
H), 4.06 (td, J = 13.5, 4.5 Hz, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H),
3.76 (s, 3 H), 2.62 (qd, J = 19.2, 3.3 Hz, 1 H), 2.44–2.22 (m, 2 H),
0.80 (s, 9 H), 0.09 (s, 3 H), –0.17 (s, 3 H) ppm. 13C NMR: δ =
152.2 (C), 150.3 (C), 141.1 (CH), 140.0 (C), 139.2 (C), 138.0 (C),
134.7 (CH), 128.3 (C), 109.4 (CH2), 108.9 (CH), 62.0 (CH3), 61.7
(CH3), 60.8 (CH), 55.9 (CH3), 30.8 (CH2), 30.1 (CH2), 25.7 (CH3),
for C20H20O6 356.1260; found 356.1267.
Diels–Alder Reaction of Diene 10. Cycloadduct 28: A solution of
methyl β-nitroacrylate (27, 56 mg, 0.421 mmol) and ketone 10
(76 mg, 0.28 mmol) in CH2Cl2 (0.5 mL) was stirred at room tem-
perature for 7.5 h. The volatiles were removed by evaporation under
reduced pressure, and the residue was purified by chromatography
on silica gel (EtOAc/petroleum ether, 1:2, then 1:1) to give 28
(111 mg, 0.274 mmol, 97%) as a colorless oil as a mixture of two
diastereoisomers (4:1) separable by chromatography on silica gel.
18.0 (C), –4.8 (CH ), –5.1 (CH ) ppm. IR (neat): νmax = 2928, 2855,
˜
3
3
1637, 1598 cm–1. HMRS (EI): m/z calcd. for C22H34O4Si 390.2226;
found 390.2220.
1
Alcohol 19: Tetrabutylammonium fluoride (30 mL, 30 mmol, 1 
Major Isomer: H NMR: δ = 6.42 (s, 1 H), 5.93 (q, J = 3.0 Hz, 1
solution in THF) was added to neat diene 23 (1.62 g, 4.17 mmol). H), 5.15 (t, J = 9.4 Hz, 1 H), 4.63 (dq, J = 9.4, 3.0 Hz, 1 H), 3.83
4944
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4938–4948

Allocolchicinoids with Seven- and Eight-Membered B-Rings
(s, 3 H), 3.76 (s, 3 H), 3.75 (s, 3 H), 3.69 (s, 3 H), 3.66 (td, J = 9.4,
(s, 3 H), 2.54–2.48 (m, 1 H), 2.44–2.36 (m, 2 H), 2.05 (s, 3 H), 1.84–
7.2 Hz, 1 H), 3.29–3.23 (m, 1 H), 2.82 (dtd, J = 18.4, 6.8, 2.4 Hz, 1.77 (m, 1 H) ppm. 13C NMR: δ = 169.3 (C), 152.9 (C), 151.0 (C),
1 H), 2.78–2.67 (m, 2 H), 2.63–2.54 (m, 2 H) ppm. 13C NMR: δ =
205.6 (C), 172.1 (C), 153.6 (C), 153.3 (C), 142.9 (C), 140.4 (C),
136.2 (C), 124.5 (CH), 117.6 (C), 107.7 (CH), 86.4 (CH), 60.9
149.4 (C), 140.0 (C), 136.3 (C), 133.8 (C), 131.8 (C), 130.9 (C),
127.1 (CH), 125.4 (CH), 123.4 (CH), 123.4 (C), 107.2 (CH), 61.1
(CH3), 60.8 (CH3), 55.9 (CH3), 51.9 (CH3), 49.6 (CH), 39.0 (CH2),
(CH3), 60.5 (CH3), 55.8 (CH3), 52.5 (CH3), 45.2 (CH2), 43.6 (CH), 30.2 (CH ), 23.2 (CH ) ppm. IR (CHCl ): νmax = 2935, 2855, 1729,
˜
2
3
3
39.2 (CH), 29.5 (CH2), 27.1 (CH2) ppm. Minor Isomer: H NMR: 1645, 1596 cm–1. MS (CI, NH3): m/z (%) = 368 [M – OMe]+· (40),
1
δ = 6.36 (s, 1 H), 6.06 (q, J = 3.2 Hz, 1 H), 5.68 (dd, J = 5.2, 400 [M + 1]+· (100). HMRS (EI): m/z calcd. for C22H25NO6
2.8 Hz, 1 H), 4.54–4.50 (m, 1 H), 3.97 (s, 3 H), 3.84 (s, 3 H), 3.83
(s, 3 H), 3.82 (s, 3 H), 3.59–3.50 (m, 1 H), 3.42–3.40 (m, 1 H), 2.90–
2.71 (m, 3 H), 2.60–2.47 (m, 2 H) ppm. 13C NMR: δ = 207.8 (C),
170.9 (C), 153.2 (C), 152.4 (C), 140.8 (C), 140.7 (C), 137.4 (C),
125.6 (CH), 118.0 (C), 108.5 (CH), 83.4 (CH), 61.1 (CH3), 60.7
(CH3), 55.8 (CH3), 52.9 (CH3), 44.6 (CH2), 41.1 (CH), 36.1 (CH),
399.1682; found 399.1689.
(؎)-Allocolchicine 5: This compound was prepared from 8 accord-
ing to the same procedure as for rac-4, to give rac-5 (57%) as a
white solid as a 2:1 mixture of atropoisomers in CDCl3 solution.
1
M.p. 181–183 °C. Major Atropoisomer: H NMR: δ = 8.17 (d, J =
2.0 Hz, 1 H), 8.00 (dd, J = 8.0, 2.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz,
1 H), 6.58 (s, 1 H), 5.82 (d, J = 7.6 Hz, 1 H, NH), 4.90–4.84 (m, 1
H), 3.95 (s, 3 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 3.56 (s, 3 H), 2.56–
2.46 (m, 2 H), 2.30–2.23 (m, 1 H), 2.07 (s, 3 H), 1.86–1.80 (m, 1
H) ppm. 13C NMR: δ = 169.2 (C), 167.2 (C), 153.1 (C), 151.3 (C),
144.2 (C), 141.4 (C), 134.7 (C), 134.5 (C), 131.5 (CH), 128.6 (C),
128.4 (CH), 124.1 (C), 122.4 (CH), 107.6 (CH), 61.3 (CH3), 61.2
(CH3), 56.1 (CH3), 52.1 (CH3), 49.5 (CH), 39.5 (CH2), 30.3 (CH2),
29.3 (CH ), 23.1 (CH ) ppm. IR (CHCl ): νmax = 2953, 2856, 1743,
˜
2
2
3
1708, 1594, 1556 cm–1. MS (CI, NH3): m/z (%) = 423 [M +
18]+· (100). HMRS (EI): m/z calcd. for C20H23O6N 405.1423; found
405.1431.
Methyl Ester 8: DBU (80 µL, 0.5 mmol) was added to a solution
of 28 (104 mg, 0.256 mmol) in THF (2 mL). The reaction mixture
was stirred at room temperature under N2 for 4 h. The volatiles
were removed in vacuo, and the residue was filtered through a thin
plug of silica gel (EtOAc/petroleum ether, 1:3) to give, after solvent
evaporation, 76 mg of elimination product. This was dissolved in
CH2Cl2 (2 mL), and DDQ (90 mg, 0.40 mmol) was added. The
solution was stirred at room temperature for 2 weeks. The solvent
was evaporated, and the crude mixture was filtered through a layer
of Al2O3 (25% EtOAc in petroleum ether) to give, after solvent
removal, ester 8 (45 mg, 0.126 mmol, 50%) as a colorless oil. Rf =
0.3 (EtOAc/petroleum ether, 1:2). 1H NMR: δ = 8.24 (d, J = 1.6 Hz,
1 H), 8.02 (dd, J = 8.0, 1.6 Hz, 1 H), 7.59 (d, J = 8.0 Hz, 1 H),
6.61 (s, 1 H), 3.94 (s, 1.5 H), 3.96 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3
H), 3.59 (s, 3 H), 3.10–2.80 (m, 3 H), 2.70 (brd, J = 9.0 Hz, 1 H)
ppm. 13C NMR: δ = 206.4 (C), 166.5 (C), 153.5 (C), 152.2 (C),
143.0 (C), 141.6 (C), 135.5 (C), 134.2 (C), 132.6 (CH), 131.9 (C),
128.2 (CH), 127.6 (CH), 123.4 (C), 107.0 (CH), 61.24 (CH3), 61.10
(CH3), 56.0 (CH3), 52.4 (CH3), 47.9 (CH2), 29.9 (CH2) ppm. IR
23.3 (CH ) ppm. IR (CHCl ): ν = 2934, 2855, 1723, 1687,
˜
max
3
3
1596 cm–1. MS (CI, NH3): m/z (%) = 341 (10), 400 [M + 1]+· (100).
HMRS (EI): m/z calcd. for C22H25NO6 399.1682; found 399.1683.
Alcohol (+)-(7R)-30: The ketone 8 (42 mg, 0.117 mmol) was dis-
solved in a solution of -(+)-TarB-NO2 (0.5 , 0.325 mmol,
0.65 mL) in THF under argon. The solution was stirred at room
temperature for 15 min, and NaBH4 (14.5 mg, 0.38 mmol) was then
added to the ketone/-(+)-TarB-NO2 solution in a single portion,
causing rapid gas evolution. The reaction mixture was stirred for
60 min and then slowly quenched with HCl (3 ), until gas evol-
ution was no longer observed. The mixture was brought to pH =
12 with NaOH (3 ) and extracted with diethyl ether (3ϫ5 mL).
The combined ether extracts were washed with H2O (2ϫ5 mL) and
dried with MgSO4. The volatiles were removed in vacuo, and the
residue was purified by chromatography on silica gel (EtOAc/petro-
leum ether, 1:4) to give (+)-30 (36 mg, 0.100, 86%) as a colorless
oil. HPLC (column: Chiralcel OD-H; n-heptane/propan-2-ol):
90% ee. [α]2D5 = +20.0 [c = 0.46, CHCl3, 90% ee (HPLC)]. Rf = 0.15
(EtOAc/cyclohexane, 3:7). 1H NMR: δ = 8.11 (d, J = 1.8 Hz, 1 H),
8.03 (dd, J = 8.1, 1.8 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 6.59 (s,
1 H), 4.66 (dd, J = 9.3, 7.8 Hz, 1 H), 3.92 (s, 3 H), 3.912 (s, 3 H),
3.909 (s, 3 H), 3.66 (s, 3 H), 2.65–2.53 (m, 1 H), 2.47–2.41 (m, 1
H), 2.32–2.21 (m, 1 H), 2.10–2.07 (br. s, 1 H, OH), 1.98–1.88 (m,
1 H) ppm. 13C NMR: δ = 167.3 (C), 153.1 (C), 150.9 (C), 146.8
(C), 141.2 (C), 135.5 (C), 133.3 (C), 131.1 (CH), 128.5 (C), 128.3
(CH), 123.7 (C), 122.8 (CH), 107.6 (C), 70.0 (CH), 61.0 (2 CH3),
56.0 (CH3), 52.0 (CH3), 41.4 (CH2), 30.3 (CH2) ppm. IR (neat):
(CHCl ): νmax = 2944, 2860, 1728, 1691, 1595 cm–1. MS (CI, NH3):
˜
3
m/z (%) = 357 [M + 1]+· (70), 374 [M + 18]+· (100). HMRS (EI):
m/z calcd. for C20H20O6 356.1260; found 356.1255.
Representative Procedure for the Reductive Amination of Ketone 7.
(؎)-Allocolchicine 4: A solution of ketone 7 (17 mg, 0.047 mmol),
NH4OAc (35 mg, 0.45 mmol), and NaBH3CN (3 mg, 0.047 mmol)
in MeOH (300 µL) was heated in a sealed tube at 60 °C for 18 h.
After the mixture had cooled to room temperature, concentrated
HCl (0.35 mL) was added, and the mixture was vigorously stirred
for 15 min. After that, water (0.6 mL) was added, and the mixture
was extracted twice with Et2O. The ethereal layers were combined
and set aside, the aqueous layer was treated with NaOH (10%) and
extracted once with CH2Cl2 and once with Et2O. The organic layers
were combined, dried with MgSO4, and concentrated under re-
duced pressure to give the crude amine (12 mg), which was dis-
solved in CH2Cl2 (300 µL) and Ac2O (25 µL). Pyridine (25 µL) was
added dropwise to this solution, with stirring. After 45 min at room
temperature, the mixture was quenched with water (1 mL). The
aqueous phase was extracted twice with CH2Cl2. The combined
organic layers were washed with HCl (10%), dried with MgSO4,
and concentrated under reduced pressure to give allocolchicine rac-
4 (13 mg, 0.032 mmol, 69% in two steps) as a white solid as a 2:1
mixture of atropoisomers in CDCl3 solution. M.p. 206–209 °C.
Major Rotamer: 1H NMR: δ = 7.79 (dd, J = 7.2, 1.2 Hz, 1 H),
7.46–7.38 (m, 2 H), 6.59 (s, 1 H), 5.80 (d, J = 7.2 Hz, 1 H, NH),
4.73–4.68 (m, 1 H), 3.91 (s, 3 H), 3.89 (s, 3 H), 3.68 (s, 3 H), 3.38
ν
= 3488, 2937, 2858, 1719, 1598 cm–1. HMRS (EI): m/z calcd.
˜
max
for C20H22O6 358.1416; found 358.1417.
Azide (–)-(7S)-31: Methanesulfonyl chloride (0.504 mL, 6.51 mmol)
was added dropwise at 0 °C under argon to a solution of alcohol
30 (203 mg, 0.563 mmol) in dry pyridine (3.3 mL). The reaction
mixture was stirred at 0 °C for 1 h and at room temperature for 3 h
and diluted with CH2Cl2 (30 mL). The organic phase was washed
with aqueous saturated CuSO4 solution (2ϫ20 mL) and brine
(20 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was diluted with dry DMF (5.6 mL), and
NaN3 (170 mg, 2.55 mmol) was added. The reaction mixture was
warmed at 80 °C for 4 h, allowed to cool to room temperature,
stirred at room temp. for 15 h, and diluted with CH2Cl2 (40 mL)
and water (10 mL). The mixture was separated, and the aqueous
Eur. J. Org. Chem. 2008, 4938–4948
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4945

F.-D. Boyer, I. Hanna
FULL PAPER
phase was extracted with CH2Cl2 (3ϫ20 mL). The combined or-
ganic layers were washed with water (2ϫ10 mL) and brine
(10 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
Aldehyde 33: A solution of LiAlH4 (95 mg, 2.50 mmol) in THF
(2.5 mL) was added dropwise under argon to a solution of ester
32 (610 mg, 1.44 mmol) in anhydrous THF (20 mL). The reaction
mixture was stirred at –10 °C for 30 min and quenched by success-
(EtOAc/petroleum ether, 1:4) to give azide 31 (155 mg, 0.404 mmol, ive addition of H2O (95 µL), NaOH solution (15%, 95 µL), and
71%) as a colorless oil. [α]2D5 = –47.5 (c =1.03, CHCl3). Rf = 0.55
(EtOAc/cyclohexane, 3:7). 1H NMR: δ = 8.14 (d, J = 1.5 Hz, 1 H),
8.04 (dd, J = 8.4, 1.5 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 6.59 (s,
H2O (285 µL). The solution was filtered, and the granular inor-
ganic precipitate was rinsed with Et2O (50 mL). The combined or-
ganic layers were concentrated under reduced pressure to give the
1 H), 4.48 (dd, J = 11.1, 6.6 Hz, 1 H), 3.931 (s, 3 H), 3.927 (s, 3 crude alcohol (590 mg), which was used in the next step without
H), 3.918 (s, 3 H), 3.71 (s, 3 H), 2.62–2.44 (m, 2 H), 2.30–2.22 (m, further purification. This crude alcohol (590 mg) was dissolved in
1 H), 2.06–1.97 (m, 1 H) ppm. 13C NMR: δ = 167.0 (C), 162.5 (C), dry CH2Cl2 (17 mL). PDC (1.652 g, 4.38 mmol) was added at room
153.4 (C), 151.0 (C), 142.1 (C), 141.4 (C), 134.6 (C), 134.2 (C),
131.4 (CH), 129.0 (C), 128.5 (CH), 123.8 (CH), 123.5 (C), 107.7
(CH), 61.0 (2ϫCH3 + CH), 56.0 (CH3), 52.0 (CH3), 38.8 (CH2),
temperature under argon, and the mixture was stirred for 24 h. The
reaction mixture was diluted with Et2O (100 mL) and filtered
through Florisil®, and the Florisil® was rinsed with Et2O. The fil-
trate was concentrated under reduced pressure to give aldehyde 33
30.2 (CH ) ppm. IR (neat): ν
= 2929, 2856, 2102, 1721,
˜
2
max
1598 cm–1. HMRS (EI): m/z calcd. for C20H21N3O5 383.1481; (450 mg, 1.15 mmol, 79%) as a colorless oil. Rf = 0.23 (EtOAc/
1
found 383.1483.
cyclohexane, 1:4). H NMR: δ = 9.83 (t, J = 0.9 Hz, 1 H), 6.53 (s,
1 H), 6.05 (d, J = 2.4 Hz, 1 H), 3.86 (s, 3 H), 3.83 (s, 6 H), 3.46–
3.36 (m, 1 H), 3.30–3.20 (m, 1 H), 2.87–3.81 (m, 2 H), 2.50 (d, J
= 2.4 Hz, 1 H), 0.88 (s, 9 H), 0.17 (s, 3 H), 0.07 (s, 3 H) ppm. 13C
NMR: δ = 202.0 (C), 153.0 (C), 150.5 (C), 140.0 (C), 136.5 (C),
125.6 (C), 109.7 (CH), 85.3 (C), 72.8 (CH), 61.6 (CH3), 60.7 (CH3),
57.3 (CH), 55.8 (CH3), 45.8 (CH2), 25.7 (3 CH3), 24.9 (CH2), 18.1
(–)-(7S)-Allocolchicine 5: 5% Pd/CaCO3/3.5% Pb (10 mg) as cata-
lyst was added to a solution of azide 31 (50 mg, 0.130 mmol) in
absolute EtOH (3 mL). The flask was flushed with H2, and a posi-
tive pressure of H2 was maintained. The mixture was stirred at
room temperature under 1 atm of H2 for 20 h. The mixture was
then filtered through a layer of Celite, the Celite was washed with
acetone, and the solvents were removed under reduced pressure.
The residue was dissolved in dry CH2Cl2 (0.6 mL), and then pyr-
idine (0.3 mL) was added to the solution. Ac2O (0.3 mL) was added
dropwise to the stirred solution. After 1 h of stirring at room tem-
perature, the mixture was concentrated under reduced pressure.
The residue was purified by chromatography on silica gel (EtOAc/
cyclohexane, 1:9 to 7:3) to give (7S)-5 (30.5 mg, 0.076 mmol, 58%)
as a white solid. Recrystallization from a mixture of hexane and
EtOAc. HPLC (column: Chiralcel OD-H; n-heptane/propan-2-ol)
93.6% ee. M.p. 177 °C. [α]2D0 –21.0 [c = 0.45, CHCl3, 94% ee
(HPLC)]. Rf = 0.5 (EtOAc/cyclohexane, 3:7).
(C), –4.8 (CH ), –5.1 (CH ) ppm. IR (neat): ν = 3281, 2930,
˜
max
3
3
2857, 2717, 2112, 1724, 1597 cm–1. HMRS (EI): m/z calcd. for
C21H32O5Si 392.2019; found 392.2000.
Aldehyde 34: Potassium tert-butoxide (1.025 g, 9.13 mmol) was
added under argon at 10 °C to a solution of (methoxymethyl)tri-
phenylphosphonium chloride (3.47 g, 10.09 mmol) in dry THF
(40 mL). The resulting orange-red solution was stirred at room
temperature for 45 min and then cooled to 15 °C; a solution of
aldehyde 33 (973 mg, 2.48 mmol) in dry THF (11 mL) solution was
added dropwise under argon to the resulting ylide solution, which
was maintained at 15 °C. The reaction mixture was stirred at room
temperature for 1 h, and water (20 mL) was added. The biphasic
mixture was separated, and the aqueous phase was extracted with
Et2O (3ϫ25 mL). The combined organic extracts were washed
with brine (30 mL), dried (MgSO4), and concentrated under re-
duced pressure. The residue was purified by chromatography on
silica gel (cyclohexane/EtOAc, 9:1) to give the alkene (861 mg,
2.05 mmol, 82%) as a colorless oil. This alkene was dissolved in
Et2O (79 mL). An aqueous solution of HClO4 (7%, 27 mL) was
added, and the biphasic mixture was stirred at room temperature
for 36 h. The biphasic mixture was separated, and the aqueous
phase was extracted with Et2O (3ϫ75 mL). The combined organic
extracts were washed with saturated aqueous sodium hydrogencar-
bonate solution (50 mL) and brine (50 mL), dried (MgSO4), and
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (cyclohexane/EtOAc, 4:1) to give al-
dehyde 34 (470 mg, 1.15 mmol, 47%) as a colorless oil. Rf = 0.26
Propargyl Silyl Ether 32: Ethynylmagnesium bromide (16 mL,
8.0 mmol, 0.5  solution in THF) was added dropwise at 0 °C under
argon to a solution of aldehyde 14 (2.00 g, 7.08 mmol) in dry THF
(10 mL). The reaction mixture was stirred at 0 °C for 3 h, saturated
aqueous ammonium chloride solution (10 mL) was added, and the
mixture was diluted with Et2O (50 mL). The biphasic mixture was
allowed to warm to room temperature and separated, and the aque-
ous phase was extracted with Et2O (2ϫ50 mL). The combined or-
ganic extracts were washed with brine (50 mL), dried (MgSO4), and
concentrated under reduced pressure to give the crude propargyl
alcohol. This crude propargyl alcohol was immediately dissolved in
dry DMF (6.4 mL). Imidazole (1.44 g, 21.17 mmol) and tert-butyldi-
methylsilyl chloride (3.20 g, 21.27 mmol) were added at room tem-
perature under argon, and the mixture was stirred for 18 h. The reac-
tion mixture was diluted with Et2O (100 mL), washed with HCl solu-
tion (1.2 , 50 mL), H2O (50 mL), and brine (50 mL), dried
(MgSO4), and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (cyclohexane/EtOAc, 9:1)
to give propargyl silyl ether 32 (2.83 g, 6.69 mmol, 81%) as a color-
1
(cyclohexane/EtOAc, 4:1). H NMR: δ = 9.81 (t, J = 1.5 Hz, 1 H),
6.57 (s, 1 H), 6.04 (d, J = 2.1 Hz, 1 H), 3.87 (s, 3 H), 3.85 (s, 3 H),
3.84 (s, 3 H), 3.11–2.90 (m, 2 H), 2.53 (dt, J = 7.2, 1.5 Hz, 1 H),
2.47 (d, J = 2.1 Hz, 1 H), 2.07–1.96 (m, 1 H), 0.88 (s, 9 H), 0.18
(s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR: δ = 202.3 (C), 152.9 (C),
150.6 (C), 139.9 (C), 137.4 (C), 125.5 (C), 109.5 (CH), 85.6 (C),
72.4 (CH), 61.6 (CH3), 60.7 (CH3), 57.3 (CH), 55.9 (CH3), 43.9
(CH2), 31.7 (CH2), 25.7 (3 CH3), 23.9 (CH2), 18.1 (C), –4.9 (CH3),
1
less oil. Rf = 0.32 (EtOAc/cyclohexane, 3:7). H NMR: δ = 6.56 (s,
1 H), 6.03 (d, J = 2.4 Hz, 1 H), 3.86 (s, 3 H), 3.83 (s, 6 H), 3.69 (s,
3 H), 3.46–3.36 (m, 2 H), 3.27–3.17 (m, 2 H), 2.48 (d, J = 2.4 Hz, 1
H), 0.88 (s, 9 H), 0.17 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR: δ =
173.8 (C), 153.0 (C), 150.6 (C), 140.1 (C), 136.7 (C), 125.7 (C), 109.8
(CH), 85.4 (C), 72.2 (CH), 61.6 (CH3), 60.7 (CH3), 57.4 (CH), 55.9
(CH3), 51.4 (CH3), 36.1 (CH2), 27.8 (CH2), 25.8 (3 CH3), 18.1 (C),
–5.1 (CH ) ppm. IR (neat): ν
= 3299, 2934, 2857, 2720, 2109,
˜
3
max
1725, 1597 cm–1. HMRS (EI): m/z calcd. for C22H34O5Si 406.2176;
found 406.2178.
–4.9 (CH ), –5.0 (CH ) ppm. IR (neat): ν = 3276, 2950, 2933,
˜
max
3
3
2856, 2109, 1736, 1598 cm–1. HMRS (EI): m/z calcd. for C22H34O6Si
Enyne 35: n-Butyllithium (2.9 mL, 4.64 mmol, 1.6  solution in
422.2125; found 422.2131.
hexane) was added dropwise under argon at room temperature to
4946
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4938–4948

Allocolchicinoids with Seven- and Eight-Membered B-Rings
solution of methyltriphenylphosphonium bromide (1.64 g,
a
H), 2.65 (t, J = 6.3 Hz, 2 H), 2.46 (t, J = 6.3 Hz, 1 H), 2.10–2.03
(m, 2 H) ppm. 13C NMR: δ = 203.2 (C), 154.6 (C), 152.9 (C), 140.2
(C), 137.7 (C), 137.3 (C), 135.2 (CH), 132.5 (CH), 123.2 (C), 115.5
(CH2), 108.2 (CH), 61.3 (CH3), 60.8 (CH3), 55.9 (CH3), 38.0 (CH2),
4.60 mmol) in dry THF (12 mL). The resulting yellow-orange solu-
tion was stirred at room temperature for 45 min and cooled to
15 °C; a solution of aldehyde 34 (470 mg, 1.15 mmol) in dry THF
(12 mL) was added dropwise under argon to the resulting ylide
solution, which was maintained at 15 °C. The reaction mixture was
stirred at room temperature for 30 min, and water (20 mL) was
added. The biphasic mixture was separated, and the aqueous phase
was extracted with Et2O (3ϫ25 mL). The combined organic ex-
tracts were washed with brine (30 mL), dried (MgSO4), and con-
centrated under reduced pressure. The residue was purified by
chromatography on silica gel (cyclohexane/EtOAc, 95:5 to 9:1) to
give enyne 35 (286 mg, 0.70 mmol, 61%) as a colorless oil. Rf =
0.45 (EtOAc/cyclohexane, 1:9). 1H NMR: δ = 6.56 (s, 1 H), 6.04
(d, J = 2.4 Hz, 1 H), 5.95–5.82 (m, 1 H), 5.05 (qd, J = 17.1, 1.5 Hz,
1 H), 4.97 (br. d, J = 9.9 Hz, 1 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 3.85
(s, 3 H), 3.08–2.85 (m, 2 H), 2.47 (d, J = 2.4 Hz, 1 H), 2.21 (q, J
= 6.9 Hz, 2 H), 1.82–1.71 (m, 2 H), 0.90 (s, 9 H), 0.20 (s, 3 H), 0.07
(s, 3 H) ppm. 13C NMR: δ = 152.8 (C), 150.6 (C), 139.7 (C), 138.8
(CH), 138.6 (C), 125.5 (C), 114.4 (CH2), 109.5 (CH), 85.6 (C), 72.3
(CH), 61.6 (CH3), 60.7 (CH3), 57.4 (CH), 55.8 (CH3), 34.2 (CH2),
30.9 (CH2), 25.8 (3 CH3), 18.1 (C), –4.8 (CH3), –5.0 (CH3) ppm.
32.8 (CH ), 32.5 (CH ) ppm. IR (film): ν = 2933, 2854, 1654,
˜
max
2
2
1620, 1591 cm–1. HMRS (EI): m/z calcd. for C17H20O4 288.1362;
found 288.1358.
Tricyclic Ketone 9: This compound was prepared from 37 according
to the same procedure as for 8. Diels–Alder Reaction of Diene 37.
Cycloadduct 38: This compound was obtained from 37 (92%) as a
white solid. M.p. 67–69 °C. 13C NMR: δ = 204.3 (br. s, 1 C), 171.8
(C), 153.5 (C), 152.4 (C), 143.7 (C), 141.2 (br. s, 1 C), 136.8 (br. s,
1 C), 124.0 (br. s, 1 C), 121.0 (CH), 109.0 (CH), 86.0 (br. s, CH),
60.6 (CH3), 59.9 (br. s, CH3), 55.7 (CH3), 52.4 (CH3), 44.0 (br. s,
CH2), 42.3 (br. s, CH), 40.2 (br. s, CH), 34.8 (br. s, CH2), 29.4 (br.
s, CH ), 26.8 (CH ) ppm. IR (neat): νmax = 2925, 2853, 1736, 1691,
˜
2
2
1652, 1596, 1551 cm–1. Ketone 9: DBU (160 µL, 1 mmol) was added
to a solution of 38 (203 mg, 0.48 mmol) in THF (6.28 mL). The
reaction mixture was stirred at room temperature under argon for
4.5 h. The volatiles were removed in vacuo, and the residue was
purified by chromatography on silica gel (EtOAc/cyclohexane, 1:4
to 3:7) to give ketone 9 (75 mg, 0.20 mmol, 41%) as a colorless oil
and alcohol 39 (88 mg, 0.23 mmol, 49%) as a white solid. 9: Rf =
IR (neat): ν
= 3306, 2954, 2928, 2857, 1641, 1597 cm–1. HMRS
˜
max
(EI): m/z calcd. for C23H36O4Si 404.2383; found 404.2376.
1
0.33 (EtOAc/cyclohexane, 3:7). H NMR: δ = 8.17 (d, J = 8.7 Hz,
1 H), 8.04 (dd, J = 8.7, 1.8 Hz, 1 H), 7.97 (d, J = 1.8 Hz, 1 H),
6.55 (s, 1 H), 3.94 (s, 3 H), 3.934 (s, 3 H), 3.932 (s, 3 H), 3.61 (s, 3
H), 2.66–2.40 (m, 4 H), 2.12–2.00 (m, 1 H), 1.82–1.75 (m, 1 H)
ppm. 13C NMR: δ = 202.2 (C), 166.4 (C), 154.1 (C), 151.3 (C),
141.7 (C), 141.1 (C), 136.5 (C), 135.1 (CH), 134.8 (C), 132.5 (C),
129.0 (CH), 127.8 (CH), 126.7 (C), 107.1 (CH), 61.1 (2ϫCH3),
56.1 (CH3), 52.3 (CH3), 40.1 (CH2), 31.0 (CH2), 27.8 (CH2) ppm.
RCM of 35. Alcohol 36: Grubbs catalyst II (17, 87 mg, 10 mol-%)
was added under argon to a degassed solution of enyne 35 (249 mg,
0.61 mmol) in dry CH2Cl2 (250 mL). The mixture was heated at
reflux for 4 h. The solvent was removed, and the residue was sub-
jected to flash chromatography on silica gel (EtOAc/cyclohexane,
5:95) to give the protected diene (236 mg, 0.58 mmol, 95%) as a
colorless oil. Rf = 0.54 (EtOAc/cyclohexane, 1:9). 1H NMR: δ =
6.43 (s, 1 H), 6.32 (dd, J = 17.4, 10.8 Hz, 1 H), 5.92 (s, 1 H), 5.83
(t, J = 7.5 Hz, 1 H), 5.35 (dd, J = 17.4, 1.2 Hz, 1 H), 5.02 (d, J =
10.8 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.75 (s, 3 H), 3.56–3.46
(m, 1 H), 2.50 (dd, J = 12.9, 5.1 Hz, 1 H), 1.84–1.71 (m, 2 H),
1.64–1.48 (m, 2 H), 0.75 (s, 9 H), 0.06 (s, 3 H), –0.05 (s, 3 H) ppm.
13C NMR: δ = 152.9 (C), 151.2 (C), 143.1 (C), 141.1 (CH), 139.7
(C), 139.4 (C), 128.9 (CH), 127.5 (C), 111.6 (CH2), 109.0 (CH),
65.5 (CH), 61.9 (CH3), 60.9 (CH3), 55.9 (CH3), 30.5 (CH2), 29.8
(CH2), 25.7 (3 CH3), 23.1 (CH2), 18.1 (C), –5.0 (CH3), –5.3 (CH3)
IR (neat): ν
= 2927, 2854, 1724, 1670, 1643, 1595 cm–1. HMRS
˜
max
(EI): m/z calcd. for C21H22O6 370.1416; found 370.1402. 39: Rf =
0.15 (EtOAc/cyclohexane, 3:7). M.p. 118–119 °C. 1H NMR: δ =
8.06 (d, J = 8.1, 1.5 Hz, 1 H), 7.91 (d, J = 1.5 Hz, 1 H), 7.80 (d, J
= 8.1 Hz, 1 H), 6.55 (s, 1 H), 4.48 (d, J = 8.2 Hz, 1 H), 3.90 (s, 3
H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.64 (s, 3 H), 2.53 (dd, J = 13.4,
8.9 Hz, 1 H), 2.18–2.00 (m, 3 H), 1.85–1.60 (m, 2 H) ppm. 13C
NMR: δ = 167.1 (C), 153.5 (C), 150.5 (C), 150.4 (C), 140.3 (C),
138.9 (C), 133.6 (C), 131.6 (CH), 129.0 (CH), 127.9 (C), 124.7
(CH), 124.4 (C), 107.8 (C), 70.6 (CH), 61.0 (CH3), 60.9 (CH3), 55.9
(CH3), 52.0 (CH3), 38.8 (CH2), 31.9 (CH2), 27.6 (CH2) ppm. IR
ppm. IR (film): νmax = 2925, 2854, 1632, 1595 cm–1. Tetra-n-butyl-
˜
ammonium fluoride (4.8 mL, 1  solution in THF) was added to
a solution of the preceding diene (236 mg, 0.58 mmol) in THF
(0.5 mL). The reaction mixture was stirred for 72 h at room tem-
perature and concentrated under reduced pressure. The crude prod-
uct was purified by chromatography on silica gel (cyclohexane/
EtOAc, 4:1 then 7:3) to give alcohol 36 (148 mg, 0.51 mmol) as a
colorless oil (84% from 35). Rf = 0.23 (cyclohexane/EtOAc, 8:2).
1H NMR: δ = 6.46 (s, 1 H), 6.38 (dd, J = 17.4, 10.8 Hz, 1 H), 6.02
(s, 1 H), 5.80 (t, J = 7.5 Hz, 1 H), 5.46 (dd, J = 17.4, 1.2 Hz, 1 H),
5.08 (d, J = 10.8 Hz, 1 H), 3.834 (s, 3 H), 3.831 (s, 3 H), 3.82 (s, 3
H), 3.24 (dt, 1 H), 2.65 (td, J = 12.9, 5.1 Hz, 1 H), 1.93–1.86 (m,
1 H), 1.76–1.57 (m, 3 H) ppm. 13C NMR: δ = 152.9 (C), 151.5 (C),
142.6 (C), 140.0 (CH), 139.9 (C), 137.8 (C), 130.1 (CH), 126.7 (C),
112.1 (CH2), 109.4 (CH), 64.9 (CH), 61.8 (CH3), 60.7 (CH3), 55.8
(neat): ν
= 3479, 2934, 2858, 1720, 1596 cm–1. HMRS (EI): m/z
˜
max
calcd. for C21H24O6 372.1573; found 372.1548.
(؎)-Allocolchicine 6: This compound was prepared from 9 accord-
ing to the same procedure as for compound rac-4 (44%), as a white
solid as a 2:1 mixture of atropoisomers in CDCl3 solution. M.p.
1
156–158 °C. Major Atropoisomer: H NMR: δ = 7.96 (dd, J = 8.0,
1.6 Hz, 1 H), 7.90 (d, J = 1.6 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H),
6.64 (s, 1 H), 5.53 (t, J = 7.6 Hz, 1 H), 5.04 (d, J = 7.6 Hz, 1 H,
NH), 3.94 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.61 (s, 3 H), 2.65
(dd, J = 13.2, 7.6 Hz, 1 H), 2.18–1.45 (m, 5 H), 1.59 (s, 3 H) ppm.
13C NMR: δ = 168.3 (C), 166.7 (C), 154.0 (C), 150.3 (C), 146.4
(C), 140.7 (C), 137.4 (C), 133.5 (C), 133.3 (CH), 129.8 (CH), 128.8
(CH), 126.1 (C), 124.0 (C), 108.2 (CH), 61.0 (CH3), 60.5 (CH3),
56.1 (CH3), 53.1 (CH), 52.0 (CH3), 32.6 (CH2), 32.1 (CH2), 25.4
(CH ), 30.8 (CH ), 29.4 (CH ), 23.8 (CH ) ppm. IR (neat): ν =
˜
max
3
2
2
2
3492, 3086, 2935, 2849, 1631, 1595 cm–1. HMRS (EI): m/z calcd.
(CH ), 23.2 (CH ) ppm. IR (CHCl ): ν = 3437, 2995, 2935,
˜
max
2
3
3
2855, 1724, 1685, 1593 cm–1. HMRS (EI): m/z calcd. for
for C17H22O4 288.1518; found 288.1507.
C23H27NO6 413.1838; found 413.1831.
Ketone 37: This compound was prepared from 36 by the same pro-
cedure as for 10 (76%), as a yellow oil. Rf = 0.64 (cyclohexane/
Supporting Information (see footnote on the first page of this arti-
EtOAc, 7:3). 1H NMR: δ = 7.54 (s, 1 H), 6.84 (dd, J = 17.3, cle): Experimental procedures, characterization data for com-
10.8 Hz, 1 H), 6.56 (s, 1 H), 5.58 (dt, J = 17.3, 1.2 Hz, 1 H), 5.22
(dt, J = 17.3, 1.2 Hz, 1 H), 3.93 (s, 3 H), 3.91 (s, 3 H), 3.89 (s, 3
pounds 12a, 12b, 12c, 12e, 15, 16, and 18 and X-ray crystallo-
graphic data for compound 39.
Eur. J. Org. Chem. 2008, 4938–4948
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4947

F.-D. Boyer, I. Hanna
FULL PAPER
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Acknowledgments
We gratefully thank Dr. X. Le Goff (DCPH, Ecole Polytechnique)
for the X-ray structure determination of compound 39 and Mr. J.-
P. Pulicani (DCSO, Ecole Polytechnique) for the determination of
the optical purities of compounds 30 and (7S)-5 by HPLC.
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The X-ray structure of compound 39 and a short crystallo-
graphic summary can be found in the Supporting Information.
CCDC-689496 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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[14] The preparation of dienyne 12e is described in the Supporting
Information.
Received: June 19, 2008
Published Online: September 5, 2008
4948
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Eur. J. Org. Chem. 2008, 4938–4948