Synthesis of podophyllotoxin analogues: δ-lactone-containing picropodophyllin, podophyllotoxin and 4′-demethyl-epipodophyllotoxin derivatives

Article abstract of DOI:10.1016/j.tet.2004.01.017

Non-epimerizable cis and trans δ-lactone analogues of podophyllotoxin have been prepared. Thus the synthesis of the cis isomer 4 has been achieved in 8 steps and 4% overall yield from podophyllotoxin 1 via the reduction of the γ lactone ring into the tran

Full text of DOI:10.1016/j.tet.2004.01.017

Tetrahedron 60 (2004) 2657–2671
Synthesis of podophyllotoxin analogues: d-lactone-containing
picropodophyllin, podophyllotoxin and 40-demethyl-
epipodophyllotoxin derivatives
*
Philippe Meresse, Claude Monneret and Emmanuel Bertounesque
UMR 176 CNRS-Institut Curie, 26 rue d’Ulm, 75248 Paris Cedex 05, France
Received 25 July 2003; revised 18 December 2003; accepted 5 January 2004
Abstract—Non-epimerizable cis and trans d-lactone analogues of podophyllotoxin have been prepared. Thus the synthesis of the cis isomer
4 has been achieved in 8 steps and 4% overall yield from podophyllotoxin 1 via the reduction of the g lactone ring into the trans diol, selective
protection of the 4-OH and 11-OH as a benzylidene acetal, and Wittig elongation at C-13 with inversion of configuration at C-2. Same
elongation at C-13 but via the formation of a mesylate and introduction of a cyano group, led to the trans d-lactone 5 (7 steps from 1 and 6%
overall yied) with a small amount of its C-4 epimer 6. The synthesis of non-epimerizable d-lactone analogues of 40-demethyl-
epipodophyllotoxi0n 7 and of 4-demethyl podophyllotoxin 8 are also reported. The synthesis of 7 and 8 was based upon the reduction of the
g-lactone ring of 4 -demethyl-4-epipodophyllotoxin followed by selective protection at C-11 and elongation at C-13. (8–15% and 4% overall
yields). Compounds 4, 5 and 7 did not display relevant cytotoxicity in vitro against L1210 murine leukemia.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Despite the fact that they derived from podophyllotoxin,
there was early evidence that these drugs did not share the
same mechanism. In 1976, Loike and Horwitz made
relevant observations5 which ultimately led to the identifi-
cation of DNA topoisomerase II as the intracellular target
for the action of these drugs. Although etoposide has been
used successfully in the clinic for many years in the
treatment of small-cell lung cancer, testicular carcinoma,
lymphoma, and Kaposi’s sarcoma,6,7 several problems still
exist. Besides the poor solubility of etoposide and the
development of drug resistance, the metabolism of etopo-
side results in inactivation by epimerisation of the trans
lactone ring giving the cis isomer, the picropodophyllin
analogue which is 100-fold less toxic.8 A second metabolite
(2)-Podophyllotoxin 1 is a naturally occurring aryltetralin
from Podophyllum peltatum and P. emodi.1 Interest in
podophyllotoxin has been heightened by its potent anti-
mitotic activity.2 Podophyllotoxin inhibits the assembly of
tubulin protein into microtubules through tubulin binding at
the colchicin site3 but failed to advance in human clinical
trials because of toxic side-effects. Extensive structure
modifications have been performed since the 1950s,
principally at Sandoz Laboratories4 which led to the semi-
synthetic etoposide (VP-16, 2) and teniposide (VM-26, 3).
Both derivatives demonstrated significant activity and low
toxicity in clinical trials (Fig. 1).
Figure 1.
Keywords: Podophyllotoxin analogues; d-Lactones.
*
Corresponding author. Tel.: þ33-1-42-34-66-59; fax: þ33-1-42-34-66-31; e-mail address: emmanuel.bertounesque@curie.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.017

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P. Meresse et al. / Tetrahedron 60 (2004) 2657–2671
Figure 2.
is the cis-hydroxy acid which results from the opening of the
lactone ring with subsequent epimerisation and which is
500-fold less cytotoxic than etoposide. In order to avoid or
minimize the C-2 epimerization and/or the lactone ring
opening, two main alternatives have been proposed. The
first included the replacement of the g-lactone with furan,
thiolane, cyclopentane rings9 whereas the second took
advantage of the preparation of derivatives substituted at the
2-position such as methyl, halogeno, hydroxy10,11 or
nitrogen derivatives.12 On the other hand, a few years ago,
the groups of Gordaliza13 and Subrahmanyam14 have
reported that podophyllotoxin analogues lacking the lactone
ring are still endowed with relevant cytotoxic effects
towards colon cancer cell lines. However, as no in vivo
evaluation were reported in both cases, it remains to
ascertain whether they present a relevant anti-tumour
activity and lack of general toxicity.
observed when treated with 1,3-dithianyl anions prepared
from 1,3-dithiane-2-yl-triphenylphosphonium chloride,21
diethyl(1,3-dithian-2-yl)phosphonate,22 or 2-trimethylsilyl-
1,3-dithiane23 for Wittig, Horner–Emmons and Peterson
olefinations, respectively. Interestingly, the unprotected
lactol reacted with methyl(triphenylphosphoranylidene)-
acetate and pyridine in toluene at 90 8C to produce the
expected a,b-unsaturated ester.14b
The alternative way involved the reductive cleavage of the
lactone moiety into triol 11 by LAH. Indeed such a
reductive method24 is one among the few methods which
allow the reductive opening of the lactone ring of
podophyllotoxin with preservation of the 2,3-trans relation-
ship25 However, the crucial and immediate problem which
is attached to this transformation is due to the fact that triol
11 is prone to dehydration during the work-up to readily
afford the neoanhydropodophyllol 12.26
As part of our ongoing research program aimed at the
synthesis and biological evaluation of new anti-tumour
analogues15–18 related to podophyllotoxin and etoposide,
we have already been engaged in the synthesis of analogues
including six-membered lactone ring since enhancement of
the lactone ring may give access to more stable isomers.
Thus we recently reported the synthesis of the d-cis-lactone
analogue of picropodophyllin17 in which the carbonyl group
was adjacent to the epimerizable C-2 as in natural lignans.
Herein we describe the synthesis of non-epimerizable
d-lactone analogues of picropodophyllin 4 and of podo-
phyllotoxin 5 and 6, and the synthesis of non-epimerizable
d-lactone analogues of 40-demethyl-epipodophyllotoxin 7
and of 4-demethyl podophyllotoxin 8, possessing the
carbonyl in b-position of the C/D ring junction. Exploratory
evaluation of the biological activity of 4, 5 and 7 is also
presented (Fig. 2).
Formation of this side-product has been contradictorily
attributed to an acidic medium24 and later to a basic
medium26 involved during the different work-up. In our
laboratory, we observed that 12 is ineluctably formed upon
addition of EtOAc and HCl, we decided to carefully remove
the excess of hydride with successive addition of water and
NaOH at low temperature.27 Interestingly, under these
conditions, triol 11 was obtained in 60% yield without any
traces of 12. The following step consisted in selectively
protection of the C-11 hydroxyl by taking into account its
vicinal situation with the C-4 hydroxyl to form a cyclic
acetal. Moreover it was expected that treatment of 11
with a,a-dimethoxypropane would selectively afford a
6-membered isopropylidene. This acetonide protection
have been previously used for the 1,3-diol system of the
tetraline intermediate in the synthesis of (^)-podophyllo-
toxin.28 In fact, such a treatment led to a mixture of three
products which contained the expected isopropylidene
acetal 13 along with the hemiketal derivative 14 and with
the 7-membered acetal 15, in 7, 62 and 28% yields,
respectively. Additional amount of 13 could be obtained by
selective deprotection at C-13 (AcOH, H2O, MeOH, 88%)
of 14. Alternatively, addition of Et3N (10 equiv.) to the
crude reaction mixture, followed by concentration in vacuo
and heating at 60 8C for 8 h in aqueous methanolic solution,
afforded compounds 13 (54%) and 15 (15%) without any
traces of the hemiketal 14, allowing an easier purification of
13. The structure of 15 was determined by 1H NMR and by
chemical means upon periodinane oxidation29 of 15 leading
to the corresponding keto-derivative 16 (74%). A compound
having a similar skeleton had been already obtained by
Pelter et al.30
2. Results and discussion
Our point of departure for the synthesis of 4–6 was the
reduction of podophyllotoxin 1: two different ways have
been successively followed which consist in partial or total
reduction of the lactone ring with retention of configuration
at C-2 (Scheme 1). First, podophyllotoxin 1 was converted
into silyl ether 917 which was next reduced according to Lee
et al.19 in the presence of DIBAL-H to afford 10 in 87%
yield. Unfortunately, subsequent attempts to introduce a
side-chain via a Wittig reaction, using for example the ylide
obtained from methoxymethyltriphenylphosphonium
bromide,20 did not succeed, even in the case of the free
lactol at C-4. The same lack of reactivity of the lactol was

P. Meresse et al. / Tetrahedron 60 (2004) 2657–2671
2659
Scheme 1. Reagents and conditions: (a) TBDMSOTf, 2,6-lutidine, CH2Cl2, 0 8C, 1.3 h, 92%; (b) DIBALH, toluene, 278 8C, 40 min, 87%; (c) LAH, THF,
0 8C, 4 h, then basic work up according Ref. 27 gave 11 (60%), or work up according Refs. 24 or 26 gave 12; (d) a,a-DMP, PTSA, rt, 7 h, 13 (7%), 14 (62%)
and 15 (28%); (e) a,a-DMP, PTSA, rt, 3.5 h, then Et3N, MeOH/H2O (10/1), 8 h, 60 8C, 13 (54%) and 15 (15%); (f) Dess–Martin periodinane, CH2Cl2, rt,
40 min, 74%; (g) AcOH/H2O (1/1), MeOH, rt, 3.5 h, 88%; (h) Dess–Martin periodinane, CH2Cl2, rt, 30 min, 87%; (i) Ph3PCH3,Br, n-BuLi, THF, 278 8C,
45 min, 86%; (j) 9-BBN, THF, rt, 3.5 h, then H2O2 (30%), MeOH, pH 7.2 phosphate buffer, 74% (two steps); (k) Dess–Martin periodinane, CH2Cl2, rt, 1 h,
92%.
Scheme 2. Reagents and conditions: (a) a,a-dimethoxytoluene, PTSA, rt, 40 min, 73%; (b) AcOH/H2O (1/1), MeOH, CH2Cl2, rt 5 days, 66%; (c) a,a-
dimethoxytoluene, PTSA, CH2Cl2, rt, 10 min, 23 (37%), 22 (8%) and 12 (32%) (d) Dess–Martin periodinane, CH2Cl2, rt, 30 min, 87%; (e) Ph3PCH3,Br,
K2CO3, 18-crown-6, THF, reflux, 19 h, 92%; (f) 9-BBN, THF, rt, 1.75 h, then H2O2 (30%), MeOH, pH 7.2 phosphate buffer, rt, 3 h, 80%; (g) Dess–Martin
periodinane, CH2Cl2, rt, 1 h, 65%; (h) NaClO2, NH2SO3H, t-BuOH/H2O (2/1), rt, 25 min, 76%; (i) CSA, THF/H2O (10/1), 80 8C, 6 h, 66%.

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Once isolated, isopropylidene acetal 13 was oxidized in the
presence of Dess–Martin reagent (87%) and the aldehyde
derivative 17 (80 mg scale) was submitted to Wittig reagent
to give 18. The stereochemical assignment of 18 was based
on J3,4¼(10.1 Hz) and J1,2¼(6.4 Hz) coupling constants,
respectively consistent with 3,4-trans and 1,2-cis relation-
ships, and a comparison with similar compounds.28,31
Hydroboration followed by a second Dess–Martin oxi-
dation of alcohol 19, afforded 20 in 68% overall yield from
18. On 500 mg scale for the synthesis of 13, we noted the
preponderant formation of the seven-membered during the
first step (13:15¼13:86 instead of 78:22). In addition, Wittig
olefination of 17 (300 mg scale) provided an inseparable
mixture of 18 and 21 which was attributed to the
pronounced basic character of the ylide. This led us to
consider the benzylidene protection for 11 (Scheme 2). This
protective group was exploited in an exploratory approach
towards podophyllotoxin32 and epipodophyllotoxin.
cis-vinyl derivative 25 (92% yield). The assignment of the
relative stereochemistry was based upon J1,2 and J2,3¼(2.9
and 8.9 Hz). Note that the reaction of 24 with methylene-
triphenylphosphorane (Ph3PCH3,Br, n-BuLi, THF, 278 8C,
1 h 30) furnished an inseparable stereoisomeric mixture of
25 and of the 2,3-trans isomer (30:70 ratio) in 81% yield.
The same result was observed under various conditions of
time, temperature, or in the presence of various ratios of the
reagents versus the starting material. Furthermore, sub-
sequent hydroboration of this mixture led to the separation
problem again. Hydroboration of 25 gave alcohol 26 in 80%
yield. Periodinane oxidation followed by sodium chlorite
oxidation of aldehyde 27 led to the expected carboxylic acid
28 (76%) along with a small amount of 29 (8%) resulting
from the chloration of the aromatic ring. Unfortunately,
direct oxidation of the aformentioned vinyl or alcohol
mixture at C-2 into the corresponding acids failed.34 Acid
hydrolysis of the benzylidene moiety of 28 took place
without inversion35 at C-4 (J3,4¼8.2 Hz) to provide the
d-lactone-containing picropodophyllin derivative 4 in 66%
yield (e.g., 8 steps from 1 and 4% overall yield).
Treatment of 11 with a,a-dimethoxytoluene, both as
reagent and solvent, and PTSA exclusively afforded the
six-membered benzylidene acetal 22 (73%) which was next
converted into 23 by aqueous acidic hydrolysis (48% overall
yield) (Scheme 3). Removal of a,a-dimethoxytoluene
proved more troublesome than expected on larger scale.
Alternatively, the use a stoichiometric amount of the reagent
in dichloromethane led to a separable mixture of the desired
acetal 23, 22 and neoanhydropodophyllol 12. Upon
periodinane oxidation of 23, the resulting aldehyde 24 was
treated with the required ylide prepared in situ by
deprotonation of methyl triphenylphosphonium bromide
with potassium carbonate and 18-crown-633 to afford the
To obtain the corresponding trans isomer 5 of podophyllo-
toxin configuration (Scheme 3), compound 23 was first
mesylated (99%) and mesylate 30 readily afforded the cyano
derivative 31 (95%).
Next, hydrolysis of nitrile 31 was carried out in the presence
of a large excess of NaOH (40 equiv.) in EtOH under reflux
giving amide 32 in 83% yield. Carboxylic acid 33 could be
obtained as a mixture with 32 by prolonging the reaction
time to 16 h. Exposure of 32 to PTSA in MeOH led
Scheme 3. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0 8C, 30 min, 99%; (b) NaCN, DMF, 85 8C, 6 h, 95%; (c) NaOH (25%), EtOH, reflux, 7 h, 32
(83%)/reflux 16 h, mixture of 32 (24%) and 33 (47%); (d) CSA, THF/H2O (1/1), 85 8C, 17 h, 5 (28%), 6 (7%) and 36 (13%).

P. Meresse et al. / Tetrahedron 60 (2004) 2657–2671
2661
exclusively to 34 as an epimeric mixture at C-4 whereas
80% aqueous AcOH gave 5, 35 as an epimeric mixture, and
36. To circumvent the problem of substitution at C-4, the
reaction was carried out with CSA in THF/H2O (1/1). Under
these conditions, 32 was converted to the d-lactone-
containing podophyllotoxin derivative 5 (28%), along with
a small amount of 6 (7%) and 36 (13%). Homolactone 5
showed a broad triplet at 4.51 (J3,4¼J4,OH¼7.6 Hz) and
homolactone 6 showed a broad singlet at 4.76 due to H-4,
respectively, indicating 3,4-trans and 3,4-cis relationships.
The synthesis of 5 proceeds in 7 steps from 1 and in 6%
overall yield.
expected isopropylidene acetal 40, along with the hemiketal
derivative 41 and with the 40-demethyl-neoanhydropodo-
phyllol derivative 42. The 7-membered acetal was not
detected. Prior to chromatographic isolation of 40, the crude
mixture was then treated in acidic medium to carry out
selective deprotection at C-13. Under these conditions, 40
was more easily isolated (41%, 3 steps from 38).
Mesylation of 40, and cyanation with concomitant loss of
the TBDMS group, gave 44 in 53% overall yield.
Hydrolysis of nitrile 44 furnished amide 45 in acceptable
(44%) albeit lower yield than in the podophyllotoxin series.
One-pot deketalization and lactonization of 45 by a two-fold
acidic treatment led to a mixture of three compounds: the
expected d-lactone 7 (31%), and an inseparable mixture of
two other d-lactone derivatives postulated from our
previous results as being the epimer at C-4 8 and the
regioisomeric lactone 46. Homolactone 7 showed a large
singulet at 4.75 due to H-4 indicating a 3,4-cis relationship.
The chemistry developed in the podophyllotoxin series was
extended to 40-demethyl-4-epipodophyllotoxin 37. Protec-
tion of this latter as the tert-butyldimethylsilyl ether 38,
followed by treatment with LAH, afforded triol 39
(Scheme 4). Treatment of 39 with a,a-dimethoxypropane
led to a mixture of three compounds which contained the
Scheme 4. Reagents and conditions: (a) TBDMSCl, imidazole, DMF, rt, 1.5 h, 89%; (b) LAH, THF, 0 8C, 1.5 h, 51%; (c) a,a-DMP, PTSA, rt, 35 min,
(d) AcOH/H2O (1/1), MeOH, rt, 6 h, 40 (41%, 3 steps from 38); (e) MsCl, Et3N, CH2Cl2, 0 8C, 50 min; (f) NaCN, DMF, 85 8C, 5 h, 44 (53%, 2 steps); (g) NaOH
(25%), EtOH, 75 8C, 28 h, 44%; (h) (a) APTS, THF: H2O (10/1), 45 8C, 7 h; (b) CSA, CH2Cl2, rt, 30 min, 7 (31%); (i) TBDMSCl, imidazole, DMF, rt, 2.5 h;
(j) APTS, THF/H2O (10/1), 70 8C, 25 h, 48 (29%) and 49 (36%).

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The structure of 8 was confirmed from 1H NMR comparison
with 8 prepared otherwise (vide infra). Epimerization at C-4
occurred before the cyclization step as shown in the case of
the cyano-derivative 47 which, under these reaction
conditions, led to a mixture of 48 (29%) and 49 (36%).
The conversion of methyl epipodophyllate into methyl
podophyllate was obtained in a similar fashion during the
asymmetric total synthesis of (2)-podophyllotoxin.36
Hydrolysis of each cyano-derivative failed to furnish the
corresponding amide.
3,4-trans relationship. The syntheses of 7 and 8 proceeded
in 8–15% and 4% overall yields from 40-demethyl-
epipodophyllotoxin 37, respectively.
Exploratory evaluation of the biological activity of the six-
membered lactone derivatives 4, 5 and 7 were performed in
vitro. None of these compounds exhibited relevant cyto-
toxicity against L1210 murine leukemia since the values of
their IC50 were 73.9, 38 mM and.100 mM, respectively (1,
IC50¼0.008 mM). The lack of cytotoxic effect may be due to
the D-ring enhancement of the podophyllotoxin framework
or more probably it means that the position of the carbonyl
group on the lactone ring is important for activity.17
Our alternative synthesis of 7 involved the differential
protection of the hydroxyl groups at C-4 and C-11.
As shown in Scheme 5, bis-silylation of 37 generated 5037
which was reduced as the diol 51. Selective acylation with
2.5 equiv. of PivCl (Et3N, cat. 4-DMAP) afforded a
separable mixture of 52 (65%), 53 (27%) and 54 (8%).
Mesylation of 52 and cyanation provided 56 (54%, 2 steps).
Basic hydrolysis of the nitrile led to a polar compound—as
judged by TLC—which was presumably 57 according to
our knowledge in the podophyllotoxin series, and sub-
sequent neutralization gave 7 (32–60%) and 8 (15%). The
large coupling constant of 8 (J3,4¼8.4 Hz) is indicative of a
3. Conclusion
The synthesis of non-epimerizable d-lactone analogues of
picropodophyllin 4 and of podophyllotoxin 5 and 6 has been
achieved. Analogues 4 and 5 did not display significant
cytotoxicity in vitro against L1210. We have also completed
the synthesis of non-epimerizable d-lactone analogues of
40-demethyl-epipodophyllotoxin 7 and of 4-demethyl podo-
phyllotoxin 8. Work toward the preparation of d-lactone
Scheme 5. Reagents and conditions: (a) TBDMSOTf, 2,6-lutidine, CH2Cl2, 0 8C, 1 h, 81%; (b) LAH, THF, 0 8C to rt, 30 min, 92%; (c) PivCl, Et3N, 4-DMAP,
CH2Cl2, rt, 40 min, 52 65%), 53 (27%) and 54 (8%); (d) MsCl, Et3N, CH2Cl2, rt, 2 h; (e) NaCN, DMF, 85 8C, 24 h (54%, 2 steps); (f) NaOH (25%), EtOH,
85 8C, 7 h; (g) 1 N HCl (!pH 2–3), then work-up and stirring overnight of the combined organic phases. 7 (32–60%) and 8 (15%).

P. Meresse et al. / Tetrahedron 60 (2004) 2657–2671
2663
analogues having the carbonyl in a-position of the C/D ring
junction is under investigation.
with methylene chloride (20 mL) and with an aqueous
saturated solution of sodium hydrogenocarbonate (15 mL).
The aqueous layer was separated and washed with
methylene chloride (15 mL). The combined organic layers
were dried (MgSO4), and.concentrated under reduced
pressure. Flash chromatography (cyclohexane/EtOAc 3:1,
then 2:1 and 1:1) successively gave 13 (17.2 mg, 7%) as a
white solid, 15 (68.8 mg, 28%) as a white solid, and 14
(176 mg, 62%) as an amorphous solid.
4. Experimental
4.1. Materials and methods
1H NMR spectra were recorded on a Bruker AM-250 or a
Brucker AC-300 instrument. IR spectra were recorded on a
Perkin–Elmer 1710 infrared spectrophotometer. Optical
rotations were measured with a Perkin–Elmer 241 polari-
meter. Melting points were determined on either a Kofler
hot-stage instrument or an Electrothermal digital melting
point apparatus and are not corrected. Mass spectra (MS)
were registered on a Nermag R10-10C mass spectrometer
under chemical ionisation (CI) conditions. Elemental
analyses were performed by the ‘Service d’Analyse du
CNRS, Vernaison, France’. All reactions were monitored by
thin-layer chromatography (TLC) carried out on 0.25 mm
E. Merck silica gel plates (60F-254) using UV light and 7%
ethanolic phosphomolybdic acid-heat as a developing agent.
E Merck silica gel (particle size 0.040–0.063 mm) was used
for flash column chromatography. All reactions were carried
out using heat gun-dried glassware under an argon
atmosphere with dry, freshly distilled solvents under
anhydrous conditions unless otherwise noted. Yields refer
to chromatographically and spectroscopically pure com-
pounds unless otherwise stated. Podophyllotoxin was
purified by flash chromatography before use.
Procedure 2. Podophyllol 11 (52.5 mg, 0.125 mmol) was
treated as above but, after 3.5 h, as a tlc control indicated
disappearance of 11 and appearance of 13, 14 and 15, Et3N
(20 mL, 0.143 mmol) was added to the mixture and, 15 min
later, the reaction mixture was concentrated under reduced
pressure. The solid was dissolved in MeOH (1.8 mL) and
water (0.2 mL), and the solution was heated at 60 8C for 8 h.
Work-up and flash chromatography as above led to isolation
of 13 (31.1 mg, 54%), and 15 (8.7 mg, 15%).
Compound 13. Mp 169–170 8C (CH2Cl2); [a]2D0¼2133 (c
0.62, CHCl3); IR (CDCl3) 3620 (OH), 2939, 1590, 1505,
1
1482 cm21; H NMR (300 MHz, CDCl3) d 6.99 (s, 1H,
H-5), 6.36 (s, 1H, H-8), 6.35 (s, 2H, H-20, H-60), 5.90 (d, 1H,
J¼1.4 Hz, OCH2O), 5.88 (d, 1H, J¼1.3 Hz, OCH2O), 4.71
(d, 1H, J¼9.2 Hz, H-4), 4.18 (d, 1H, J¼5.4 Hz, H-1), 3.94
(dd, 1H, J¼11.1, 4.2 Hz, H-11), 3.805 (m, 1H, H-11), 3.83 (s,
3H, OCH3-40), 3.78 (s, 6H, OCH3-3 ,50), 3.51 (m, 1H, H-13),
3.41 (m, 1H, H-13), 2.24–2.05 (m, 2H, H-2, H-3), 1.60 (s,
3H, CH3), 1.53 (s, 3H, CH3); MS (DCI, NH3) m/z 458 [M]þ,
476 [MþNH4]þ.
4.1.1. 4-O-(tert-Butyldimethylsilyl)-13-hydroxypodo-
phyllotoxin (10). Compound 10 was prepared according
to Lee et al.19
Compound 14. [a]2D0¼2139.5 (c 0.63, CHCl3); IR (CDCl3)
2940, 1590, 1505, 1483 cm21; 1H NMR (300 MHz, CDCl3)
d 6.98 (s, 1H, H-5), 6.36 (s, 1H, H-8), 6.33 (s, 2H, H-20,
H-60), 5.90 (d, 1H, J¼1.4 Hz, OCH2O), 5.88 (d, 1H,
J¼1.4 Hz, OCH2O), 4.69 (d, 1H, J¼9.1 Hz, H-4), 4.20 (d,
1H, J¼5.6 Hz, H-1), 3.83 (m, 01H, H-11), 3.83 (s, 3H,
OCH3-40), 3.77 (s, 6H, OCH3-3 ,50), 3.77 (m, 1H, H-11),
3.17 (s, 3H, OCH3), 3.05 (m, 2H, H-13), 2.16 (m, 2H, H-2,
H-3), 1.61 (s, 3H, CH3), 1.52 (s, 3H, CH3), 1.33 (s, 3H,
CH3), 1.26 (s, 3H, CH3); MS (DCI, NH3) m/z 530
[M2H2OþNH4]þ.
4.1.2. Podophyllol 11. To a suspension of LAH (18.44 g,
486 mmol) in THF (315 mL) at 0 8C was added podophyl-
lotoxin 1 (24.26 g, 58.54 mmol) in THF (250 mL) over a
period of 1.5 h. The mixture was stirred for an additional
2.5 h at the same temperature and under argon atmosphere
prior to successive additions of water (18.5 mL), 15%
aqueous solution of NaOH (18.5 mL) and water (56 mL).
The crude mixture was filtered, washed with THF
(4£100 mL) and the filtrate was concentrated under reduced
pressure to c.a. 150 mL. The aqueous residue was extracted
thrice with EtOAc (250 mL and then 2£150 mL) and the
combined organic layers were washed with brine
(2£250 mL), dried (MgSO4) and concentrated in vacuo.
The yellow solid residue was triturated with MeOH (75 mL)
and the crystals were separated by precipitation to give
podophyllol 11 (14.82 g, 60%) as a white powder, pure
enough for the next step. Mp 178–179 8C (MeOH);
[a]2D0¼2234.5 (c 0.25, EtOH). [Lit.25: mp 179–181 8C;
[a]D18.5¼2179 (c 0.27, CHCl3); Lit.26: mp 186–188 8C
(EtOAc); [a]1D9¼2203 (c 0.25, EtOH)].
Compound 15. Mp 150–152 8C (CH2Cl2); [a]2D0¼2199.5 (c
0.75, CHCl3); IR (CDCl3) 3594 (OH), 2938, 1590, 1505,
1
1483 cm21; H NMR (300 MHz, CDCl3) d 7.06 (s, 1H,
H-5), 6.37 (s, 1H, H-8), 6.18 (s, 2H, H-20, H-60), 5.92 (s, 2H,
OCH2O), 4.31 (t, 1H, J¼8.4 Hz, H-4), 4.10 (dd, 1H,
J¼11.6, 2.7 Hz, H-11), 3.82 (s, 3H, OCH3-40), 3.78 (s, 6H,
OCH3-30,50), 3.70 (m, 1H, H-11), 3.63 (m, 1H, H-13), 3.24
(m, 1H, H-13), 2.03 (m, 2H, H-2, H-3), 1.73 (d, 1H exch.
D2O, J¼8.4 Hz, OH), 1.33 (s, 3H, CH3), 1.20 (s, 3H, CH3);
MS (DCI, NH3) m/z 458 [M2H2OþNH4]þ.
4.1.4. Ketone 16. Dess–Martin periodinane (26 mg,
61.5 mmol) was added to a solution of 15 (23.5 mg,
51 mmol) in methylene chloride (2 mL) at rt. After
40 min, the mixture was diluted with methylene chloride
(3 mL), then a 10% aqueous NaHSO3 solution (2 mL) and a
saturated aqueous saturated NaHCO3 solution (2 mL) were
added. The aqueous layer was extracted with methylene
chloride, and the combined organic layers were dried
4.1.3. 4,11-O-Isopropylidene podophyllol (13), 11,13-O-
isopropylidene podophyllol (15) and 4,11-O-isopropyl-
idene-9-(2-methoxyisopropylether) podophyllol (14).
Procedure 1. To a suspension of podophyllol 11 (224 mg,
0.53 mmol) in 2,2-dimethoxypropane (13 mL), p-toluene-
sulfonic acid monohydrate (10.2 mg, 53.5 mmol) was
added. The reaction mixture was stirred at rt for 7 h, diluted

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P. Meresse et al. / Tetrahedron 60 (2004) 2657–2671
(MgSO4), and concentrated under reduced pressure. Flash
chromatography (cyclohexane/EtOAc 5:1) led to ketone 16
(17.3 g, 74%) as a syrup; IR (CDCl3) 2941, 1669, 1590,
After further stirring for 2.5 h, the mixture was diluted with
methylene chloride (15 mL) and poured into water (10 mL).
The aqueous layer was extracted with methylene chloride
(15 mL), and the combined organic layers were washed with
water (2£20 mL) and brine (20 mL), dried (MgSO4), and
concentrated under reduced pressure. Flash chromatography
(cyclohexane/EtOAc 3:1, then 2:1) gave compound 19
(41 mg, 74%) as a syrup; [a]2D0¼2161.5 (c 0.13, CHCl3); IR
1H NMR (300 MHz, CDCl3) d 6.97 (s, 1H, H-5), 6.34 (s,
1H, H-8), 6.28 (s, 2H, H-20, 60), 5.88 (s, 1H, OCH2O), 5.86
(s, 1H, OCH2O), 4.67 (d, 1H, J¼8.8 Hz, H-4), 3.90 (dd, 1H,
J¼11.3, 3.7 Hz, H-11), 3.82 (s, 3H, OCH3-40), 3.77 (s, 6H,
OCH3-30,50), 3.80–3.70 (m, 3H, H-11, H-14), 2.22–2.10
(m, 2H, H-2, H-3), 1.59 (s, 3H, CH3), 1.52 (s, 3H, CH3),
1.31 (m, 3H, H-13, OH); MS (DCI, NH3) m/z 490
[MþNH4]þ.
1
1505, 1480 cm21; H NMR (300 MHz, CDCl3) d 7.49 (s,
1H, H-5), 6.52 (s, 1H, H-8), 6.15 (s, 2H, H-20, H-60), 6.02 (s,
2H, OCH2O), 4.42 (dd, 1H, J¼12.6, 3.7 Hz, H-11), 4.20 (d,
1H, J¼4.6 Hz, H-1), 3.84 (dd, 1H, J¼12.6,0 9.8 Hz, H-11),
3.83 (s, H, OCH3-40), 3.76 (s, 6H, OCH3-30,5 ), 3.72 (dd, 1H,
J¼11.9, 3 Hz, H-13), 3.40 (dd, 1H, J¼11.9, 10.4 Hz, H-13),
2.88 (m, 1H, H-3), 2.52 (m, 1H, H-2), 1.32 (s, 3H, CH3),
1.22 (s, 3H, CH3).
(CDCl3) 3690, 3629 (OH), 2934, 1590, 1505, 1482 cm21
;
4.1.5. Aldehyde 17. Periodinane (374 mg, 0.885 mmol) was
added to a solution of 13 (338 mg, 0.737 mmol) in
methylene chloride (35 mL) at rt. After stirring for
30 min, the reaction mixture was poured into a 10%
aqueous NaHSO3 solution (25 mL) and a saturated aqueous
NaHCO3 solution (25 mL). The aqueous layer was extracted
with methylene chloride (25 mL), and the combined organic
layers were washed with water (2£30 mL) and brine
(30 mL), dried (MgSO4), and concentrated under reduced
pressure. Flash chromatography (cyclohexane/EtOAc 4:1)
led to aldehyde 17 (293 mg, 87%) as an amorphous solid;
[a]2D0¼2116 (c 0.05, CHCl3); IR (CDCl3) 2936, 1719,
1592, 1505, 1483 cm21; 1H NMR (300 MHz, CDCl3) d 9.11
(d, 1H, J¼3.9 Hz, CHO), 7.01 (s, 1H, H-5), 6.37 (s, 1H, H-
8), 6.23 (s, 2H, H-20, H-60), 5.92 (s, 2H, OCH2O),4.68 (d,1H,
J¼10 Hz, H-4), 4.40 (d, 1H, J¼6.8 Hz, H-1), 3.94 (dd, 1H,
J¼11.5, 4.1 Hz, H-11), 3.82 (s, 3H, OCH3-40), 3.78 (s, 7H,
OCH3-30,50, H-11), 2.71 (m, 1H, H-2), 2.55 (m, 1H, H-3),
1.60 (s, 3H, CH3), 1.55 (s, 3H, CH3); MS (DCI, NH3) m/z
457 [MþH]þ, 4.74 [MþNH4]þ.
4.1.8. Aldehyde 20. Dess–Martin periodinane (34 mg,
81 mmol) was added to a solution of 19 (31.5 mg,
66.7 mmol) in methylene chloride (5 mL) at rt. After 1 h,
a 10% aqueous NaHSO3 solution (2.5 mL) and a saturated
aqueous NaHCO3 solution (2.5 mL) were added. The
aqueous layer was extracted with methylene chloride
(5 mL), and the combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. Flash
chromatography (cyclohexane/EtOAc 4:1) provided 20
1
(28.9 mg, 92%) as a syrup; H NMR (300 MHz, CDCl3) d
9.75 (s, 1H, CHO), 6.98 (s, 1H, H-5), 6.32 (s, 1H, H-8), 6.16
(s, 2H, H-20, H-60), 5.90 (d, 1H, J¼1.3 Hz, OCH2O), 5.88 (d,
1H, J¼1.3 Hz, OCH2O), 4.72 (d, 1H, J¼9.9 Hz, H-4), 4.16
(d, 1H, J¼6.2 Hz, H-1), 3.83 (s, 3H, OCH3-40), 3.77 (s, 6H,
OCH3-30,50), 3.75–3.65 (m, 2H, H-11), 2.66 (m, 1H, H-2),
2.18 (d, 2H, J¼6.8 Hz, H-13), 2.10 (m, 1H, H-3), 1.60 (s,
3H, CH3), 1.53 (s, 3H, CH3); MS (DCI, NH3) m/z 488
[MþNH4]þ.
4.1.6. Vinyl 18. To a suspension of methyltriphenyl-
phosphonium bromide (315 mg, 0.883 mmol) in tetra-
hydrofuran (4 mL) at 278 8C was added n-butyl lithium
(2.5 M in hexane, 0.32 mL, 0.795 mol). After 5 min, a
solution of 17 (80.6 mg, 0.177 mmol) in tetrahydrofuran
(2 mL) was added and the resulting mixture was stirred at
278 8C for 45 min, quenched by addition of acetone
(0.5 mL) and allowed to reach rt. Upon addition of
methylene chloride (10 mL) and H2O (10 mL), the aqueous
layer was extracted with methylene chloride (10 mL). The
combined organic layers were dried (MgSO4), and con-
centrated under reduced pressure. Flash chromatography
(cyclohexane/EtOAc 6:1) gave 18 (68.7 mg, 86%) as a
syrup; [a]2D0¼2195.5 (c 0.07, CHCl3); IR (CDCl3) 2926,
1592, 1505, 1483 cm21; 1H NMR (300 MHz, CDCl3) d 7.00
(s, 1H, H-5), 6.36 (s, 1H, H-8), 6.19 (s, 2H, H-20, 60), 5.91 (d,
1H, J¼1.4 Hz, OCH2O), 5.89 (d, 1H, J¼1.4 Hz, OCH2O),
5.11–4.99 (m, 3H, 3H-vinyl), 4.67 (d, 1H, J¼10.1 Hz, H-4),
4.03 (d, 1H, J¼6.4 Hz, H-1), 3.83 (s, 3H, OCH3-40), 3.76
(s, 6H, OCH3-30,50), 3.69–3.54 (m, 2H, H-11), 2.56
(m, 1H, H-2), 2.13 (m, 1H, H-3), 1.59 (s, 3H, CH3), 1.53
(s, 3H, CH3); MS (DCI, NH3) m/z 455 [MþH]þ, 4.72
[MþNH4]þ.
4.1.9. Hemiacetal 22. p-Toluene sulfonic acid monohydrate
(8.7 mg, 0.046 mmol) was added to a suspension of
podophyllol 11 (191 mg, 0.456 mmol) in benzaldehyde
dimethylacetal (5 mL) at rt. After 40 min, the mixture was
diluted with methylene chloride (20 mL) and poured into a
saturated aqueous NaHCO3 solution (10 mL). The aqueous
layer was extracted with methylene chloride (10 mL), and
the combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. Flash chromatography
(cyclohexane then cyclohexane/EtOAc 95:5 then 90:10)
gave 22 (210 mg, 73%) as a mixture of diastereoisomers at
C-13 (ratio 60:40 from 1H NMR data). Such a mixture was
not purified further but, after MS control (DCI, NH3 m/z 644
[MþNH4]þ), engaged into the following step.
4.1.10. Alcohol 23. From podophyllol 11. Benzaldehyde
dimethylacetal (0.23 mL, 1.43 mmol) and p-toluenesulfonic
acid monohydrate (22.7 mg, 0.12 mmol) were successively
added to a suspension of podophyllol (500 mg, 1.19 mmol)
in methylene chloride (30 mL). The reaction mixture was
stirred for 10 min at rt, and then treated with a saturated
aqueous NaHCO3 solution (30 mL). After 30 min, the
aqueous layer was extracted with methylene chloride
(20 mL), and the combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. Flash
chromatography (cyclohexane/EtOAc 5:1 then 1:1 then 1:2)
4.1.7. Alcohol 19. A solution of 9-BBN (0.5 M in THF,
1.2 mL, 0.6 mmol) was added to a solution of 18 (53.1 mg,
0.117 mmol) in anhydrous THF (3 mL) and the reaction
mixture was stirred for 3.5 h at rt prior to addition of pH 7.2
phosphate buffer (1.5 mL), methanol (4.5 mL) and a 35%
(weight) aqueous solution of hydrogen peroxide (3 mL).

P. Meresse et al. / Tetrahedron 60 (2004) 2657–2671
2665
successively afforded 22 (62 mg, 8%), 23 (224 mg, 37%)
and 12 (153 mg, 32%).
H-vinyl), 4.73 (d, 1H, J¼10.6 Hz, H-4), 4.06–4.00 (m, 2H,
H-1, H-11), 3.95 (t, 1H, J¼10.4 Hz, H-11), 3.83 (s, 3H,
OCH3-40), 3.77 (s, 6H, OCH3-30,50), 2.53 (dd, 1H, J¼8.9,
2.9 Hz, H-2), 2.39 (m, 1H, H-3); MS (DCI, NH3) m/z 520
[MþNH4]þ; Anal. Calcd for C30H30O7: C, 71.70; H, 6.02.
Found: C, 71.66; H, 6.07.
From hemiacetal 22. A solution of 22 (71 mg, 0.113 mmol)
in a mixture of methylene chloride (6 mL), H2O (0.6 mL)
and acetic acid (0.6 mL) was stirred for 4 days at rt. After
dilution with methylene chloride (10 mL), the organic layer
was washed with a saturated aqueous NaHCO3 solution
(15 mL) and brine (10 mL), dried (MgSO4) and concen-
trated under reduced pressure. Flash chromatography
(cyclohexane/EtOAc 2:1) furnished 23 (37.7 mg, 66%) as
a white solid. Mp 159–160 8C; [a]2D0¼295.5 (c 0.56,
4.1.13. Alcohol 26. A solution of 9-BBN in THF (0.5 M,
10.8 mL, 5.4 mmol) was added to a solution of 25 (270 mg,
0.537 mmol) in anhydrous THF (25 mL) at rt. After stirring
for 1.75 h, an aqueous solution of pH 7.2 phosphate buffer
(8 mL), methanol (22 mL) and a 30% aqueous H2O2
solution (13.2 mL) were successively added to the reaction
mixture. Further stirring was maintained for 3 h at rt, then
the reaction mixture was diluted with ethyl acetate (40 mL).
The aqueous layer was extracted with ethyl acetate
(2£30 mL), and the combined organic layers were washed
with brine (10 mL), dried (MgSO4) and concentrated under
reduced pressure. Flash chromatography (cyclohexane/
EtOAc 3:1) afforded 26 (223.6 g, 80%) as a syrup; IR
CHCl3); IR (CDCl3) 3621, 1590, 1505, 1484 cm21 1H
;
NMR, (300 MHz, CDCl3) d 7.62–7.60 (m, 2H, Ar–H),
7.44–7.38 (m,0 3H, Ar–H), 7.10 (s, 1H, H-5), 6.38 (s, 3H,
H-8, H-20, H-6 ), 5.91 (s, 2H, OCH2O), 5.81 (s, 1H, CHPh),
4.69 (d, 1H, J¼9.8 Hz, H-4), 4.37 (dd, 1H, J¼10.8, 4.1 Hz,
H-11), 4.22 (d, 1H, J¼6 Hz, H-1), 3.87 (t, 1H, J¼0 10.8 Hz,
H-11), 3.83 (s, 3H, OCH3-40), 3.79 (s, 6H, OCH3-3 ,50), 3.54
(m, 1H, H-13), 3.46 (m, 1H, H-13), 2.41 (m, 1H, H-3), 2.19
(m, 1H, H-2); MS (DCI, NH3) m/z 524 [MþNH4]þ; Anal.
Calcd for C29H30O8: C, 68.76; H, 5.97. Found: C, 68.49; H,
6.01.
1
(CDCl3) 3614, 2933, 1590, 1505, 1485 cm21; H NMR
(300 MHz, CDCl3) d 7.59–7.56 (m, 2H, Ar–H), 7.42–7.37
(m, 3H, 0Ar–H), 7.11 (s, 1H, H-5), 6.45 (s, 1H, H-8), 6.23 (s,
2H, H-2 , 60), 5.94 (d, 1H, J¼1.3 Hz, OCH2O), 5.92 (m, 1H,
J¼1.3 Hz, OCH2O), 5.76 (s, 1H, CHPh), 4.77 (d, 1H,
J¼10.6 Hz, H-40), 4.09–3.90 (m, 5H, H-1, H-11, H-14), 3.83
(s, 3H, OCH3-4 ), 3.78 (s, 6H, OCH3-30,50), 2.47–2.33 (m,
1H, H-2), 2.05 (m, 1H, OH), 1.90–1.80 (m, 1H, H-3), 1.68–
1.50 (m, 2H, H-13).
4.1.11. Aldehyde 24. Dess–Martin periodinane (2.9 g,
6.84 mmol) was added to a solution of 23 (2.31 g,
4.56 mmol) in methylene chloride (350 mL) at rt. After
20 min, a 10% aqueous NaHSO3 solution (220 mL) and a
saturated aqueous NaHCO3 solution (220 mL) were added
to the reaction mixture. After stirring for 30 min, the organic
layer was washed with water (2£450 mL) and brine
(450 mL), dried (MgSO4) and concentrated under reduced
pressure. Flash chromatography (cyclohexane/EtOAc 4:1)
led to 24 (1.95 g, 87%) as an amorphous solid; IR (CDCl3)
4.1.14. Aldehyde 27. Dess–Martin periodinane (810 mg,
1.91 mmol) was added to a solution of derivative 26
(506 mg, 0.972 mmol) in methylene chloride (150 mL) at rt.
After 1 h, a 10% aqueous NaHSO3 solution (50 mL) and a
saturated aqueous NaHCO3 solution (50 mL) were succes-
sively added to the reaction mixture. After further stirring
for 15 min, the organic layer was washed with brine
(100 mL), dried (MgSO4) and concentrated under reduced
pressure. Flash chromatography (cyclohexane/EtOAc 4:1)
led to 27 (327.6 g, 65%) as a white foam; [a]2D0¼210 (c
0.25, CHCl3); IR (CDCl3) 2939, 1724, 1591, 1505,
1
2935, 1720, 1592, 1505, 1484 cm21; H NMR (250 MHz,
CDCl3) d 9.19 (d, 1H, J¼3.3 Hz, CHO, 7.62–7.55 (m, 2H,
Ar–H), 7.46–7.36 (m, 3H, Ar–H), 7.11 (s, 1H, H-5), 6.39
(s, 1H, H-8), 6.24 (s, 2H, H-20, H-60), 5.92 (s, 2H, OCH2O),
5.81 (s, 1H, CHPh), 4.65 (d, 1H, J¼8.5 Hz, H-4), 4.45 (d,
1H, J¼5.7 Hz, H-1), 4.40 (dd, 1H, J¼110, 30.5 Hz, H-11),
3.82 (s, 3H, OCH3-40), 3.77 (s, 6H, OCH3-3 , 5 ), 3.73 (t, 1H,
J¼11 Hz, H-11), 2.79–2.72 (m, 2H, H-2, H-3); MS (DCI,
NH3) m/z 505 [MþH]þ, 5.22 [MþNH4]þ; Anal. Calcd for
C29H28O8: C, 69.04; H, 5.59. Found: C, 68.85; H, 5.62.
1
1484 cm21; H NMR (300 MHz, CDCl3) d 9.45 (s, 1H,
CHO), 7.58–7.55 (m, 2H, Ar–H), 7.42–7.37 (m, 3H,
Ar–H), 7.11 (s, 1H, H-5), 6.42 (s, 1H, H-8), 6.37 (s, 2H,
H-20, H-60), 5.94 (s, 1H, OCH2O), 5.93 (s, 1H, OCH2O),
5.76 (s, 1H, CHPh), 4.69 (d, 1H, J¼10.7 Hz, H-4), 4.03 (dd,
1H, H-1, J¼10.9, 4 Hz, H-11), 3.93 (ls, 1H, H-1), 3.87 (t,
1H, J¼10.9 Hz, H-11), 3.84 (s, 3H, OCH3-40), 3.84 (s, 6H,
OCH3-30,50), 3.81 (m, 1H, H-13), 2.72–2.60 (m, 2H, H-2,
H-13), 2.46 (m, 1H, H-3); MS (DCI, NH3) m/z 536
[MþNH4]þ; Anal. Calcd for C30H30O8: C, 69.49; H, 5.83.
Found: C, 69.23; H, 5.86.
4.1.12. Vinyl 25. To a solution of methyltriphenyl-
phosphonium bromide (1.03 g, 2.88 mmol) and anhydrous
potassium carbonate (349.4 mg, 2.53 mmol) in tetrahydro-
furan (20 mL) was added a solution of 24 (1.037 g,
2.055 mmol) in tetrahydrofuran (20 mL). The reaction
mixture was refluxed for 19 h and, after cooling to rt,
diluted with ethyl acetate (150 mL). The mixture was
washed successively with 1 N HCl (50 mL), water
(2£150 mL) and brine (150 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure.
Flash chromatography (cyclohexane/EtOAc 6:1 then 5:1)
afforded 25 as a white crystalline solid (0.95 g, 92%). Mp
162–163 8C; [a]2D0¼237.5 (c 0.25, CHCl3); IR (CDCl3)
2939, 1591, 1505, 1485 cm21; 1H NMR (250 MHz, CDCl3)
d 7.59–7.55 (m, 2H, Ar–H), 7.43–7.35 (m, 3H, Ar–H),
7.11 (s, 1H, H-5), 6.44 (s, 1H, H-8), 6.23 (s, 2H, H-20, 60),
5.93 (s, 2H, OCH2O), 5.92 (m, 1H, H-vinyl), 5.72 (s, 1H,
CHPh), 5.30 (br s, 1H, H-vinyl), 5.15 (br d, 1H, J¼10.3 Hz,
4.1.15. Carboxylic acid 28. Sulfamic acid (53.8 mg,
0.554 mmol) and sodium chlorite (49.2 mg, 0.435 mmol)
were added to a suspension of 27 (205.3 mg, 0.396 mmol) in
tert-butanol (16 mL) and H2O (8 mL). The reaction mixture
was stirred for 30 min at rt, at which point the reaction was
poured into water (15 mL) and ethyl acetate (50 mL). The
aqueous layer was extracted with ethyl acetate (3£20 mL)
and the combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. Flash chromatography
(cyclohexane/EtOAc/AcOH 2:1:0.1) successively gave 28

2666
P. Meresse et al. / Tetrahedron 60 (2004) 2657–2671
(161 mg, 76%) as a syrup and 29 (18 mg, 8%) as a white
solid.
SO2CH3), 2.46 (m, 2H, H-2, H-3); MS (ES) m/z 607
[MþNa]þ.
Compound 28. [a]2D0¼0 (c 0.5, CHCl3); IR (CDCl3) 3679,
4.1.18. Cyanide 31. A solution of sodium cyanide (25.8 mg,
0.526 mmol) in anhydrous dimethylformamide (15 mL)
was added to a solution of mesylate 30 (153.7 mg,
0.263 mmol) ar rt. The reaction medium was heated at
85 8C for 6 h and, after cooling to rt, poured into water
(75 mL). The mixture was extracted with ether (4£40 mL),
and the combined organic extracts were dried (MgSO4) and
concentrated under reduced pressure. Flash chromatography
(cyclohexane/EtOAc 4:1) gave 31 (129 mg, 95%) as a white
solid; [a]2D0¼2175 (c 0.88, CHCl3); IR (CDCl3) 2933, 1591,
1506, 1485 cm21; 1H NMR (300 MHz, CDCl3) d 7.60–7.57
(m, 2H, Ar–H), 7.46–7.39 (m, 3H, Ar–H), 7.09 (s, 1H,
H-5), 6.41 (br s, 3H, H-8, H-20, H-60), 5.93 (s, 1H, OCH2O),
5.92 (s, 1H, OCH2O), 5.79 (s, 1H, CHPh), 4.67 (d, 1H,
J¼9.1 Hz, H-4), 4.31 (d, 1H, J¼5.3 Hz, H-1), 4.21 (dd, 1H,
J¼10.6,0 3.8 Hz, H-11), 3.84 (s and overlapped m, 4H,
OCH3-4 , H-11), 3.81 (s, 6H, OCH3-30,50), 2.40 (m, 2H, H-2,
H-3), 2.22 (dd, 1H, J¼16.5, 3.9 Hz, H-13), 1.88 (dd, 1H,
J¼16.5, 10.6 Hz, H-13); MS (DCI) m/z 533 [MþNH4]þ;
Anal. Calcd for C30H29NO7: C, 69.89; H, 5.67; N, 2.72.
Found: C, 69.77; H, 5.71; N, 2.70.
1
2929, 1709, 1591, 1505, 1485 cm21; H NMR (300 MHz,
CDCl3) d 7.58–7.55 (m, 2H, Ar–H), 7.42–7.36 (m, 3H,
Ar–H), 7.11 (s, 1H, H-5), 6.44 (s, 1H, H-8), 6.33 (s, 2H,
H-20, H-60), 5.95 (s, 1H, OCH2O), 5.94 (s, 1H, OCH2O),
5.76 (s, 1H, CHPh), 4.69 (d, 1H, J¼10.5 Hz, H-4), 4.05 (m,
1H, H-11), 4.05 (br s, 1H, H-1), 3.92 (t, 1H, J¼10.9 Hz,
H-11), 3.83 (s, 3H, OCH3-40), 3.77 (s, 6H, OCH3-30,50),
2.66–2.43 (m, 4H, H-2, H-3, H-13); MS (DCI, NH3) m/z
552 [MþNH4]þ.
Compound 29. Mp 131–133 8C; [a]2D0¼0 (c 0.6, CHCl3); IR
(CDCl3) 3680, 2939, 1709, 1573, 1505, 1485 cm21 1H
;
NMR (300 MHz, CDCl3) d 7.57–7.54 (m, 2H, Ar–H),
7.41–7.37 (m, 3H, Ar–H), 7.11 (s, 1H, H-5), 6.41 (s, 1H,
H-8), 5.99 (s, 1H, H-60), 5.95 (s, 1H, OCH2O), 5.94 (s, 1H,
OCH2O), 5.77 (s, 1H, CHPh), 4.76 (d, 1H, J¼10.5 Hz, H-4),
4.44 (br s, 1H, H-1), 4.08 (dd, 1H, J¼10.9, 3.8 Hz, H-11),
3.97 (s and partially overlapped m, 4H, OCH3, H-11), 3.86
(s, 3H, OCH3), 3.58 (s, 3H, OCH3) 2.73–2.41 (m, 4H, H-2,
H-3, H-13); MS (DCI, NH3) m/z 569 [MþH]þ, 586
[MþNH4]þ.
4.1.19. Amide 32 and carboxylic acid 33. A solution of
aqueous sodium hydroxide (6.25 M, 1.86 mL, 11.6 mmol)
was added to a solution of 31 (143 mg, 0.277 mmol) in 95%
ethanol (11 mL) at rt. The reaction mixture was heated at
80 8C for 7 h and then allowed to cool to rt. After quenching
with 1 N HCl (11 mL), the reaction mixture was diluted
with ethyl acetate (30 mL) and the aqueous layer was
extracted with ethyl acetate (10 mL). The combined organic
layers were washed with brine, dried (MgSO4) and
concentrated under reduced pressure. Flash chromatography
(methylene chloride/MeOH 97:3) afforded 32 (123 mg,
83%) as a white solid. Prolonged reaction time (16 h) gave a
mixture of 32 (24%) and 33 (47%).
4.1.16. Homolactone 4. CSA (34 mg, 0.146 mmol) was
added to a solution of acid 28 (71.1 mg, 0.133 mmol) in
THF (4 mL) and water (0.4 mL) at rt. The reaction mixture
was heated at 80 8C for 6 h, then allowed to cool to rt. After
dilution with ethyl acetate (10 mL) and water (5 mL), the
aqueous layer was extracted with ethyl acetate (5 mL), and
the organic layers were combined, dried (MgSO4) and
concentrated under reduced pressure. Flash chromatography
(cyclohexane/EtOAc 1:1) furnished 4 (37.5 mg, 66%) as a
white solid. Mp 171–172 8C; [a]2D0¼þ9.5 (c 0.27, CHCl3);
1
IR (CDCl3) 3624, 2939, 1739, 1592, 1504, 1482 cm21; H
NMR (300 MHz, CDCl3) d 7.02 (s, 1H, H-5), 6.36 (s, 2H,
H-20, H-60), 6.29 (s, 1H, H-8), 5.93 (d, 1H, J¼1.3 Hz,
OCH2O), 5.92 (s, 1H, J¼1.3 Hz, OCH2O), 4.65 (d, 1H exch.
with D2O, J¼8.2 Hz, H-4), 4.49 (m, 2H, H-11), 3.87 (s, 3H,
OCH3-40), 3.83 (s, 6H, OCH3-30,50), 3.52 (d, 1H, J¼9.3 Hz,
H-1), 2.67 (m, 1H, H-2), 2.58 (dd, 1H, J¼16.2, 6.1 Hz,
H-13), 2.41 (dd, 1H, J¼16.2, 6.1 Hz, H-13), 2.39 (m, 1H,
H-3); MS (DCI, NH3) m/z 446 [MþNH4]þ; Anal. Calcd for
C23H24O8: C, 64.48; H, 5.65. Found: C, 64.27; H, 5.69.
Compound 32. Mp 140–142 8C; [a]2D0¼2118 (c 1.02,
CHCl3); IR (CDCl3) 3523, 3408 (NH2), 2939, 1683, 1595,
1
1590, 1595, 1484 cm21; H NMR (300 MHz, CDCl3) d
7.62–7.58 (m, 2H, Ar–H), 7.45–7.27 (m, 3H, Ar–H), 7.08
(s, 1H, H-5), 6.34 (s, 2H, H-8), 6.28 (s, 2H, H-20, H-60), 5.90
(d, 1H, J¼1.4 Hz, OCH2O), 5.89 (d, 1H, J¼1.4 Hz,
OCH2O), 5.78 (s, 1H, CHPh), 5.38 and 5.33 (2 br s, 2H
exch. D2O, NH2), 4.71 (d, 1H, J¼9.7 Hz, H-4), 4.28 (d, 1H,
J¼6.1 Hz, H-1),0 4.20 (dd, 1H, J¼10.9, 4.2 Hz, H-11), 3.83
(s, 3H, OCH3-4 ), 3.77 (s and overlapped m, 7H, OCH3-
30,50, H-11), 2.71 (m, 1H, H-2), 2.32 (m, 1H, H-3), 2.01 (dd,
1H, J¼16.3, 4.9 Hz, H-13), 1.82 (dd, 1H, J¼16.3, 9.6 Hz,
H-13); MS (DCI) m/z 551 [MþNH4]þ.
Compound 33. [a]2D0¼2130.5 (c 0.78, CHCl3); IR (CDCl3)
3522, 3400–2500, 2939, 1708, 1590, 1505, 1484 cm21; 1H
NMR (300 MHz, CDCl3) d 7.621–7.57 (m, 2H, Ar–H),
7.44–7.39 (m, 3H, Ar–H), 7.09 (s, 1H, H-5), 6.35 (s, 2H,
H-8), 6.23 (br s, 2H, H-20, H-60), 5.90 (br s, 2H, OCH2O),
5.78 (s, 1H, CHPh), 4.69 (d, 1H, J¼9.7 Hz, H-4), 4.22 (m,
2H, H-1, H-11), 3.83 (s, 3H, OCH3-40), 3.76 (s and
overlapped m, 7H, OCH3-30,50, H-11), 2.58 (m, 1H, H-2),
2.33 (m, 1H, H-3), 2.13 (m, 2H, H-13); MS (DCI, NH3) m/z
552 [MþNH4]þ.
4.1.17. Mesylate 30. To a cooled 0 8C solution of 23
(530 mg, 1.046 mmol) in methylene chloride (50 mL), were
added successively triethylamine (1.45 mL, 10.46 mmol)
and methanesulfonyl chloride (0.410 mL, 5.27 mmol). After
stirring for 30 min at 0 8C, the reaction mixture was
quenched with water (50 mL), and the organic layer was
dried (MgSO4) and concentrated under reduced pressure.
Flash chromatography (cyclohexane/EtOAc 2:1) gave 30
(604 mg, 99%) as a white foam; [a]2D0¼2114 (c 1, CHCl3);
IR (CDCl3) 2937, 1590, 1505, 1484 cm21 1H NMR
;
(300 MHz, CDCl3) d 7.61–7.58 (m, 2H, Ar–H), 7.46–
7.39 (m, 3H, Ar0–H), 7.09 (s, 1H, H-5), 6.38 (s, 1H, H-8),
6.32 (s, 2H, H-2 , H-60), 5.92 (s, 1H, OCH2O), 5.91 (s, 1H,
OCH2O), 5.81 (s, 1H, CHPh), 4.70 (d, 1H, J¼8.7 Hz, H-4),
4.28–4.24 (m, 1H, H-11), 4.03–3.88 (m, 3H, H-11, H-13),
3.84 (s, 3H, OCH3-40), 3.79 (s, 6H, OCH3-30,50), 2.97 (s, 3H,

P. Meresse et al. / Tetrahedron 60 (2004) 2657–2671
2667
4.1.20. Homolactones 5, 6 and 36. CSA (161 mg,
0.693 mmol) was added to a solution of amide 32
(246 mg, 0.462 mmol) in THF (15 mL) and water (15 mL)
at rt. The reaction mixture was heated at 85 8C for 17 h, then
allowed to cool to rt. The reaction mixture was poured into a
saturated aqueous NaHCO3 solution (15 mL) and extracted
with ethyl acetate (30 mL). The organic layer was washed
with brine (10 mL), dried (MgSO4) and concentrated under
reduced pressure. Flash chromatography (cyclohexane/
EtOAc 6:4 then 1:1) gave 5 (55.4 mg, 28%), 6 (14 mg,
7%) and 36 (26 mg, 13%) as amorphous solids.
(d, 1H, J¼1.3 Hz, OCH2O), 5.91 (d, 1H, J¼1.3 Hz,
OCH2O), 4.96 (d, 1H, J¼3.1 Hz, H-4), 4.18 (d, 1H,
J¼5.5 Hz, H-1), 4.05 (dd, 1H, J¼12, 1.9 Hz, H-11), 3.93
(dd, 1H, J¼12, 4.1 Hz, H-11), 03.77 (dd, 1H, J¼11, 4 Hz,
H-13), 3.68 (s, 6H, OCH3-30,5 ), 3.64 (m, 1H exch. with
D2O, OH), 3.46 (dd, 1H, J¼11, 6.8 Hz, H-13), 3.08 (m, 1H
exch. with D2O, OH), 2.10 (m, 1H, H-3), 0.99 (s, 9H,
(CH3)3CSi), 0.10 (s, 6H, (CH3)2Si); MS (ES) m/z (%) 541
[MþNa]þ.
4.1.22. (1a,2a,3b,4b)-4,11-O-Isopropylidene-40-tert-
butyldimethylsilanyloxy)-podophyllol 40. Monohydrated
p-toluenesulfonic acid (51.1 mg, 0.269 mmol) was added to
a solution of crude 39 (1.39 g, 2.68 mmol) in 2,2-
dimethoxypropane (125 mL). After 35 min at rt, the
reaction mixture was concentrated under reduced pressure
until it reached a volume of 50 mL. A saturated aqueous
NaHCO3 solution (20 mL) and ethyl acetate (100 mL) were
then added. The organic layer was washed with water
(100 mL), dried (MgSO4) and concentrated under reduced
pressure, affording a crude residue (1.65 g) as a beige foam,
which was poured into methanol (85 mL). Water (1.2 mL)
and acetic acid (1.2 mL) were then added. Stirring was
maintained for 6 h at rt before addition of a saturated
aqueous NaHCO3 solution (35 mL) and ethyl acetate
(100 mL). In order to obtain decantation, brine (100 mL)
was added. The aqueous layer was extracted with ethyl
acetate (80 mL), and the combined organic layers were
dried (MgSO4) and concentrated under reduced pressure.
Flash chromatography (cyclohexane/EtOAc 4:1) afforded
acetonide 40 (901 mg, 60%) as a white foam; [a]2D0¼250 (c
Compound 5. [a]2D0¼118 (c 0.77, CHCl3); IR (CDCl3) 3610,
2927, 1733, 1590, 1505, 1595, 1484 cm21 1H NMR
;
(300 MHz, CDCl3) d 7.02 (s, 1H, H-5), 6.43 (s, 1H, H-8),
6.21 (s, 2H, H-20, H-60), 5.95 (s, 2H, OCH2O), 4.79 (dd, 1H,
J¼11.3, 5.3 Hz, H-11), 4.51 (br t, 1H, J¼7.6 Hz, H-4), 4.18
(dd, 1H, J¼11.3, 10.1 Hz, H-11), 3.92 (d, 1H, J¼5.4 Hz,
H-1), 3.83 (s, 3H, OCH3-40), 3.79 (s, 6H, OCH3-30,50), 2.62
(dd, 1H, J¼17.4, 12, 5.6 Hz, H-13), 2.51–2.39 (m, 1H,
H-2), 2.37–2.25 (m, 1H, H-3), 2.19 (d, 1H exch. with D2O,
J¼7.6 Hz, OH), 2.09 (dd, 1H, J¼17.4, 11.7 Hz, H-13); MS
(DCI, NH3) m/z 446 [MþNH4]þ; Anal. Calcd for C23H24O8:
C, 64.48; H, 5.65. Found: C, 64.36; H, 5.67.
Compound 6. IR (CDCl3) 3597, 2927, 1733, 1506, 1595,
1
1485 cm21; H NMR (300 MHz, CDCl3) d 6.84 (s, 1H,
H-5), 6.45 (s, 1H, H-8), 6.06 (s, 2H, H-20, H-60), 5.96 (s, 1H,
OCH2O), 5.95 (s, 1H, OCH2O), 4.76 (br s, 1H, H-4), 4.58–
4.50 (m, 2H, H-11), 4.03 (d, 1H, J¼0 6.2 Hz, H-10), 3.82 (s,
3H, OCH3-40), 3.77 (s, 6H, OCH3-3 ,50), 2.90–2.80 (m, 1H,
H-2), 2.67 (dd, 1H, J¼17.8, 6.4 Hz, H-13), 2.40–2.30 (m,
1H, H-3), 2.08 (dd, 1H, J¼17.8, 11.6 Hz, H-13); MS (DCI,
NH3) m/z 446 [MþNH4]þ.
1, CHCl3); IR (CDCl3) 3564, 2931, 1586, 1506, 1485 cm21
;
1H NMR (300 MHz, CDCl3) d 6.75 (s, 1H, H-5), 6.43 (s,
1H, H-8), 6.22 (s, 2H, H-20, H-60), 5.92 (d, 1H, J¼1.3 Hz,
OCH2O), 5.87 (d, 1H, J¼1.3 Hz, OCH2O), 4.94 (d, 1H,
J¼3.6 Hz, H-4), 4.20 (d, 1H, J¼5.4 Hz, H-l), 4.07 (dd, 1H,
J¼12.3, 4.3 Hz, H-11), 3.89 (dd, 1H, J¼12.3, 3.5 Hz,
H-11), 3.82 (dt, 1H, Jgem¼11.7 Hz, J13,2¼J13,OH¼3 Hz,
H-13), 3.70 (s, 6H, OCH3-30,50), 3.63 (m, 1H, H-13), 2.76
(m, 1H, H-2), 2.06 (m, 1H, H-3), 1.63 (s, 3H, CH3), 1.42 (s,
3H, CH3), 0.99 (s, 9H, (CH3)3CSi), 0.90 (dd, 1H exch. with
D2O, J¼3, 9 Hz, OH), 0.10 (s, 6H, (CH3)2Si); MS (DCI,
NH3) m/z (%) 559 [MþH]þ; Anal. Calcd for C30H42O7Si:
C, 64.49; H, 7.58. Found: C, 64.28; H, 7.59.
Compound 36. [a]2D0¼211.5 (c 0.65, CHCl3); IR (CDCl3)
3608, 2927, 1735, 1590, 1504, 1485, 1484 cm21; 1H NMR
(300 MHz, CDCl3) d 6.80 (s, 1H, H-5), 6.51 (s, 1H, H-8),
6.48–6.10 (m, 2H, H-20, H-60), 5.97 (d, 1H, J¼1.1 Hz,
OCH2O), 5.95 (d, 1H, J¼1.1 Hz, OCH2O), 5.24 (t, 1H,
J¼2.4 Hz, H-4), 4.28 (d, 1H, J¼5.8 Hz, 0H-l), 3.86 (s, 3H,
OCH3-40), 3.83–3.73 (m, 8H, OCH3-30,5 , H-11), 2.83 (m,
1H, H-3), 2.65–2.59 (m, 1H, H-2), 2.50–2.45 (m, 2H,
H-13); MS (DCI, NH3) m/z 446 [MþNH4]þ.
4.1.21. 40-tert-Butyldimethylsilanyloxy-podophyllol 39.
To a suspension of LiAlH4 (134 mg, 3.53 mmol) in THF
(12 mL) cooled to 0 8C was added alcohol 38 (227 mg,
0.441 mmol) in solution in THF (7 mL). After 1.5 h at 0 8C,
4.1.23. Cyanide 44. Triethylamine (4 mL, 28.62 mmol) and
methanesulfonyl chloride (0.57 mL, 7.182 mmol) were
added to a solution of 40 (800 mg, 1.431 mmol) in
methylene chloride (60 mL), cooled to 0 8C. After 50 min
at 0 8C, water (60 mL) and methylene chloride (100 mL)
were poured into the reaction mixture. The organic layer
was washed with brine, acidified with 1 N HCl until pH 2,
neutralized with water, dried (MgSO4), and concentrated
under reduced pressure to afford the crude mesylate 43
(939.6 mg). The latter was dissolved into anhydrous DMF
(80 mL), and sodium cyanide (143.1 mg, 2.916 mmol) was
added. The mixture was heated at 85 8C for 5 h, then
allowed to reach rt. The reaction mixture was then poured
into water (300 mL), the aqueous layer was extracted with
ethyl acetate (3£150 mL) [Bad decantation can be remedied
by addition of brine into the emulsion]. The combined
organic layers were dried (MgSO4) and concentrated
under reduced pressure. The remaining DMF traces were
water (0.140 mL),
a 25% NaOH aqueous solution
(0.140 mL), and water (0.420 mL) were successively
added to the reaction mixture. The precipitate was
eliminated by filtration, and the filtrate was diluted with
ethyl acetate (25 mL) and washed with Rochelle’s salt
saturated water (25 mL). The organic layer was washed with
brine (25 mL), dried (MgSO4) and concentrated under
reduced pressure. The crude residue, often directly used for
the following reactions, could also be purified by flash
chromatography (cyclohexane/EtOAc 1:2, 1:4), leading to
39 (117.4 mg, 51%) as a white solid. Mp 180–181 8C;
[a]2D0¼298.5 (c 1, CHCl3); IR (CDCl3) 3600–3200, 2936,
1587, 1505, 1485 cm21; 1H NMR (300 MHz, CDCl3) d 6.83
(s, 1H, H-5), 6.41 (s, 1H, H-8), 6.12 (s, 2H, H-20, H-60), 5.93

2668
P. Meresse et al. / Tetrahedron 60 (2004) 2657–2671
eliminated by evaporation under high vacuum. Flash
chromatography (cyclohexane/EtOAc 2:1) gave cyanide
44 (345.6 mg, 53% for the two steps) as a syrup; IR (CDCl3)
(3.7 mg, 0.016 mmol). After 30 min (TLC control showed
the disappearance of polar compounds), the reaction was
diluted with methylene chloride (8 mL), washed with brine
(8 mL), dried (MgSO4) and concentrated under reduced
pressure. Preparative chromatography on silica gel
(methylene chloride/MeOH 95:5) led to 7 (12.8 mg, 31%)
and to an inseparable mixture (7.2 mg) containing its
4-epimer 8 and the postulated bridged d-lactone 46.
3540, 2940, 1619, 1519, 1505, 1485 cm21 1H NMR
;
(300 MHz, CDCl3) d 6.75 (s, 1H, H-5), 6.46 (s, 1H, H-8),
6.31 (br s, 2H, H-20, H-60), 5.94 (d, 1H, J¼1.3 Hz, OCH2O),
5.90 (d, 1H, J¼1.3 Hz, OCH2O), 5.44 (s, 1H exch. with
D2O, OH), 4.93 (d, 1H, J¼3.6 Hz, H-4), 4.34 (d, 1H,
J¼5.1 Hz, H-1), 4.06 (dd, 1H, J¼12.6, 4.1 Hz, H-11), 3.81
(s, 6H, OCH3-30, 50), 3.68 (dd 1H, J¼12.6, 3.4 Hz H-11),
3.04 (m, 1H, H-2), 2.56 (dd, 1H, J¼16.5, 3.5 Hz, H-13),
1.94 (m, 1H, H-3), 1.87 (dd, 1H, J¼16.5, 12 Hz, H-13), 1.62
(s, 3H, CH3), 1.42 (s, 3H, CH3); MS (DCI, NH3) m/z 471
[MþNH4]þ.
Homolactone 7. Mp 135–137 8C; [a]2D0¼2126 (c 0.29,
CHCl3); IR (CDCl3) 3544, 2917, 1734, 1619, 1519,
1
1485 cm21; H NMR (300 MHz, CDCl3) d 6.83 (s, 1H,
H-5), 6.44 (s, 1H, H-8), 6.07 (s, 2H, H-20, H-60), 5.95 (s, 2H,
OCH2O), 5.45 (s, 1H, exch. with D2O, OH-40), 4.75 (br s,
1H, H-4), 4.60–4.50 (m, 2H0, H-11), 4.02 (d, 1H, J¼6.1 Hz,
H-1), 3.80 (s, 6H, OCH3-3 ,50), 2.89–2.77 (m, 1H, H-2),
2.65 (dd, J¼17.7, 6.3 Hz, H-13), 2.39–2.27 (m, 1H, H-3),
2.06 (dd, 1H, J¼17.7, 11.3 Hz, H-13); HRMS (DCI, NH3)
m/z (%) Calcd: 415.1393 [MþH]þ. Found: 415.1384
[MþH]þ; Anal. Calcd for C22H22O8: C, 63.76; H, 5.35.
Found: C, 63.53; H, 5.31.
4.1.24. Amide 45. A 6.25 M sodium aqueous solution
(0.181 mL, 1.13 mmol was added to a solution of 44
(12.2 mg, 26.9 mmol) in ethanol. The reaction mixture was
heated at 75 8C for 28 h. After cooling, the mixture was
neutralized with 1 N HCl. The aqueous layer was extracted
with ethyl acetate (2£8 mL), and the combined organic
layers were washed with brine (2£10 mL), dried (MgSO4)
and concentrated under reduced pressure. Flash chromato-
graphy (methylene chloride/MeOH 97:3) gave 45 (5.8 mg,
44%) as a syrup; IR (CDCl3) 3694, 3527, 3409, 2926, 1681,
Homolactone 8. IR (CDCl3) 3541, 2898, 1729, 1620, 1517,
1
1484 cm21; H NMR (300 MHz, CDCl3) d 7.01 (s, 1H,
H-5), 6.42 (s, 1H, H-8), 6.22 (s, 2H, H-20, H-60), 5.94 (s, 2H,
OCH2O), 5.46 (s, 1H, exch. with D2O, H-40), 4.78 (dd, 1H,
J¼11.3, 5.3 Hz, H-11), 4.50 (br d, 1H, J¼8.3 Hz, H-4), 4.18
(dd, 1H, J¼11.3, 9.7 Hz, H-11), 3.91 (d, 1H, J¼5.4 Hz,
H-1), 3.83 (s, 6H, OCH3-30,50), 2.60 (dd, 1H, J¼17.5,
5.6 Hz, H-13), 2.49–2.37 (m, 1H, H-2), 2.34–2.24 (m, 1H,
H-3), 2.07 (dd, 1H, J¼17.5, 11.7 Hz, H-13); HRMS (DCI,
NH3) m/z (%) Calcd: 415.1393 [MþH]þ. Found 415.1386
[MþH]þ.
1
1484 cm21; H NMR (300 MHz, CDCl3) d 6.76 (s, 1H,
H-5), 6.42 (s, 1H, H-8), 6.21 (s, 2H, H-20, H-60), 5.91 (d, 1H,
J¼1.3 Hz, OCH2O), 5.87 (d, 1H, J¼1.3 Hz, OCH2O), 5.55
(br s, 1H exch. with D2O, NH), 5.39 (s, 1H (d, 1H exch. with
D2O, OH), 5.35 (br s, 1H exch. with D2O, NH), 4.92 (d, 1H,
J¼3.9 Hz, H-4), 4.34 (d, 1H, J¼5 Hz, H-1),0 4.001 (dd, 1H,
J¼12.3, 4.9 Hz, H-11), 3.80 (s, 6H, OCH3-3 ,5 ), 3.74 (dd,
1H, J¼12.3, 4.5 Hz, H-11), 3.03 (m, 1H, H-2), 2.30 (dd, 1H,
J¼15.7, 3.8 Hz, H-13), 2.01 (m, 1H, H-3), 1.86 (dd, 1H,
J¼15.7, 10.9 Hz, H-13), 1.62 (s, 3H, CH3), 1.42 (s, 3H,
CH3); MS (DCI, NH3) m/z (%) 489 [MþNH4]þ.
4.1.26. Cyanide 17. Imidazole (1.22 g, 8.94 mmol) and tert-
butyldimethylsilyl chloride (1.35 g, 8.94 mmol) were added
at rt to a solution of cyanide 44 (700 mg, 1.54 mmol) in
anhydrous DMF (25 mL). After 2.5 h the reaction mixture
was poured into water (100 mL) and ethyl acetate (50 mL)
was added. The aqueous layer was extracted thrice
(3£50 mL), and the combined organic layers were washed
with brine (2£50 mL), dried (MgSO4) and concentrated
under reduced pressure. Flash chromatography (cyclo-
hexane/EtOAc 5:1) gave cyanide 47 (537 mg, 61%) as a
4.1.25. Homolactones 7 and 8. From cyanide 44. A
solution of nitrile 44 (105 mg, 0.172 mmol) in 95% ethanol
(14 mL) containing a 25% aqueous NaOH solution
(1.15 mL, 7.2 mmol) was heated at 85 8C for 7 h. After
cooling to rt, the reaction mixture was neutralized with 1 N
HCl (7.2 mL) (the bright yellow color disappeared). A small
excess of 1 N HCl (0.5 mL) was added to obtain pH 3–4,
and after 10 min the mixture was poured into ethyl acetate
(30 mL) and water (10 mL). The aqueous layer was
extracted twice with ethyl acetate (2£10 mL), and the
combined organic layers were stirred for 15 h, then washed
with brine (30 mL), dried (MgSO4) and concentrated under
reduced pressure. Flash chromatography (methylene
chloride/MeOH 98:2 then 97:3) afforded 7 (36.2 mg, 51%)
as a white powder and 8 (8.5 mg, 12%) as a syrup.
1
white foam. IR (CDCl3) 2932, 1587, 1506, 1486 cm21; H
NMR (300 MHz, CDCl3) d 6.74 (s, 1H, H-5), 6.47 (s, 1H,
H-8), 6.25 (s, 2H, H-20, H-60), 5.94 (d, 1H, J¼1.3 Hz,
OCH2O), 5.89 (d, 1H, J¼1.3 Hz, OCH2O), 4.92 (d, 1H,
J¼3.4 Hz, H-4), 4.31 (d, 1H, J¼5.1 Hz, H-1), 4.05 (dd, 1H,
J¼12.5, 4.1 Hz, H-11), 3.72 (s, 6H, OCH3-30,50), 3.68 (dd,
1H, J¼12.5, 3.5 Hz, H-11), 3.02 (m, 1H, H-2), 2.53 (dd, 1H,
J¼16.4, 3.5 Hz, H-13), 1.95 (m, 1H, H-3), 1.84 (dd, 1H,
J¼16.4, 11.9 Hz, H-13), 1.62 (s, 3H, CH3), 1.41 (s, 3H,
CH3), 1.00 (s, 9H, (CH3)3CSi), 0.11 (s, 6H, CH3Si); MS
(DCI, NH3) m/z (%) 585 [MþNH4]þ.
From amide 45. p.Toluenesulfonic acid (23 mg, 0.12 mmol)
was added to a solution of 45 (48.6 mg, 0.1 mmol) in THF
(5 mL) and water (0.5 mL). The reaction mixture was
heated at 45 8C for 7 h and subsequently poured into brine
(3 mL) and ethyl acetate (5 mL). The aquous layer was
extracted twice with ethyl acetate (2£10 mL), and the
combined organic layers were washed with brine (10 mL),
dried (MgSO4) and concentrated under reduced pressure.
The crude residue (56.1 mg) in anhydrous methylene
chloride (3 mL) was treated with camphorsulfonic acid
4.1.27. Cyanides 48 and 49. Monohydrated p-toluene-
sulfonic acid (3.4 mg, 0.0176 mmol) was added to a solution
of 47 (100 mg, 0.176 mmol) in a mixture of THF (10 mL)
and water (1 mL), and the reaction mixture was heated at
70 8C for 25 h. The mixture was then diluted with water and
ethyl acetate. The aqueous layer was extracted twice with
ethyl acetate (2£10 mL) and the combined organic layers

P. Meresse et al. / Tetrahedron 60 (2004) 2657–2671
2669
were dried (MgSO4) and concentrated under reduced
pressure. Flash chromatography (methylene chloride/
MeOH 98:1) furnished a mixture of 48 (27 mg, 29%) and
49 (33.8 mg, 36%).
(200 mL), dried (MgSO4) and concentrated under reduced
pressure. Flash chromatography (cyclohexane/EtOAc 9:1
then 8:2) successively gave 52 (4.2 g, 65%), 53 (1.75 g,
27%) and 54 (0.5 g, 8%) as foams.
Compound 48. Mp 144–145 8C; [a]2D0¼2182 (c 0.59,
Compound 52. [a]D20¼230.5 (c 1, CHCl3); IR (CDCl3)
CHCl3); IR (CDCl3): 3616, 2932, 1587, 1505, 1485 cm21
;
3630, 2931, 1719, 1587, 1507, 1483 cm21 1H NMR
;
1H NMR (250 MHz, CDCl3) d 6.80 (s, 1H, H-5), 6.49 (s,
1H, H-8), 6.24 (s, 2H, H-20, H-60), 5.96 (d, 1H, J¼1.1 Hz,
OCH2O), 5.95 (d, 1H, J¼1.1 Hz, OCH2O), 4.97 (t, 1H,
J¼3.7 Hz, H-4), 4.38 (d, 1H, J¼5.3 Hz, 0H-1), 4.05 (br d,
1H, J¼12 Hz, H-11), 3.71 (s, 6H, OCH3-3 ,50), 3.67 (m, 1H,
H-11), 3.05–2.90 (m, 2H, H-2, H-3), 2.79 (dd, 1H, J¼16.3,
3.6 Hz, H-13), 2.09 (d, 1H exch. with D2O, J¼3.7 Hz,
OH-4), 2.06 (m, 1H exch. with D2O, OH-11), 1.85 (dd,
1H, J¼16.3, 11.8 Hz, H-13), 0.99 (s, 9H, (CH3)3CSi),
0.10 (s, 6H, (CH3)2Si); MS (DCI, NH3) m/z (%) 545
[MþNH4]þ.
(300 MHz, CDCl3) d 6.80 (s, 1H, H-5), 6.44 (s, 1H, H-8),
6.27 (s, 2H, H-20, H-60), 5.91 (s, 2H, OCH2O), 4.93 (d, 1H,
J¼3.4 Hz, H-4), 4.32–4.25 (m, 2H, H-1, H-11),04.015 (dd,
1H, J¼11, 7.5 Hz, H-11), 3.70 (s, 6H, OCH3-3 ,5 ), 3.60
(dd, 1H, J¼11.3, 5 Hz, H-13), 3.42 (dd, 1H, J¼11.3, 7.2 Hz,
H-13), 2.59 (m, 1H, H-2), 2.49 (m, 1H, H-3), 1.20 (s,
9H, (CH3)3CCO), 1.00 (s, 9H, (CH3)3CSi), 0.88 (s,
9H, (CH3)3CSi), 0.18 (s, 3H, CH3Si), 0.12 (s, 6H,
(CH3)2Si), 0.02 (s, 3H, CH3Si); MS (DCI, NH3) m/z 734
[MþNH4]þ.
Compound 53. IR (CDCl3) 3629, 2930, 1718, 1603, 1507,
1
Compound 49. Mp 100–102 8C; [a]2D0¼2215.5 (c 0.66,
1484 cm21; H NMR (300 MHz, CDCl3) d 6.84 (s, 1H,
CHCl3); IR (CDCl3): 3628, 2932, 1588, 1503, 1485 cm21
;
H-5), 6.46 (s, 1H, H-8), 6.18 (s, 2H, H-20, H-60), 5.92 (s, 2H,
OCH2O), 5.08 (d, 1H, J¼4 Hz, H-4), 4.23 (d, 1H, J¼6.1 Hz,
H-1), 4.00–3.85 (m, 03H, H-11, H-13), 3.74 (m, 1H, H-13),
3.69 (s, 6H, OCH3-3 ,50), 2.64 (m, 1H, H-2), 2.29 (m, 1H,
H-3), 1.17 (s, 9H, (CH3)3CCO), 1.00 (s, 9H, (CH3)3CSi),
0.92 (s, 9H, (CH3)3CSi), 0.19 (s, 3H, CH3Si), 0.13 (s, 6H,
(CH3)2Si), 0.05 (s, 3H, CH3Si); MS (DCI, NH3) m/z 734
[MþNH4]þ.
1H NMR (300 MHz, CDCl3) d 7.03 (s, 1H, H-5), 6.45 (s,
1H, H-8), 6.39 (s, 2H, H-20, H-60), 5.93 (s, 2H, OCH2O),
4.80 (br d, 1H, J¼8.4 Hz, H-4), 4.21 (d, 1H, J¼4.6 Hz,
H-1), 4.000 (br dd, J¼10.6, 3.4 Hz, H-11), 3.73 (s, 6H,
OCH3-30, 5 ), 3.70 (m, 1H, H-11), 2.85 (br s, 1H exch. with
D2O, OH), 2.52 (dd, 1H, J¼16.2, 4.3 Hz, H-13), 2.41 (m,
1H, H-2), 2.06 (m, 1H, H-3), 1.91 (dd, 1H, J¼16.2, 10.7 Hz,
H-13), 1.88 (m, 1H exch. with D2O, OH), 1.00 (s, 9H,
(CH3)3CSi), 0.13 (s, 6H, (CH3)2Si); MS (DCI, NH3) m/z (%)
545 [MþNH4]þ.
Compound 54. IR (CDCl3) 2932, 1722, 1587, 1504,
1
1483 cm21; H NMR (300 MHz, CDCl3) d 6.77 (s, 1H,
H-5), 6.42 (s, 1H, H-8), 6.15 (s, 2H, H-20, H-60), 5.91 (s, 2H,
OCH2O), 4.94 (d, 1H, J¼3.3 Hz, H-4), 4.34 (dd, 1H,
J¼11.2, 6.6 Hz, H-11), 4.25 (d, 1H, J¼5.8 Hz, H-1), 4.11
(dd, 1H, J¼11.2, 7.6 Hz, H-11), 3.94 (dd, 1H, J¼11.4,
6.3 Hz, H-13), 03.83 (dd, 1H, J¼11.4, 7.6 Hz, H-13), 3.68 (s,
6H, OCH3-30,5 ), 2.74 (m, 1H, H-2), 2.42 (m, 1H, H-3), 1.19
(s, 9H, (CH3)3CCO), 1.16 (s, 9H, (CH3)3CCO), 0.99 (s, 9H,
(CH3)3CSi), 0.87 (s, 9H, (CH3)3CSi), 0.17 (s, 3H, CH3Si),
0.11 (s, 6H, (CH3)2Si), 0.00 (s, 3H, CH3Si); MS (DCI, NH3)
m/z 818 [MþNH4]þ.
4.1.28. Alcohol 51. A solution of 5041 (6.7 g, 10.65 mmol)
in THF (200 mL) was cooled to 0 8C, and lithium
aluminium hydride (0.61 g, 16 mmol) was slowly added.
After 15 min at 0 8C, the reaction mixture was warmed to rt
for 15 min. The reaction was quenched by successive
additions of water (0.6 mL), a 15% NaOH aqueous solution
(0.6 mL) and water (1.8 mL). The precipitate was removed
by filtration and the filtrate was concentrated under reduced
pressure. Flash chromatography (cyclohexane/EtOAc 3:1)
furnished diol 51 (6.22 g, 92%) as a white solid. Mp 156–
158 8C (Lit.37: mp 160–162 8C); [a]D20¼250.5 (c 1, CHCl3);
4.1.30. Cyanide 56. To a solution of 52 (4.2 g, 5.86 mmol)
in methylene chloride (300 mL) were added, at rt,
triethylamine (4.1 mL, 29.3 mmol) and methanesulfonyl
chloride (1.14 mL, 14.64 mmol). After 2 h, the reaction was
poured into water (250 mL) and acidified with 1 N HCl until
pH 2–3. The aqueous layer was extracted twice with
methylene chloride (2£100 mL), and the combined organic
layers were washed with brine (200 mL), dried (MgSO4)
and concentrated under reduced pressure. Sodium cyanide
(860 mg, 17.54 mmol) was added to a solution of the crude
mesylate 55 (4.65 g) in anhydrous DMF (300 mL) at rt, and
the mixture was heated to 85 8C for 24 h. After cooling to rt,
the mixture was concentrated under reduced pressure until
to obtain a residual volume of 20 mL. Addition of water
(100 mL) to this residue was followed by extraction with
ethyl acetate (3£50 mL). The combined organic layers were
washed with brine (100 mL), dried (MgSO4) and concen-
trated under reduced pressure. Flash chromatography
(cyclohexane/EtOAc 3:1) led to 56 (1.95 g, 54%) as a
foam. Mp 83–85 8C; [a]2D0¼288 (c 1.01, CHCl3); IR
1
IR (CDCl3) 3688, 3573, 2938, 1586, 1505, 1484 cm21; H
NMR (400 MHz, CDCl3) d 6.78 (s, 1H, H-5), 6.40 (s, 1H,
H-8), 6.21 (s, 2H, H-20, H-60), 5.92 (s, 2H, OCH2O), 5.01 (d,
1H, J¼3.2 Hz, H-4),4.16(d,1H, J¼6.3 Hz, H-1), 3.85(m, 2H,
H-11), 3.70 (s, 6H, OCH3-30,50), 3.67 (m, 2H, H-13), 2.66 (m,
1H, H-2), 2.32 (m, 1H, H-3), 1.00 (s, 9H, (CH3)3CSi), 0.88 (s,
9H, (CH3)3CSi), 0.20 (s, 3H, CH3Si), 0.11 (s, 6H, (CH3)2Si),
20.02 (s, 3H, CH3Si); MS (DCI, NH3) m/z 650 [MþNH4]þ;
Anal. Calcd for C33H52O8Si2: C, 62.62; H, 8.28. Found: C,
62.38, H, 8.25.
4.1.29. Pivaloyls 52 and 53, and bis-pivaloyl 54. To a
solution of 51 (5.71 g, 9.02 mmol) in methylene chloride
(325 mL) were added, at rt, triethylamine (6.3 mL,
435.3 mmol), 4-DMAP (110 mg, 0.9 mmol) and pivaloyl
chloride (2.8 mL, 22.5 mmol). After 25 min, the reaction
mixture was poured into water (300 mL) and acidified with
1 N HCl until pH 2–3. The aqueous layer was extracted
twice with methylene chloride (2£100 mL), and the
combined organic layers were washed with brine
(CDCl3) 3540, 2931, 1724, 1519, 1505, 1485 cm21 1H
;

2670
P. Meresse et al. / Tetrahedron 60 (2004) 2657–2671
Heterocycles 1999, 51, 1443–1470. (b) Pearce, H. L.; Bach,
N. J.; Cramer, T. L. Tetrahedron Lett. 1989, 30, 907–910.
NMR (300 MHz, CDCl3) d 6.77 (s, 1H, H-5), 6.44 (s, 1H,
H-8), 6.29 (s, 2H, H-20, H-60), 5.93 (s, 2H, OCH2O), 5.46 (s,
1H exch. with D2O, OH), 4.93 (d, 1H, J¼3.2 Hz, H-4),
4.39–4.34 (m, 2H, H-1, H-11), 4.03 (dd, 1H, J¼11.2, 8 Hz,
H-11), 3.82 (s, 6H, OCH3-30,50), 2.89 (m, 1H, H-2), 2.45 (m,
1H, H-3), 2.38 (dd, 1H, J¼16.7, 6 Hz, H-13), 1.87 (dd, 1H,
J¼16.7, 10.3 Hz, H-13), 1.16 (s, 9H, (CH3)3CCO), 0.89 (s,
9H, (CH3)3CSi), 0.22 (s, 3H, CH3Si), 0.04 (s, 3H, CH3Si);
MS (DCI, NH3) m/z 629 [MþNH4]þ.
´
13. Gordaliza, M.; Castro, M. A.; Miguel del Corral, J. M.; Lopez-
´
´ ´
Vazquez, M. L.; Garcıa, P. A.; San Feliciano, A.; Garcıa-
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Gravalos, M. D.; Broughton, H. B. Tetrahedron 1997, 53,
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4.1.31. Homolactones 7 and 8 from 56. A 25% aqueous
NaOH solution (1.15 mL, 7.2 mL) was added to a solution
of nitrile 56 (105 mg, 0.172 mmol) in 95% ethanol (14 mL).
The reaction mixture was heated at 85 8C for 7 h. Ater
cooling to rt, the mixture was neutralized with 1 N HCl
(7.2 mL) until the bright yellow color disappeared. A small
amount of 1 N HCl (0.5 mL) was added until pH 3–4. After
stirring for 10 min at rt, the mixture was poured into ethyl
acetate (30 mL) and water (10 mL). The aqueous layer was
extracted twice (2£15 mL), and the combined organic layer
was stirred for 15 h. The latter was then washed with brine
(30 mL), dried (MgSO4) and concentrated under reduced
pressure. Flash chromatography (methylene chloride/
MeOH 98:2 then 97:3) led to 7 (36.2 mg, 51%) as a white
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Acknowledgements
This work was financially supported by the Centre National
de la Recherche Scientifique and the Institut Curie. We
thank also the Laboratoires Servier, France, for biological
evaluations.
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