Synthetic application of sequential palladium-catalyzed allylic acetate alkylation and michael addition carbocyclization: Synthesis of (±)-dihydroerythramine

Article abstract of DOI:10.1002/1099-0690(200110)2001:19<3631::AID-EJOC3631>3.0.CO;2-8

A new synthetic route to aromatic Erythrina alkaloids is reported. (Nitromethyl)arene 3 underwent a palladium-catalyzed annulation reaction with allylic acetate 11 to provide nitro esters 12a and 12b by an (η³-allyl)palladium complex alkylation/Michael addition domino sequence. Reduction of the nitro group of 12a, followed by cyclization of the resulting amino group on the acetate appendage, afforded the bicyclic lactam 29. Two-carbon elongation at the nitrogen atom of 29 by hetero Michael addition of vinyl phenyl sulfoxide, followed by Pummerer-type cyclization, gave cis-11-phenylthioerythrinan-8-one (32a, 32b) along with the rearranged lactam 34. Reductive desulfurization at C-11, and oxidative cleavage of the C-3 exocyclic double bond afforded the 15,16-(methylenedioxy)erythrinan-3,8-dione (42). Reduction of the C-3 carbonyl group and methylation of the resulting alcohol afforded hexahydrocrystamidine (44), which was further reduced by aluminum hydride to give (±)-dihydroerythramine (9).

Full text of DOI:10.1002/1099-0690(200110)2001:19<3631::AID-EJOC3631>3.0.CO;2-8

FULL PAPER
Synthetic Application of Sequential Palladium-Catalyzed Allylic Acetate
Alkylation and Michael Addition Carbocyclization:
Synthesis of (؎)-Dihydroerythramine
[a]
[b]
[b]
[a]
´
`
¨
Celine Jousse-Karinthi, Claude Riche, Angele Chiaroni, and Didier Desmaele*
Keywords: Alkaloids / Annulation / Michael additions / Nitrogen heterocycles
A new synthetic route to aromatic Erythrina alkaloids is re- lowed by Pummerer-type cyclization, gave cis-11-phenylthio-
ported. (Nitromethyl)arene 3 underwent a palladium-cata- erythrinan-8-one (32a, 32b) along with the rearranged lac-
lyzed annulation reaction with allylic acetate 11 to provide
nitro esters 12a and 12b by an (η3-allyl)palladium complex
alkylation/Michael addition domino sequence. Reduction of
tam 34. Reductive desulfurization at C-11, and oxidative
cleavage of the C-3 exocyclic double bond afforded the
15,16-(methylenedioxy)erythrinan-3,8-dione (42). Reduction
the nitro group of 12a, followed by cyclization of the resulting of the C-3 carbonyl group and methylation of the resulting
amino group on the acetate appendage, afforded the bicyclic
lactam 29. Two-carbon elongation at the nitrogen atom of 29
alcohol afforded hexahydrocrystamidine (44), which was fur-
ther reduced by aluminum hydride to give (±)-dihydroer-
by hetero Michael addition of vinyl phenyl sulfoxide, fol- ythramine (9).
Introduction
work, which constitutes an ideal testing ground for new
ring-forming methodologies. Following the early pioneering
studies by Belleau,[3] Mondon et al.,[4] and Prelog et al,[5]
numerous synthetic approaches for construction of the Er-
ythrina ring system have been developed[6Ϫ9](Figure 1).
The Erythrina alkaloids are a widely distributed family
of structurally interesting and biologically active natural
products.[1] Aromatic Erythrina alkaloids, exemplified by er-
ythramine (2), have the basic skeleton 1, characteristically
possessing a tetrahydroisoquinoline system (C and D rings)
fused to a perhydroindole subunit (A and B rings), sharing
a common nitrogen atom and a spiro carbon center. Most
Erythrina alkaloids possess curare-like activity, due to nico-
tinic cholinergic receptor-blocking properties. Their phar-
macological application, however, has been impeded by
poor selectivity between the different cholinergic sites, indu-
cing a large array of physiological responses.[2] The consid-
erable synthetic attention received by Erythrina alkaloids is
most probably due to their polycondensed carbon frame-
We recently described an efficient route to the tetracyclic
lactam 8, possessing a full erythrinane carbon frame-
work.[10a] The most notable feature of our strategy was the
elaboration of the C ring from the ABD subunit 5, through
hetero-Michael addition of vinyl phenyl sulfoxide 6, fol-
lowed by Pummerer-type cyclization of the resulting sulfox-
ide 7. Lactam 5, bearing the required angular aryl group,
was obtained from nitro ester 4 by reduction of the nitro
group, followed by five-membered annulation involving nu-
cleophilic attack of the amino group thus formed on the
acetate appendage. Nitro ester 4 had been prepared by a
four-step sequence from (nitromethyl)arene 3 (Scheme 1).
In order to extend this strategy to the synthesis of naturally
occurring Erythrina alkaloids, the introduction of the alkoxy
residue at C-3 needs to be addressed. In this context, we have
recently reported a new annulation reaction involving an (η3-
allyl)palladium complex alkylation/Michael addition dom-
ino sequence, designed to prepare nitro ester 12 from (nitro-
methyl)arene 3 and allylic acetate 11.[11] This sequential reac-
tion opened up a one-step route to an erythrinane AD subu-
nit, in which the future methoxy group at C-3 might easily be
derived from the exocyclic double bond (Scheme 2).
Figure 1. Structure and numbering system of the erythrinane skel-
eton, and structure of erythramine
In this paper we wish to give a full account of the syn-
thesis of the nitro ester 12 by applying this domino carbocy-
clization reaction, and describe the successful conversion of
12 into 15,16-methylenedioxyerythrinan-3,8-dione (10),
from which most Erythrina alkaloids should be derivable.
As an illustration, the pivotal lactam 10 was further con-
verted into (Ϯ)-dihydroerythramine (9).[12]
[a]
´
´
Unite de Chimie Organique Associee au CNRS, Centre
´
d’Etudes Pharmaceutiques, Universite Paris Sud,
´
ˆ
5 rue J.-B. Clement, 92296 Chatenay-Malabry, France
Fax: (internat.) ϩ 33-1/46835752
E-mail: didier.desmaele@cep.u-psud.fr
[b]
Institut de Chimie des Substances Naturelles, CNRS,
Avenue de la Terrasse, 91198 Gif sur Yvette, France
Eur. J. Org. Chem. 2001, 3631Ϫ3640
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/1019Ϫ3631 $ 17.50ϩ.50/0
3631

C. Jousse-Karinthi, C. Riche, A. Chiaroni, D. Desmae¨le
FULL PAPER
with methyl (triphenylphosphoranylidene)acetate, and then
acetylated to provide the desired unsaturated ester 11 as a
4:1 mixture of (E) and (Z) isomers in 74% overall yield from
16 (Scheme 3).
Scheme 1. Synthesis of the 15,16-methylenedioxy-cis-erythrinan-8-
one 8; reagents and conditions: (a) Raney nickel, H2, MeOH, 20
°C, 16 h; (b) toluene, reflux, 2 h (42% from 4); (c) i: NaHMDS,
THF, 0 °C, ii: 6, HMPA, 20 °C, 5 h (58%); (d) i: Ac2O, reflux, 1 h,
ii: SnCl4, CH2Cl2, 15 min, 0 °C (56%); (e) nBu3SnH, AIBN cat.,
toluene reflux, 30 min (75%)
Scheme 3. Synthetic route to the allylic acetate 11; reagents and
conditions: (a) EtO2CCH2CO2Et, EtONa, EtOH, 80 °C, 3 h (71%);
(b) KOH, EtOH, 20 °C, 12 h (93%); (c) formalin 40%, Me2NH,
DMSO, 100 °C, 2 h (70%); (d) Me2NCH(OMe)2, toluene 110 °C,
1 h (87%); (e) DIBAH, CH2Cl2, Ϫ78 °C; 1 h (72%); (f) HCl 2 ,
THF, 20 °C, 6 h; (g) 2 equiv. Ph3PϭCHCO2Me, THF, 20 °C, 24 h
(77% from 16); (h) Ac2O, CH2Cl2, Et3N, DMAP, 20 °C, 30 min
(97%); (i) iPrOCOCl, CH2Cl2, py, 20 °C, 8 h (88%)
(Nitromethyl)arene 3[16] was initially condensed with al-
lylic acetate 11 [(E)/(Z) ϭ 4:1] using the lithium nitronate
20, preformed from 3 by treatment with lithium methoxide
in methanol (Scheme 4).[11] Thus, treatment of 20 with 1.1
equiv. of acetate 11 in THF in the presence of 3 mol-%
of tetrakis(triphenylphosphane)palladium and 6 mol-% of
triphenylphosphane as catalyst provided nitro esters 12a
and 12b as a ca. 2:1 mixture of diastereomers in 56% yield,
along with 10% of tetrahydropyran 21. The last product
presumably arose from deacetylation of acetate 11 by a
small amount of lithium methoxide contaminating the
nitronate 20, followed by intramolecular hetero Michael
type addition of the resulting alkoxide on the unsaturated
ester moiety.[17] If a more hindered base such as lithium
tert-butoxide was used to prepare the lithium nitronate 20,
the tetrahydropyran 21 was no longer detectable; the yield
of nitro esters 12 was found to have decreased slightly, how-
ever. A more satisfactory result was obtained when Cs2CO3
Scheme 2. Retrosynthetic analysis of C-3-functionalized erythrin-
ane, and synthesis of the A-ring synthon 11 from (nitromethyl)ar-
ene 3 by the (η3-allyl)palladium complex alkylation/Michael addi-
tion domino sequence
Results and Discussion
The requisite acetoxy ester 11 was prepared by a variant
on our initial procedure, allowing a more effective synthetic
route on multigram scales.[11] Commercially available
bromo ketal 13 was treated with diethyl malonate in the
presence of sodium ethoxide according to the procedure of
Sakai et al.[13] to afford adduct 14a in 71% yield. Saponi-
fication of both ester groups of compound 14a with potas-
sium hydroxide gave diacid 14b in 93% yield. Upon decarb-
oxylative Mannich reaction using formalin and dimethyl-
amine,[14] diacid 14b provided the unsaturated acid 15a,
which was then treated with N,N-dimethylformamide di-
methyl acetal to give ester 15b in 61% overall yield. Selective
1,2-reduction of the unsaturated ester group in 15b was
achieved using DIBAH.[15] Hydrolysis of the ketal group of
Scheme 4. Condensation of lithium nitronate 20 with allylic acetate
16 afforded the sensitive hemiketal 17, which was treated 11, and relative configuration of nitro ester 12a
3632
Eur. J. Org. Chem. 2001, 3631Ϫ3640

Synthesis of (±)-Dihydroerythramine
FULL PAPER
was used as a base. Thus, condensation of (nitromethyl)ar-
ene 3 with acetate 11 [2 equiv. of Cs2CO3, 3 mol-% of Pd
(PPh3)4, 6 mol-% of PPh3, 8 h in refluxing THF] gave rise
to a 4:1 mixture of nitro esters 12a and 12b in a 79% com-
bined yield. The use of DMF as a solvent gave 12a and 12b
in a similar yield, but with a reduced stereoselectivity (12a/
12b ϭ 2:1). Interestingly, when the reaction was conducted
using pure (Z)-11, the adducts 12a and 12b were obtained
in 80% yield with the same 4:1 ratio of stereoisomers. At-
tempts at using allylic carbonate 19 as the electrophilic part-
ner without additional base[18] afforded only the monoalky-
lated compound 22, in 83% yield. The annulating process
could be restored by addition of lithium tert-butoxide to
the reaction mixture to induce the Michael addition. Never-
theless, since neither the yield nor the selectivity was im-
proved, the former method was preferred.
1
The relative stereochemistry of 12a was assigned by H
NMR, by means of NOE and decoupling experiments. The
coupling constants between 1-H (δ ϭ 2.98) and the two
vicinal 6-H protons (δ ϭ 1.55 and 1.85) were obtained after
having simplified the signals by irradiation of the methylene
group of the acetate appendage. These values [J(1-H/6ax-
H) ϭ 10.0 Hz and J(1-H/6eq-H) ϭ 3.7 Hz] are in agreement
with an axial orientation for 1-H. Furthermore, the syn ar-
rangement of the aromatic nucleus respective to the 1-H
proton was deduced from an 8% enhancement of the aro-
matic proton signal when 1-H was irradiated.
Since the stereochemistry of the nitro esters 12 is set in
the Michael addition step, a possible equilibration of the
adducts was suspected. However, when pure nitro esters 12a
and 12b were subjected to the same reaction conditions, no
isomerization was detected, indicating that the products
probably arose from kinetic control in the Michael addition
step (Scheme 5). We believe that the preferential formation
of nitro ester 12a results from an approach in which both
the nitronate and the unsaturated ester appendage were che-
lated by the cesium cation.[19] Indeed, when the nitro ester
22 was cyclized by using a base with a nonchelating coun-
terion such as nBu4NF, an equimolar mixture of the two
diastereomers 12a and 12b was obtained in 79% yield, dem-
Scheme 5. Oxidative cleavage of the C-3 methylene group and cyc-
lization of the B ring, and X-ray crystal structure of lactam 27a;
reagents and conditions: (a) OsO4 cat., NaIO4, THF, tBuOH, H2O,
20 °C, 2 h; (b) (TMSOCH2)2, TMSOTf, CH2Cl2, 0 °C (58% overall
from 12a)
onstrating the lack of stereochemical preference when no competitive hydrogenolysis.[22] Raney nickel reduction of
chelating cation is present in the reaction medium 25, which had successfully been used to reduce the model
(Scheme 4).
compound 4,[10a] unexpectedly gave lactam 27a in only 15%
With the advanced AD subunit 12a in hand, formation yield, the major product being the ‘‘denitrated’’ ester 26.
of ring B was next investigated. Since the reduction of the Upon attempted catalytic hydrogenation using Rh/C or
nitro group might be thwarted by competitive reduction of PtO2, the nitro ester 25 was recovered unchanged, whereas
the exocyclic double bond at C-3, we decided to perform Pd/C gave only hydrogenolysis product 26. Conventional
its oxidative cleavage first. To this end, Lemieux-Johnson nickel boride[23] or aluminum amalgam[24] afforded complex
oxidation[20] of 12a gave ketone 23. However, attempts to mixtures. Treatment of nitro ester 25 with Zn/NH4Cl[25]pro-
purify this compound by chromatography on silica gel pro- vided hydroxamic acid 27b, albeit with a low mass balance.
moted β-elimination of nitrous acid, resulting in enone 24. Since the spectroscopic data of the latter compound were
In view of the sensitivity of 23 to acid, the protection of the very close to those of lactam 27a, the structural assignment
ketone function was carried out using Noyori’s method.[21] of 27a was confirmed by X-ray diffraction analysis, unam-
Thus, treatment of crude 23 with bis(trimethylsilyloxy)e- biguously establishing the presence of the lactam function,
thane in the presence of TMSOTf provided ketal 25 in 58% and corroborating the cis AB-ring junction (Scheme 5).[26]
overall yield from 12a.
In response to these obstacles, the oxidative cleavage of
The reduction of the nitro group turned out to be much the double bond was postponed until the elaboration of the
more difficult than expected, due to steric hindrance and tetracyclic system. Thus, treatment of nitro ester 12a with
Eur. J. Org. Chem. 2001, 3631Ϫ3640
3633

C. Jousse-Karinthi, C. Riche, A. Chiaroni, D. Desmae¨le
FULL PAPER
zinc dust and ammonium chloride in refluxing methanol method provided a 1:2 mixture of thioethers 32a and
provided hydroxamic acid 28, along with a small amount 32b in a 54% combined yield, along with the ‘‘rearranged’’
of lactam 29. This crude mixture was reduced further with lactam 34 (14%).
[27]
a buffered solution of TiCl3
to give lactam 29 in 55%
The β-stereochemical orientation of the phenylthio group
1
overall yield. It is worthy of note that lactam ring-closure in 32b was inferred from H NMR spectroscopy. The me-
is spontaneous in this case, in contrast with our previous thine hydrogen atom at C-11 (δ ϭ 4.16) occurs as a doublet,
findings using the model compound 5,[10] and did not re- with a coupling constant only with the vicinal 10-Hα [J(11-
quire any thermal activation.
H/10α-H) ϭ 3.5 Hz, J(11-H/10β-H) ϭ 0 Hz]. These data are
The two-carbon elongation at the nitrogen atom of lac- consistent with a β configuration for the phenylthio group,
tam 29 was next investigated. We were pleased to find that pseudoaxially disposed on a half-chair (Scheme 7). In con-
addition of phenyl vinyl sulfoxide (6) to the sodium anion trast, the 11-H proton (δ ϭ 4.34) in the 32a isomer exhibits
of lactam 29 (NaHMDS, THF, Ϫ78 °C) provided the de- two large coupling constants (J ϭ 10.7 and 7.4 Hz) with
sired Michael adduct 30 in 85% yield. The crucial cycliza- the vicinal 10α-H (δ ϭ 3.15) and 10β-H (δ ϭ 4.77) pro-
tion of the C ring of the erythrinane core was then checked. tons, respectively.
Although previous investigations[10a][10b] had set precedents
for the Pummerer cyclization of sulfoxides of type 30, the
ease of this transformation was by no means certain, since
the double bond might compete with the aromatic ring for
attack at the sulfenium site. Supporting evidence for this
assumption was quickly obtained, since sequential treat-
ment of 30 with acetic anhydride and SnCl4 inflicted extens-
ive damage on the molecule. On the other hand, treatment
of sulfoxide 30 with trifluoroacetic anhydride (TFAA)
(CH2Cl2, Ϫ78 to 20 °C) produced a mixture of thioethers
32a (21%) and 32b (10%), olefin 33 (29%), and uncyclized
thioether 31 (25%)[28] (Scheme 6).
Scheme 7. Pummerer reaction of sulfoxide 30; reagents and condi-
tions: (a) TMSOTf, iPr2NEt, CH2Cl2; (b) nBu4NF, THF
The structure of compound 34 eluded us for quite some
time. Examination of the NMR and IR spectra revealed
1
that 34 is an isomer of lactam 32. The H NMR spectrum
shows a monosubstituted methylenedioxyphenyl group, a
phenylthio ether group, and a sharp doublet (at δ ϭ 6.23,
J ϭ 1.4 Hz) corresponding to an isolated olefinic proton.
The structure was eventually solved with the use of HMQC
and HMBC experiments, allowing complete assignment of
the CϪC and CϪH connectivities. These data clearly indic-
ate that the methine atom bearing the phenylthio group is
flanked by two methylene groups. From this information,
we were able to attribute the hitherto unknown 5-azatricy-
clo[6.2.2.01,5]dodecane ring system to lactam 34 (Scheme 7).
Formation of the lactam 34 could be tentatively ex-
plained by invoking the mechanism depicted in Scheme 8.
Initial reaction of the sulfoxide group of 30 with TMSOTf
gave thionium ion 36. Intramolecular attack by the lactam
oxygen atom on the cationic center of 36 should provide
dihydroazolium ion 37,[30] which undergoes an easy β elim-
Scheme 6. Elaboration of ring B of nitro ester 12a and attempts at
forming the C ring through Pummerer-type reaction; reagents and
conditions: (a) Zn, NH4Cl, MeOH, reflux, 4 h; (b) 17% aq. TiCl3,
AcONa, 20 °C, 3 h; (c) i: NaHMDS, THF, 0 °C, 15 min, ii: H2Cϭ
CHSOPh (6), Ϫ 78 °C to 20 °C, 12 h
ination, giving rise to the diene 38. Further reaction of the
oxazoline moiety with TMSOTf induces ring fragmenta-
tion, with the formation of the sulfenium ion 39. Attack on
this species by the exocyclic double bond then affords the
A more satisfactory result was obtained by treatment of stabilized cation 40, which finally cyclizes to the tricyclic
sulfoxide 30 with TMSOTf in the presence of iPr2NEt.[29] lactam 34 (Scheme 8).
Since a substantial amount of the C-silylated lactam 35 was
Upon treatment with tri-n-butyltin hydride and 2,2Ј-azo-
formed during the Pummerer cyclization, the crude product bis(isobutyronitrile) in refluxing toluene, the above mixture
was directly subjected to desilylation with nBu4NF. This of lactams 32a and 32b was smoothly converted into the
3634
Eur. J. Org. Chem. 2001, 3631Ϫ3640

Synthesis of (±)-Dihydroerythramine
FULL PAPER
[33]
reduction of the carbonyl group of 44 with AlH3
gave
(Ϯ)-dihydroerythramine (9)[12] in 78% yield (Scheme 9).
Conclusion
In summary, (Ϯ)-dihydroerythramine (9) has been syn-
thesized from (nitromethyl)arene 3 by a linear sequence of
10 chemical operations, with an overall yield of 4.9%. A
sequential palladium-catalyzed annulation reaction was
used to assemble the AD subunit 12a rapidly. Completion
of the construction of the erythrinane skeleton was
achieved by elaboration of the C ring through Pummerer-
type cyclization, followed by introduction of the methoxy
group at C-3. This tandem intermolecular alkylation/intra-
molecular Michael addition is particularly attractive, as two
carbonϪcarbon bonds and two stereocenters are formed in
a single step. Further applications of this method are cur-
rently under investigation in our laboratory.
Experimental Section
General: Melting points: Büchi capillary tube melting point appar-
atus, values uncorrected. Ϫ IR spectra: PerkinϪElmer 841 spectro-
meter; neat films between NaCl plates or KBr pellets. Only signific-
Scheme 8. Hypothetical mechanism for the formation of tricyclic
1
ant absorptions are listed. Ϫ The H and 13C NMR spectra were
lactam 34
recorded with Bruker AC 200 P (200 MHz and 50 MHz, for 1H and
13C, respectively) or Bruker ARX 400 (400 MHz and 100 MHz,
for 1H and 13C, respectively) spectrometers. Recognition of methyl,
methylene, methine, and quaternary carbon nuclei in the 13C NMR
spectra is based on the J-modulated spin-echo sequence. Ϫ Mass
spectra were recorded with a Hewlett Packard G 1019 A (70 eV).
Ϫ Analytical thin layer chromatography was performed on Merck
60F254 silica gel precoated glass plates (0.25 mm layer). Ϫ Column
chromatography was performed on Merck 60 silica gel (230Ϫ400
mesh ASTM). Ϫ Ether and tetrahydrofuran (THF) were distilled
from sodium/benzophenone ketyl. Methanol and ethanol were
dried with magnesium and distilled. Benzene, toluene, DMF, and
desired 3-methyleneerythrinan-8-one (41) in 75% yield.
Having completed the elaboration of the erythrinane sys-
tem, our attention turned to functionalization of the A ring.
To this end, oxidative cleavage of the exocyclic double bond
was first undertaken. In the event, LemieuxϪJohnson ox-
idation[20] of 41 gave ketone 42 in 62% yield. Luche reduc-
tion of the carbonyl group at C-3 according to the proced-
ure of Tsuda et al.[31] afforded a 3:1 mixture of epimeric
alcohols 43a and 43b in 90% yield. After chromatographic
separation, methylation of the hydroxy group of 43a pro- CH2Cl2 were distilled from calcium hydride under nitrogen. Ϫ All
vided hexahydrocrytamidine (44)[32] in 95% yield. Finally,
reactions involving air- or water-sensitive compounds were rou-
tinely conducted in glassware that had been flame-dried under pos-
itive nitrogen pressure. Ϫ Organic layers were dried with anhydrous
MgSO4. Ϫ The boiling points refer to oil-bath temperatures. Ϫ
Chemicals obtained from commercial suppliers were used without
further purification. Ϫ Elemental analyses were performed by the
ˆ
Service de microanalyse, Centre d’Etudes Pharmaceutiques, Chat-
enay-Malabry, France, with a PerkinϪElmer 2400 analyzer.
2-[2-(1,3-Dioxolan-2-yl)ethyl]propanedioic Acid (14b): Diester
14a[13] (24.0 g, 92.2 mmol) in 95% ethanol (50 mL) was added to a
solution of KOH (15.0 g, 0.268 mol) in 95% ethanol (200 mL). The
reaction mixture was stirred at 20 °C for 12 h and concentrated
under reduced pressure. The viscous residue was cooled to 0 °C
and acidified to pH ϭ 3 with 6  hydrochloric acid. The mixture
was then concentrated to dryness under vacuum while keeping the
temperature below 30 °C. The residue was taken into methanol and
filtered. The solid was thoroughly washed with methanol, and the
filtrate was concentrated to give 17.5 g of diacid 14b (93%); color-
Scheme 9. Functionalization of the A ring; reagents and condi-
tions: (a) nBu3SnH, AIBN, refluxing toluene 2 h (75%); (b) OsO4,
NaIO4, THF, H2O, MeOH (62%); (c) NaBH4, CeCl3, MeOH
(90%); (d) NaH, nBu4NHSO4, MeI, THF (95%); (e) AlH3, THF,
Et2O, 2 h, 20 °C (78%)
˜
less crystals, m.p. 94Ϫ96 °C (MeOH). Ϫ IR (neat): ν ϭ 3200Ϫ2550
cmϪ1 (OH), 1697 (CϭO), 1400, 1251. Ϫ 1H NMR ([D6]acetone,
200 MHz): δ ϭ 1.63Ϫ1.85 [m, 2 H, H2CCH(OCH2)2], 1.90Ϫ2.10
[m, 2 H, H2CCH2CH(OCH2)2], 3.44 (t, J ϭ 7.4 Hz, 1 H, HO2CCH-
Eur. J. Org. Chem. 2001, 3631Ϫ3640
3635

C. Jousse-Karinthi, C. Riche, A. Chiaroni, D. Desmae¨le
FULL PAPER
CO2H), 3.75Ϫ3.95 (m, 4 H, OCH2CH2O), 4.83 [t, J ϭ 4.5 Hz, 1 Methyl (Z)- and (E)-6-(Hydroxymethyl)hepta-2,6-dienoate (18):
H, CH(OCH2)2], 5.20Ϫ6.10 (broad, 2 H, OH). Ϫ 13C NMR ([D6]- Aqueous HCl (2 , 30 mL, 60 mmol) was added to a solution of
acetone, 50 MHz):
[H2CCH(OCH2)2], 51.7 (HO2CCHCO2H), 65.5 (2 CH2, OCH2-
CH2O), 104.5 [CH(OCH2)2], 171.2 (2 CO). Ϫ C8H12O6 (204.2): solid NaHCO3. Evaporation of the THF afforded a residue that
δ
ϭ
24.0 [H2CCH2CH(OCH2)2], 32.1 alcohol 16 (4.3 g, 27.2 mmol) in THF (60 mL). After the mixture
had been stirred for 5 h at 20 °C, the pH was brought to 10 with
calcd. C 47.06, H 5.92; found C 47.11, H 5.87.
was extracted thoroughly with CH2Cl2. The organic layers were
dried and concentrated under reduced pressure to leave hemiketal
17 as a pale yellow oil. The crude hemiketal was taken into CH2Cl2
(50 mL) and methyl (triphenylphosphoranylidene)acetate (17.0 g,
50.9 mmol) was added portionwise. The reaction mixture was
stirred at 20 °C for 16 h. The solvent was removed under reduced
pressure and the residue was taken into a mixture of ether/pentane
(1:1, 100 mL) and filtered. The filtrate was concentrated in vacuo
to leave a colorless oil. Chromatographic separation on silica gel
(cyclohexane/ethyl acetate, 4:1) first afforded 0.70 g of unsaturated
2-[2-(1,3-Dioxolan-2-yl)ethyl]propenoic Acid (15a): Aqueous form-
aldehyde (37%, 21 mL, 280 mmol), aqueous dimethylamine (40%,
8.5 mL, 68 mmol), and a drop of piperidine were added to a solu-
tion of diacid 14b (14.0 g, 68.6 mmol) in DMSO (150 mL). The
reaction mixture was heated at 100 °C for 2 h. After cooling to 0
°C, the solution was acidified to pH ϭ 3 with 1  hydrochloric
acid. The mixture was extracted with ether, dried, and concentrated
under reduced pressure. Chromatography on silica gel (hexane/ethyl
acetate, 4:1) gave 8.2 g of acid 15a (70%); colorless crystals, m.p.
56Ϫ58 °C (MeOH). Ϫ IR (neat): ν˜ ϭ 3720Ϫ2400 cmϪ1 (OH), 1676
(CO), 1628 (CϭC), 1442, 1415. Ϫ 1H NMR (CDCl3, 200 MHz):
δ ϭ 1.81Ϫ1.95 [m, 2 H, H2CCH(OCH2)2], 2.45 [t, J ϭ 8.5 Hz, 2
H, H2CCH2CH(OCH2)2], 3.78Ϫ4.02 (m, 4 H, OCH2CH2O) 4.91
[t, J ϭ 4.8 Hz, 1 H CH(OCH2)2], 5.70 (s, 1 H, HCϭC), 6.30 (s, 1
H, HCϭC). Ϫ 13C NMR ([D6]acetone, 50 MHz): δ ϭ 27.0
[H2CCH(OCH2)2], 33.4 [H2CCH2CH(OCH2)2], 65.4 (2 CH2,
OCH2CH2O), 104.4 [CH(OCH2)2], 125.6 (H2CϭC), 141.3 (H2Cϭ
C), 168.9 (CO). Ϫ C8H12O4 (172.1): calcd. C 55.81, H 7.02; found
C 55.62, H 6.93.
1
ester (Z)-18 (15%), Rf ϭ 0.57; colorless oil. Ϫ H NMR (CDCl3,
200 MHz): δ ϭ 1.79 (m, 1 H, OH), 2.24 (t, J ϭ 7.6 Hz, 2 H,
H2CCH2CHϭCHCO2Me), 2.75Ϫ2.90 (m,
2
H, H2CCHϭ
CHCO2Me), 3.71 (s, 3 H, OCH3), 4.10 (s, 2 H, HOCH2), 4.89 (s,
1 H, H2CϭC), 5.07 (s, 1 H, H2CϭC), 5.80 (dt, J ϭ 12.1, 0.4 Hz,
1 H, HCϭCHCO2CH3), 6.25 (td, J ϭ 12.1, 6.7 Hz, 1 H, HCϭ
CHCO2CH3). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 27.1 (CH2),
32.1 (CH2), 51.1 (OCH3), 65.8 (HOCH2), 110.4 (H2CϭC), 119.8
(HCϭCHCO2CH3), 147.7 (H2CϭC), 149.7 (HCϭCHCO2CH3),
166.9 (CO). Ϫ Further elution gave 2.86 g of (E)-18 (62%), Rf ϭ
Ϫ1
˜
0.48; colorless oil. Ϫ IR (neat): ν ϭ 3590Ϫ3160 cm (OH), 1720
(CϭO), 1655 (CϭC), 1436, 1272, 1200. Ϫ 1H NMR (CDCl3,
Methyl 2-[2-(1,3-Dioxolan-2-yl)ethyl]propenoate (15b): N,N-Di-
methylformamide dimethylacetal (8.3 g, 69.6 mmol) was added to
a solution of acid 15a (8.0 g, 46.5 mmol) in toluene (100 mL). After
stirring for 1 h at reflux, the mixture was concentrated under re-
duced pressure. Chromatographic purification on silica gel (hexane/
ethyl acetate/Et3N, 4:1:0.002) gave 7.5 g of ester 15b (87%); color-
200 MHz):
δ ϭ 2.24 (t, J ϭ 7.6 Hz, 2 H, H2CCH2CHϭ
CHCO2Me), 2.30Ϫ2.40 (m, 2 H, H2CCHϭCHCO2Me), 3.33 (m, 1
H, OH), 3.69 (s, 3 H, OCH3), 4.04 (s, 2 H, HOCH2), 4.86 (s, 1 H,
H2CϭC), 5.05 (s, 1 H, H2CϭC), 5.71 (dt, J ϭ 16.8, 0.4 Hz, 1 H,
HCϭCHCO2CH3), 6.84 (td, J ϭ 16.8, 5.7 Hz, 1 H, HCϭ
CHCO2CH3). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 29.9 (CH2),
30.7 (CH2), 51.3 (OCH3), 65.3 (HOCH2), 109.8 (H2CϭC), 120.9
(HCϭCHCO2CH3), 147.1 (C, H2CϭC), 148.5 (HCϭCHCO2CH3),
166.9 (CO).
less oil. Ϫ IR (neat): ν ϭ 1725 cmϪ1 (CO), 1633 (CϭC), 1440, 1411,
˜
1311. Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ 1.70Ϫ1.82 [m, 2 H,
H2CCH(OCH2)2], 2.38 [t, J ϭ 8.5 Hz, 2 H, H2CCH2CH(OCH2)2],
3.68 (s, 3 H, OCH3), 3.70Ϫ3.93 (m, 4 H, OCH2CH2O), 4.81 [t, J ϭ
4.8 Hz, 1 H, CH(OCH2)2], 5.45 (s, 1 H, H2CϭC), 6.08 (s, 1 H,
Methyl (E)-6-Acetoxymethylhepta-2,6-dienoate (11): A solution of
alcohol (E)-18 (1.50 g, 8.8 mmol) in CH2Cl2 (20 mL) was cooled to
0 °C. Triethylamine (1.8 g, 17.8 mmol), DMAP (20 mg), and acetic
anhydride (1.35 g, 13.2 mmol) were added sequentially. After this
had stirred for 1 h at 20 °C, 1  HCl was added. The organic layer
was separated and the aqueous phase extracted with CH2Cl2. After
drying, the combined organic layers were concentrated. The crude
product was purified by silica gel chromatography (cyclohexane/
ethyl acetate, 4:1) to give 1.81 g of acetate (E)-11 (97%); colorless
oil, b.p. 60Ϫ65 °C/0.5 mm. Ϫ IR (neat): ν˜ ϭ 1745 cmϪ1 (CϭO),
1731 (CϭO), 1657 (CϭC), 1440, 1376. Ϫ 1H NMR (CDCl3,
200 MHz): δ ϭ 2.00 (s, 3 H, CH3CO), 2.14 (t, J ϭ 7.6 Hz, 2 H,
H2CϭC).
Ϫ
13C NMR (CDCl3, 50 MHz):
δ
ϭ
26.2
[H2CCH2CH(OCH2)2], 32.3 [H2CCH(OCH2)2], 51.6 (OCH3), 64.7
(2 CH2, OCH2CH2O), 103.6 [CH(OCH2)2], 124.7 (H2CϭC), 139.8
(H2CϭC), 167.2 (CO). Ϫ C9H14O4 (186.2): calcd. C 58.05, H 7.58;
found C 57.90, H 7.55.
2-[2-(1,3-Dioxolan-2-yl)ethyl]prop-2-en-1-ol (16): A toluene solution
of DIBAH (1 , 8.4 mL, 84 mmol) was added dropwise to a cold
solution (Ϫ78 °C) of ester 15b (7.5 g, 40.2 mmol) in THF (70 mL).
The mixture was stirred for 1 h at Ϫ78 °C, and 5 mL of ethyl acet-
ate was then carefully added. The clear solution was poured into
an aqueous solution of potassium sodium tartrate (100 mL) and
the resulting mixture was stirred for 12 h at 20 °C. The organic
layer was separated and the aqueous phase was extracted with
ether. The combined organic phases were dried and concentrated
under reduced pressure. Chromatography on silica gel (cyclohex-
ane/ethyl acetate/Et3N, 4:1:0.002) provided alcohol 16 (4.6 g, 72%);
H2CCH2CHϭCHCO2Me), 2.30Ϫ2.35 (m,
2
H, H2CCHϭ
CHCO2Me), 3.63 (s, 3 H, OCH3), 4.43 (s, 2 H, AcOCH2), 4.88 (s,
1 H, H2CϭC), 5.00 (s, 1 H, H2CϭC), 5.77 (dt, J ϭ 15.4, 2.8 Hz,
1 H, HCϭCHCO2CH3), 6.88 (td, J ϭ 15.4, 6.5 Hz, 1 H, HCϭ
CHCO2CH3). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 20.8 (CH3CO2),
30.0 (CH2CHϭCHCO2Me), 31.3 (CH2CH2CHϭCHCO2Me), 51.2
(OCH3), 65.2 (AcOCH2), 113.3 (H2CϭC), 121.4 (HCϭ
CHCO2CH3), 142.3 (C, H2CϭC), 147.9 (HCϭCHCO2CH3), 166.7
(CO2CH3), 170.4 (CH3COO). Ϫ C11H16O4 (212.2): calcd. C 62.25,
H 7.60; found C 62.19, H 7.64.
˜
Ϫ IR (neat): ν ϭ
colorless oil b.p. 79Ϫ80 °C/0.5 Torr.
3680Ϫ3150 cmϪ1 (OH), 1657 (CϭC), 1446, 1412, 1139. Ϫ 1H
NMR (CDCl3, 200 MHz): 1.68Ϫ1.78 [m, 2H,
δ
ϭ
H2CCH(OCH2)2], 2.09 [t, J ϭ 7.3 Hz, 2 H, H2CCH2CH(OCH2)2],
2.80 (m, 1 H, OH), 3.71Ϫ4.00 (m, 4 H, OCH2CH2O), 3.95 (s, 2 H,
HOCH2), 4.78 [m, 2 H, H2CϭC and CH(OCH2)2], 4.94 (s, 1 H,
H2CϭC).
Ϫ
13C NMR (CDCl3, 50 MHz):
δ
ϭ
26.5 Methyl cis- and trans-[2-(1,3-Benzodioxol-5-yl)-4-methylene-2-nitro-
[H2CCH2CH(OCH2)2], 31.5 [HH2CCH(OCH2)2], 64.3 (2 CH2, cyclohexyl]acetate (12a and 12b): Cesium carbonate (1.8 g,
OCH2CH2O), 64.8 (HOCH2), 103.6 [CH(OCH2)2], 108.6 (H2Cϭ
C), 147.8 (H2CϭC).
5.5 mmol) was added to a solution of (nitromethyl)arene 3 (500 mg,
2.76 mmol), allylic acetate 11 [4:1 (E)/(Z) mixture, 670 mg,
3636
Eur. J. Org. Chem. 2001, 3631Ϫ3640

Synthesis of (±)-Dihydroerythramine
FULL PAPER
3.15 mmol], triphenylphosphane (52 mg, 0.2 mmol), and tetrakis- silica gel chromatography (cyclohexane/ethyl acetate/Et3N,
(triphenylphosphane)palladium (120 mg, 0.10 mmol) in THF 2:1:0.005) to give 672 mg of acetal 25 (59% from nitro ester 12a);
˜
(15 mL). The mixture was carefully degassed by means of two
freeze-pump-thaw cycles and stirred at 50 °C for 8 h. Aqueous ox-
alic acid was then added, and the mixture was extracted with ether.
The combined organic phases were dried and concentrated under
colorless crystals, m.p. 144Ϫ146 °C (MeOH). Ϫ IR (neat): ν ϭ
1723 cmϪ1 (CO), 1542 (NO2), 1492, 1439, 1246, 1038, and 928
1
(OCH2O). Ϫ H NMR (CDCl3, 200 MHz): δ ϭ 1.74Ϫ2.00 (m, 4
H, 5-H, 6-H), 2.32 (d, J ϭ 13.9 Hz, 1 H, 3-H), 2.35 (dd, J ϭ 17.0,
reduced pressure. Chromatography on silica gel (cyclohexane/ethyl 1.3 Hz, 1 H, H2CCO2Me), 2.53 (m, 1 H, HCCH2CO2Me), 2.81 (dd,
acetate, 4:1) afforded adducts 12a (582 mg, 63%, Rf ϭ 0.42) and J ϭ 17.0, 8.9 Hz, 1 H, H2CCO2Me), 2.98 (d, J ϭ 13.9 Hz, 1 H, 3-
12b (145 mg, 16%, Rf ϭ 0.36).
H), 3.59 (s, 3 H, OCH3), 3.79Ϫ4.00 (m, 4 H, OCH2CH2O), 5.97 (s,
2 H, OCH2O), 6.55Ϫ6.65 (m, 2 H, 4Ј-H, 7Ј-H), 6.75 (d, J ϭ 7.8 Hz,
1 H, 6Ј-H). Ϫ 13C NMR (CDCl3, 50 MHz) δ ϭ 25.5 (CH2, C-6),
34.5 (CH2, C-5), 34.9 (CH2CO2Me), 42.5 (CHCH2CO2Me), 43.2
(CH2, C-3), 51.5 (OCH3), 64.2 (OCH2CH2O), 64.3 (OCH2CH2O),
97.2 (ArCNO2), 101.5 (OCH2O), 105.9 (CH, C-4Ј), 106.8
[C(OCH2)2], 108.1 (CH, C-7Ј), 118.7 (CH, C-6Ј), 132.2 (C, C-5Ј),
147.4 (C, C-3Јa or C-7Јa), 148.1 (C, C-3Јa or C-7Јa), 173.0 (CO).
Ϫ C18H21NO8 (379.3): calcd. C 56.99, H 5.58, N 3.69; found C
56.92, H 5.55, N 3.62.
Compound 12a: Colorless crystals, m.p. 85Ϫ86 °C (MeOH). Ϫ IR
(neat): ν ϭ 1725 (CO) cmϪ1, 1658 (CϭC), 1539 (NO2), 1493, 1439,
˜
1250, 1034, and 927 (OCH2O). Ϫ 1H NMR (CDCl3, 400 MHz):
δ ϭ 1.55 (m, 1 H, 6-Hax), 1.85 (ddt, J ϭ 13.7, 4.9, 3.7 Hz, H 6-
Heq), 2.20 (m, 1 H, 5-Hax), 2.34 (dt, J ϭ 14.2, 4.9 Hz, 1 H, 5-Heq),
2.48 (dd, J ϭ 17.0, 2.3 Hz, 1 H, H2CCO2Me), 2.66 (dd J ϭ 17.0,
10.0 Hz, 1 H, H2CCO2Me), 2.85 (d, J ϭ 14.5 Hz, 1 H, 3-Hax), 2.98
(dddd, J ϭ 10.0, 9.8, 3.7, 2.3 Hz, HCCH2CO2Me), 3.19 (d, J ϭ
14.2 Hz, 1 H, 3-Heq), 3.65 (s, 3 H, OCH3), 4.83 (d, J ϭ 2.0 Hz, 1
H, H2CϭC), 4.86 (d, J ϭ 2.0 Hz, 1 H, H2CϭC), 5.97 (s, 2 H,
OCH2O), 6.70Ϫ6.79 (m, 3 H, 4Ј-H, 6Ј-H, 7Ј-H). Ϫ 13C NMR
(CDCl3, 50 MHz): δ ϭ 28.5 (CH2, C-6), 32.1(CH2, C-5), 34.9
(CH2CO2Me), 41.2 (CHCH2CO2Me), 44.7 (CH2, C-3), 51.6
(OCH3), 98.2 (ArCNO2), 101.5 (OCH2O), 106.0 (CH, C-4Ј), 108.2
(CH, C-7Ј), 112.0 (H2CϭC), 119.1 (CH, C-6Ј), 131.7 (C, C-5Ј),
141.7 (H2CϭC), 147.6 (C, C-3Јa or C-7Јa), 148.2 (C, C-3Јa or C-
7Јa), 172.9 (CO). Ϫ C17H19NO6 (333.3): calcd. C 61.25, H 5.75, N
4.20; found C 61.17, H 5.82, N 4.09.
cis-7a-(1,3-Benzodioxol-5-yl)-6-(1,3-dioxolan-2-yl)-3a,4,5,6,7,7a-
hexahydro-2-indolinone (27a): A solution of nitro ester 25 (443 mg,
1.16 mmol) in ethyl acetate (5 mL) was added to a suspension of
Raney nickel (ca. 2 g) in methanol (20 mL). The mixture was sub-
jected to hydrogenation at 6 bars for 16 h. The reaction mixture
was filtered through Celite, and concentrated in vacuo. The crude
oil was taken up into toluene (20 mL), and the resulting solution
was heated at reflux for 2 h. After concentration under reduced
pressure, chromatographic purification on silica gel (ethyl acetate)
afforded 140 mg of ester 26 as a colorless oil (40%), and further
elution (ethyl acetate/MeOH, 98:2) provided lactam 27a (66 mg,
Compound 12b: Colorless crystals, m.p. 111Ϫ112 °C (MeOH). Ϫ
Ϫ1
IR (KBr): ν ϭ 1730 (CO) cmϪ1, 1657 (CϭC), 1536 (NO2), 1505,
˜
15%) as colorless crystals. Ϫ IR (neat): ν ϭ 3280 cm (NH), 1693
˜
(CϭO), 1487, 1494, 1436, 1240, 1031, and 923 (OCH2O). Ϫ 1H
NMR ([D6]DMSO, 400 MHz): δ ϭ 1.45Ϫ1.57 (m, 1 H, 4-Hax),
1.58 (d, J ϭ 15.7 Hz, 3-H), 1.61Ϫ1.63 (m, 1 H, 5-H), 1.70Ϫ1.80
(m, 2 H, 4-Heq, 5-Heq), 1.79 (d, J ϭ 14.7 Hz, 1 H, 7-Heq), 1.90 (dd,
J ϭ 14.7 Hz, 1 H, 7-Hax), 1.96 (dd, J ϭ 15.7, 5.9 Hz, 1 H, 3-H),
2.42 (m, 1 H, 3a-H), 3.77 (m, 2 H, OCH2CH2O), 3.88 (m, 2 H,
OCH2CH2O), 5.98 (s, 2 H, OCH2O), 6.82 (d, J ϭ 8.1 Hz, 1 H, 7Ј-
H), 6.87 (dd, J ϭ 8.1, 1.4 Hz, 1 H, 6Ј-H), 7.04 (d, J ϭ 1.4 Hz, 1
H, 4Ј-H), 8.12 (s, 1 H, NH). Ϫ 13C NMR ([D6]DMSO, 50 MHz):
δ ϭ 26.8 (CH2, C-4), 31.9 (CH2, C-5), 37.4 (CH2CONH), 39.0
(CHCH2CONH), 43.3 (CH2, C-7), 63.1 (OCH2CH2O), 63.9 (OCH2-
CH2O), 64.8 (ArCNHCO), 101.1 (OCH2O), 106.5 (CH, C-4Ј),
107.1 [C(OCH2)2], 107.6 (CH, C-7Ј), 118.4 (CH, C-6Ј), 141.6 (C,
C-5Ј), 145.4 (C, C-7Јa), 147.4 (C, C-3Јa), 175.0 (CO). Ϫ MS (CI,
CH4): m/z (relative intensity): 318 (100) [M·ϩϩ1], 300 (9), 255 (14),
216 (15), 99 (21).
1493, 1439, 1039, and 934 (OCH2O). Ϫ 1H NMR (CDCl3,
400 MHz): δ ϭ 1.66Ϫ1.85 (m. 2 H, 6-H), 2.03 (dd, J ϭ 15.7,
3.0 Hz, 1 H, H2CCO2Me), 2.15Ϫ2.25 (m, 2 H, 5-H), 2.32 (dd, J ϭ
15.7, 11.2 Hz, 1 H, H2CCO2Me), 2.67 (d, J ϭ 14.2 Hz, 1 H, 3-Hax),
3.52 (dd, J ϭ 14.2, 1.7 Hz, 1 H, 3-Heq), 3.63 (s, 3 H, OCH3), 3.65
(m, 1 H, HCCH2CO2Me), 4.88 (br. s, 2 H, H2CϭC), 5.98 (s, 2 H,
OCH2O), 6.78 (d, J ϭ 8.6 Hz, 1 H, 7Ј-H), 6.98 (m, 2 H, 2Ј-H, 6Ј-
H). Ϫ 13C NMR (CDCl3, 100 MHz): δ ϭ 27.2 (CH2, C-6), 28.1
(CH2, C-5), 33.8 (CH2CO2Me), 37.4 (CHCH2CO2Me), 37.7 (CH2,
C-3), 51.9 (OCH3), 96.5 (ArCNO2), 101.6 (OCH2O), 106.1 (CH,
C-4Ј), 108.4 (CH, C-7Ј), 113.4 (H2CϭC), 119.2 (CH, C-6Ј), 131.5
(C, C-5Ј), 141.5 (H2CϭC), 148.5 (2 C, C-3Јa and C-7Јa), 172.0
(CO). Ϫ C17H19NO6 (333.3): calcd. C 61.25, H 5.75, N 4.20; found
C 61.17, H 5.86, N 4.21.
Methyl cis-2-[(1,3-Benzodioxol-5-yl)-4-(1,3-dioxolan-2-yl)-2-nitro-
cyclohexyl]acetate (25): A solution of OsO4 in tert-butyl alcohol
(2.5 g/L, 30 mL, 0.3 mmol) and sodium metaperiodate (3.20 g,
15 mmol) were added to a solution of nitro ester 12a (1.0 g,
3.0 mmol) in THF (80 mL) and water (20 mL). After this had
stirred at room temperature for 2 h, brine was added and the mix-
ture was extracted with ethyl acetate. The organic layer was dried
and concentrated to leave 690 mg (69%) of ketone 23 as a pale
yellow oil. Crude 23 (690 mg, 2.54 mmol) was taken into anhydrous
Crystal Data for Lactam 27a: C17H19NO5, Mw ϭ 317.33, colorless
crystal of 0.2 ϫ 0.1 ϫ 0.008 mm, monoclinic, space group P21/n,
˚
Z ϭ 4, a ϭ 10.329(2), b ϭ 7.805 (3), c ϭ 18.707(4) A, β ϭ 94.00(2)°,
3
V ϭ 1504.5(7) A , dcalcd. ϭ 1.401 gcmϪ3, F(000) ϭ 672, λ(Mo-
˚
Kα) ϭ 0.71070 A, µ ϭ 0.104 mmϪ1, Nonius Kappa CCD diffracto-
˚
meter, θ range: 2.18Ϫ27.24°, 4372 collected reflections, 2803 unique
(Rint ϭ 0.0401), 1762 observed [I Ͼ 2σ(I)]. The structure was re-
fined by full-matrix least squares with SHELXL-93, R ϭ 0.0885
for 1762 observed reflections, wR2 ϭ 0.3121 for 2803 unique
reflections, goodness of fit ϭ 1.085, residual electron density
CH2Cl2
(20 mL),
1,2-bis(trimethysilyloxy)ethane
(850 mg,
3.14 mmol) was added, and the solution was cooled to Ϫ78 °C.
TMSOTf (120 mg, 0.54 mmol) was added dropwise and the mix-
ture was stirred at Ϫ78 °C. After 1 h, the mixture was allowed to
warm to 0 °C and kept at this temperature for a further hour.
The reaction was quenched with pyridine (100 mg, 1.26 mmol) and
poured into brine. The organic layer was separated, and the aque-
ous phase extracted with CH2Cl2. After drying, the combined or-
Ϫ0.294/0.384 e·AϪ3. Atoms C12 and C13 of the methylenedioxy
˚
ring are disordered. The major position (82%) is represented in the
figure (Scheme 5).
cis-7a-(1,3-Benzodioxol-5-yl)-6-methylene-3a,4,5,6,7,7a-hexahydro-
2-indolinone (29): Nitro ester 12a (500 mg, 1.5 mmol) was heated in
ganic layers were concentrated. The crude product was purified by methanol until complete dissolution. Ammonium chloride (1.20 g,
Eur. J. Org. Chem. 2001, 3631Ϫ3640 3637

C. Jousse-Karinthi, C. Riche, A. Chiaroni, D. Desmae¨le
FULL PAPER
22.6 mmol) and zinc powder (1.40 g, 21.4 mmol) were added se-
quentially. After having been stirred at reflux for 4 h, the hot reac-
tion mixture was filtered through a pad of Celite in a sintered glass
funnel. The solid was repeatedly washed with methanol, and the
filtrate was concentrated. The residue was taken up into water and
the mixture extracted with CH2Cl2. After drying, the combined
organic layers were concentrated. The oily residue was taken into
THF (15 mL), and sodium acetate (430 mg, 5.24 mmol) was added,
followed by titanium trichloride (17% aqueous solution, 5.2 g,
5.7 mmol). The mixture was degassed through two freeze-pump-
thaw cycles and the resulting dark blue solution was stirred for 3 h
at 20 °C. Aqueous potassium sodium tartrate (5 mL) was then ad-
ded, and the mixture was stirred for 1 h at 20 °C. The mixture was
extracted with ether. The organic layers were dried and concen-
trated under reduced pressure. Chromatography on silica gel (ethyl
(C, C-1"), 143.4 (H2CϭC), 146.9 (C-7Јa or C-3Јa), 148.0 (C-3Јa or
C-7Јa), 175.6 (CO).
3-Methylene-15,16-methylenedioxy-11β-phenylthio-cis-erythrinan-8-
one (32b), 3-Methylene-15,16-methylenedioxy-11α-phenylthio-cis-er-
ythrinan-8-one (32a), and 9-Benzo[1,3]dioxol-5-yl-3-phenylsulfanyl-
5-azatricyclo[6.2.2.01,5]dodec-9-en-6-one (34): Trimethylsilyl trifluo-
romethanesulfonate (122 mg, 0.55 mmol) and N,N-diisopropylethyl-
amine (71 mg, 0.55 mmol) were added dropwise to a solution of
sulfoxide 30 (100 mg, 0.24 mmol) in CH2Cl2 (2.0 mL). The reaction
mixture was concentrated under reduced pressure, and the residue
was taken up into CH2Cl2 (5.0 mL). After stirring for 45 min, aque-
ous sodium bicarbonate was added, and the mixture was extracted
with CH2Cl2. The combined organic phases were dried and concen-
trated under reduced pressure. The oily residue was taken into THF
(2 mL), and tetrabutylammonium fluoride (1  in THF, 0.4 mL,
0.4 mmol) was added. The reaction mixture was stirred at 20 °C
for 3 h and quenched with aqueous oxalic acid. The mixture was
extracted with CH2Cl2. The organic layer was dried and concen-
trated in vacuo. Chromatographic purification on silica gel (cyclo-
hexane/ethyl acetate, 1:1) afforded 52 mg (54%) of a 1:2 mixture of
thioethers 32a and 32b, Rf ϭ 0.39, as an amorphous solid. Further
elution provided 13 mg of lactam 34 (14%, Rf ϭ 0.19), as a viscous,
colorless oil.
acetate) gave lactam 29 (225 mg, 55%); colorless crystals, m.p.
Ϫ1
˜
168Ϫ170 °C (MeOH). Ϫ IR (KBr): ν ϭ 3650Ϫ3200 cm (NH),
1696 (CϭO), 1668 (CϭC), 1505, 1493, 1478, 1434, 1401, 1037 and
928 (OCH2O). Ϫ 1H NMR (CDCl3, 400 MHz): δ ϭ 1.55Ϫ1.65 (m,
1 H, 4-H), 1.85Ϫ1.95 (m, 1 H, 4-H), 2.10 (dd, J ϭ 16.3, 5.2 Hz, 1
H, CHCON), 2.24Ϫ2.32 (m, 1 H, 5-H), 2.40 (m, 2 H, 5-H,
CHCON), 2.45 (d, J ϭ 14.4 Hz, 1 H, 7-H), 2.50Ϫ2.55 (m, 1 H,
CHCH2CONH), 2.75 (d, J ϭ 14.4 Hz, 1 H, 7-H), 4.81 (s, 1 H,
H2CϭC), 4.88 (s, 1 H, H2CϭC), 5.96 (s, 2 H, OCH2O), 6.62 (s,
NH), 6.77 (d, J ϭ 7.8 Hz, 1 H, 7Ј-H), 6.90 (dd, J ϭ 7.8, 1.0 Hz, 1
H, 6Ј-H), 6.92 (d, J ϭ 10.0 Hz, 1 H, 4Ј-H). Ϫ 13C NMR (CDCl3,
Compound 32b: IR (neat): ν ϭ 1685 cmϪ1 (CO), 1660 (CϭC), 1503,
˜
1481, 1035, and 932 (OCH2O). Ϫ 1H NMR (CDCl3, 200 MHz):
δ ϭ 1.63Ϫ1.95 (m, 2 H, 1-H), 2.00Ϫ2.64 (m, 7 H, 2-H, 4-H, 6-H,
7-H), 3.13 (dd, J ϭ 13.9, 3.5 Hz, 1 H, 10-Ηα), 4.16 (d, J ϭ 3.5 Hz,
1 H, HCSPh), 4.33 (d, J ϭ 13.9 Hz, 1 H, 10-Hβ), 4.67 (s, 1 H,
H2CϭC), 4.88 (s, 1 H, H2CϭC), 5.95 (s, 2 H, OCH2O), 6.84 (s, 1
H, 17-H), 6.90 (s, 1 H, 14-H), 7.21Ϫ7.40 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-
H), 7.61 (m, 2 H, 2Ј-H, 6Ј-H). Ϫ C24H23NO3S (405.5): calcd. C
71.08, H 5.71, N 3.45; found C 70.96, H 5.71, N 3.36.
100 MHz):
δ ϭ 27.7 (CH2, C-4), 29.9 (CH2, C-5), 36.5
(CH2CONH), 42.1 (CHCH2CONH), 44.7 (CH2, C-7), 65.1
(ArCNHCO), 101.2 (OCH2O), 106.1 (CH, C-4Ј), 107.9 (CH, C-7Ј),
110.9 (H2CϭC), 118.2 (CH, C-6Ј), 140.4 (C, C-5Ј), 143.3 (H2Cϭ
C), 146.6 (C-3Јa or C-7Јa), 147.9 (C, C-7Јa or C-3Јa), 177.3 (CO).
Ϫ C16H17O3N (271.3): calcd. C 70.83, H 6.32, N 5.16; found C
70.52, H 6.27, N 5.14.
cis-7a-(1,3-Benzodioxol-5-yl)-6-methylene-1-[2-(phenylsulfinyl)-
ethyl]-3a,4,5,6,7,7a-hexahydro-2-indolinone (30): A THF solution of
sodium bis(trimethylsilyl)amide (2 , 0.49 mL, 0.50 mmol) was ad-
ded dropwise to an ice-cooled solution of lactam 29 (220 mg,
0.81 mmol) in THF (5 mL). The pale yellow solution was stirred
at 0 °C for 15 min and then cooled to Ϫ78 °C. Phenyl vinyl sulfox-
ide (155 mg, 0.89 mmol) was then added and the resulting mixture
was stirred for 15 min. The temperature was gradually raised to 20
°C. After stirring for 12 h, 1  HCl was added, and the mixture
was extracted with CH2Cl2. The combined organic phases were
dried and concentrated under reduced pressure. Chromatography
on silica gel (cyclohexane/ethyl acetate, 1:1) afforded 292 mg of 30
(85%) as a 1:1 mixture of stereoisomers; amorphous solid. Ϫ IR
(neat): ν˜ ϭ 1688 cmϪ1 (CO), 1661 (CϭC), 1504, 1488, 1444, 1239,
1038, (SϭO), 1037 and 928 (OCH2O). Ϫ 1H NMR (CDCl3,
400 MHz), the stereogenic sulfur atom induced a splitting of most
signals: δ ϭ 1.45Ϫ1.53 (m, 1 H, 4-H), 1.60Ϫ1.75 (m, 1 H, 4-H),
Ϫ1
˜
Compound 34: IR (neat): ν ϭ 1687 cm (CO), 1617 (CϭC), 1503,
1487, 1438, 1400, 1036, and 928 (OCH2O) Ϫ 1H NMR (CDCl3,
400 MHz): δ ϭ 1.80Ϫ1.94 (m, 2 H, 11-H, 12-H), 1.93Ϫ2.03 (m, 1
H, 11-H), 2.07 (dd, J ϭ 12.9, 10.7 Hz, 1 H, 2-H), 2.37 (m, 1 H, 12-
H), 2.50 (ddd, J ϭ 12.9, 6.4, 1.5 Hz, 1 H, 2-H), 2.67 (m. 2 H,
H2CCON), 3.05 (m, 1 H, HCCH2CON), 3.35 (dd, J ϭ 12.2, 9.0 Hz,
1 H, CONCH2), 3.71 (ddt, J ϭ 10.7, 9.0, 6.4 Hz, 1 H, HCSPh),
4.21 (ddd, J ϭ 12.2, 6.4, 1.2 Hz, 1 H, CONCH2), 5.96 (s, 2 H,
OCH2O), 6.23 (d, J ϭ 1.4 Hz, 1 H, HCϭC), 6.77 (d, J ϭ 8.2 Hz,
1 H, 7Ј-H), 6.83Ϫ6.87 (m, 2 H, 4Ј-H, 6Ј-H), 7.26Ϫ7.33 (m, 3 H,
2Ј-H, 4Ј-H, 6Ј-H), 7.42Ϫ7.46 (m, 2 H, 3Ј-H, 5Ј-H). Ϫ 13C NMR
(CDCl3, 50 MHz): δ ϭ 25.4 (CH2, C-11), 33.4 (HCCH2CON), 35.7
(CH2, C-12), 41.2 (CH2CON), 41.7 (HCSPh), 46.6 (CH2, C-2), 53.1
(OCNCH2), 60.3 (C, C-1), 101.2 (OCH2O), 105.7 (CH, C-4Ј), 108.3
(CH, C-7Ј), 118.9 (CH, C-6Ј), 127.5 (C, C-4"), 129.2 (2 CH, C-2’’,
C-6"), 130.6 (HCϭCAr), 132.0 (2 CH, C-3’’, C-5"), 132.9 (C, C-
5Ј), 133.5 (C, C-1"), 146.1 (HCϭCAr), 146.9 (C, C-7Јa or C-3Јa),
148.5 (C, C-3Јa or C-7Јa), 169.1 (CO)
1
2.15Ϫ2.35 (m, 3 H, 5-H, 3-H), 2.40Ϫ2.50 (m, 2.5 H, 3-H, 3a-H, /2
1
7-H), 2.55 (d, J ϭ 15.0 Hz, 0.5 H, 7-H), 2.85Ϫ3.00 (m, 1.5 H,
/
2
7-H, NCH2CH2SOPh), 3.00 (d, J ϭ 15.0 Hz, 0.5 H, 7-H), 3-Methylene-15,16-methylenedioxy-cis-erythrinan-8-one (41): Tri-n-
3
3.20Ϫ3.40 (m, 2.5 H, NCH2CH2SOPh,
/
NCH2CH2SOPh), butyltin hydride (250 mg, 0.86 mmol) and a few crystals of 2,2Ј-
2
1
3.65Ϫ3.75 (m, 0.5 H,
/ NCH2CH2SOPh), 4.88, 4.90, 4.94, and azobis(isobutyronitrile) were added to a solution of thioethers 32a
2
4.96 (4 s, 2 H, H2CϭC), 5.95 and 5.96 (2 s, 2 H, OCH2O), 6.75 and 32b (100 mg, 0.24 mmol) in toluene (6 mL). The solution was
(m, 3 H, 4Ј-H, 6Ј-H, 7Ј-H), 7.45Ϫ7.57 (m, 5 H, C6H5SO). Ϫ 13C degassed through two freeze-pump-thaw cycles, and stirred at 110
NMR (CDCl3, 100 MHz): δ ϭ 26.1 (CH2, C-4), 28.7 (CH2, C-5), °C for 2 h. After cooling, the mixture was concentrated under re-
34.9 (CH2, C-3), 34.3 and 35.6 (NCH2CH2SOPh), 40.3 (CH2, C- duced pressure, and the residue directly purified by chromato-
7), 41.6 and 41.8 (C-3a), 53.0 and 54.7 (NCH2CH2SOPh), 69.5 and graphy over silica gel, (cyclohexane/ethyl acetate, 1:1) to give 55 mg
˜
of lactam 41 (75%); colorless oil. Ϫ IR (KBr): ν ϭ
69.6 (C, C-7a), 101.3 (OCH2O), 106.8 (CH, C-4Ј), 107.0 (CH, C-
7Ј), 111.6 (H2CϭC), 119.8 (CH, C-6Ј), 123.8 (2 CH, C-2’’, C-6"), 1682Ϫ1650 cmϪ1 (CϭO, CϭC), 1503, 1484, 1230, 1035, and 933
129.1 (2 CH, C-3’’, C-5"), 130.9 (CH, C-4"), 137.5 (C, C-5Ј), 142.9 (OCH2O). Ϫ 1H NMR (CDCl3, 400 MHz): δ ϭ 1.85 (dq, J ϭ 15.2,
3638
Eur. J. Org. Chem. 2001, 3631Ϫ3640

Synthesis of (±)-Dihydroerythramine
FULL PAPER
3.7 Hz, 1 H, 1-Heq), 2.15 (m, 1 H, 1-Hax), 2.40Ϫ2.45 (m, 4 H, 2-
H, 7-H), 2.47 (d, J ϭ 13.9 Hz, 1 H, 4-Hax), 2.50Ϫ2.57 (m, 1 H, 6-
(؎)-Hexahydrocrystamidine (44): Sodium hydride (60% in mineral
oil, 80 mg, 2.0 mmol) was added to an ice-cooled solution of alco-
H), 2.60 (d, J ϭ 13.9 Hz, 1 H, 4-Heq), 2.62 (ddd, J ϭ 15.6, 4.5, hol 43a (12 mg, 0.04 mmol) in THF (2 mL) containing a catalytic
2.0 Hz, 1 H, 11-Hα), 2.90 (ddd, J ϭ 15.6, 12.0, 6.5 Hz, 1 H, 11- amount of imidazole, and the mixture was refluxed for 30 min.
Hβ), 3.03 (ddd, J ϭ 13.0, 12.0, 4.5 Hz, 1 H, 10-H), 4.23 (ddd, J ϭ
13.0, 6.5, 2.0 Hz, 1 H, H-10), 4.70 [dd, J ϭ 2.7, 1.3 Hz, 1 H, (E)-
After cooling to 20 °C, nBu4NHSO4 (20 mg, 0.06 mmol) and iodo-
methane (1.60 g, 11.2 mmol) were added, and the resulting mixture
H2CϭC], 4.87 [s, 1 H, (Z)-H2CϭC], 5.92 (d, J ϭ 1.5 Hz, 1 H, was stirred for 2 h at 20 °C and 30 min at reflux. After cooling, 3
OCH2O), 5.91 (d, J ϭ 1.5 Hz, 1 H, OCH2O), 6.54 (s, 1 H, 17-H),
 HCl was added and the mixture was extracted with chloroform.
6.84 (s, 1 H, 14-H). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 25.8 (CH2, The organic phase was dried and concentrated. The crude product
C-1), 27.7 (CH2, C-2), 28.6 (H2CCH2NCO), 34.3 (H2CCH2NCO), was purified by silica gel chromatography (ethyl acetate/methanol,
35.7 (HCCH2CON), 38.6 (NCOCH2CH), 44.3 (CH2, C-4), 64.2 (C, 95:5) to give 12 mg of lactam 44 (95%) as a colorless gum. Ϫ IR
˜
C-5), 100.9 (OCH2O), 105.2 (CH, C-17), 108.9 (CH, C-14), 112.0 (neat): ν ϭ 1665 (CϭO), 1504, 1485, 1441, 1241, 1031, and 928
(H2CϭC), 126.2 (C, C-13), 135.4 (C, C-12), 142.2 (H2CϭC), 146.1 (OCH2O). Ϫ 1H NMR ([D6]benzene, 400 MHz): δ ϭ 1.15Ϫ1.40
(2 C, C-15, C-16), 172.6 (CO). Ϫ MS (EI): m/z (relative intensity): (m, 3 H, 1-Hax, 1-Heq, 2-Heq), 1.48 (dd, J ϭ 13.3, 10.1 Hz, 1 H, 4-
297 (14) [M·ϩ], 242 (100), 231 (6), 230 (6), 200 (6), 115 (16).
Hax), 1.55Ϫ1.60 (m, 1 H, 2-Hax), 1.91Ϫ2.00 (m, 1 H, 6-H),
2.00Ϫ2.15 (m, 3 H, 7-H, 4-Heq), 2.17 (dt, J ϭ 16.1, 5.5 Hz, 1 H,
11-Hα), 2.44 (ddd, J ϭ 16.1, 8.4, 6.9 Hz, 1 H, 11-Hβ), 2.93 (s, 3
H, OCH3), 2.95Ϫ3.08 (m, 2 H, 3-H, 10-Hα), 3.94 (ddd, J ϭ 12.9,
6.9, 5.5 Hz, 1 H, 10-Hβ), 5.36 (m, 2 H, OCH2O), 6.28 (s, 1 H, 17-
H), 6.64 (s, 1 H, 14-H). Ϫ 13C NMR ([D6]benzene, 100 MHz): δ ϭ
24.6 (CH2, C-1), 26.1 (CH2, C-2), 28.1 (CH2, C-11), 35.2 (CH2, C-
10), 35.8 (CH2, C-7), 38.0 (CH, HCCH2CON), 42.0 (CH2, C-4),
55.4 (OCH3), 63.2 (C, C-5), 75.0 (CH, C-3), 101.0 (OCH2O), 105.1
(CH, C-14), 109.6 (CH, C-17), 127.6 (C, C-12), 136.7 (C, C-13),
146.5 (2 C, C-15, C-16), 170.6 (CO).
15,16-Methylenedioxy-cis-erythrinane-3,8-dione (42): A solution of
OsO4 in tert-butyl alcohol (2.5 g/L, 6 mL, 3.0 mmol) and sodium
metaperiodate (570 mg, 2.0 mmol) were added sequentially to a so-
lution of lactam 41 (160 mg, 0.50 mmol) in THF (15 mL) and water
(5 mL). After stirring at room temperature for 2 h, brine was added
and the mixture was extracted with ethyl acetate. The organic layer
was dried and concentrated to leave a yellow oil, which was purified
by column chromatography on silica gel (ethyl acetate) to give
˜
100 mg of oxo lactam 42 (62%), colorless oil. Ϫ IR (KBr): ν ϭ
1713 cmϪ1, (CϭO), 1675 (NCϭO), 1484, 1408, 1034 and 932
1
(؎)-Dihydroerythramine (9): A solution of hexahydrocrystamidine
(44) (14 mg, 0.046 mmol) in THF was treated with an ethereal solu-
tion of aluminum hydride (2 mL, 1.2 mmol) for 2 h at 20 °C. Aque-
ous ammonia was cautiously added and the resulting mixture was
extracted with chloroform to leave 10.5 mg of (Ϯ)-dihydroerythra-
(OCH2O). Ϫ H NMR (CDCl3, 200 MHz): δ ϭ 2.04 (m, 1 H, 1-
H), 2.20Ϫ3.12 (m, 11 H, 1-H, 2-H, 4-H, 6-H, 7-H, 11-H), 4.23 (m,
1 H, 10-H), 5.94 (s, 2 H, OCH2O), 6.53 (s, 1 H, 17-H), 6.62 (s, 1
H, 14-H). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 26.7 (CH2, C-1),
27.4 (H2CCH2NCO), 34.0 (CH2), 34.8 (CH2), 36.0 (CH2), 37.0
(CH, HCCH2CON), 50.4 (CH2, C-4), 65.1 (C, C-5), 101.2
(OCH2O), 104.4 (CH, C-14), 109.1 (CH, C-17), 127.0 (C, C-12),
134.6 (C, C-13), 147.1 (2C, C-15, C-16), 173.5 (NCO), 208.2 (CO).
Ϫ HRMS (EI): calcd. for C17H17NO4 299.1164, found 299.1157.
˜
mine (9) (78%); colorless gum. Ϫ IR (neat): ν ϭ 1503, 1482, 1373,
1231, 1092, 1038, and 932 (OCH2O). Ϫ 1H NMR ([D6]benzene,
400 MHz): δ ϭ 1.35Ϫ1.46 (m, 1 H, 7-H), 1.45Ϫ1.54 (m, 1 H, 1-
H), 1.55Ϫ1.65 (m, 3 H, 7-H, 2-H), 1.70Ϫ1.76 (m, 1 H, 1-H), 1.77
(dd, J ϭ 13.8, 4.3 Hz, 1 H, 4-H), 1.93 (dd, J ϭ 13.8, 8.0 Hz, 1 H,
4-H), 2.09 (quint, J ϭ 6.9 Hz, 1 H, H-6), 2.22Ϫ2.29 (m, 1 H, 11-
H), 2.60Ϫ2.73 (m, 3 H, 11-H, 10-H, 8-H), 2.79Ϫ2.83 (m, 1 H, 8-
H), 3.06 (s, 3 H, OMe), 3.04Ϫ3.12 (m, 1 H, 10-H), 3.24 (m, 1 H,
3-H), 5.38 (m, 2 H, OCH2O), 6.46 (s, 1 H, H-17), 6.79 (s, 1 H, H-
14). Ϫ 13C NMR ([D6]benzene, 100 MHz): δ ϭ 25.8 (CH2, C-11),
25.9 (CH2, C-1), 27.9 (CH2, C-2), 29.1 (CH2, C-7), 39.4 (CH2, C-
4), 43.1 (CH2, C-10), 43.2, (CH, C-6), 48.8 (CH2, C-8), 55.5
(OCH3), 64.0 (C, C-5), 75.9 (CH, C-3), 100.6 (OCH2O), 106.2 (CH,
C-14), 109.1 (CH, C-17), 129.1 (C, C-12), 138.3 (C, C-13), 143.3
(C, C-15 or C-16), 145.9 (C, C-15 or C-16). Ϫ Picrate derivative,
m.p. 198 °C (MeOH). Ϫ C24H26N4O10 (530.5): calcd. C 54.34, H
4.94, N 10.56; found C 54.03, H 5.22, N 10.29.
3α-Hydroxy-15,16-methylenedioxy-cis-erythrinan-8-one (43a) and
3β-Hydroxy-15,16-methylenedioxy-cis-erythrinan-8-one
(43b):
Cerium trichloride hexahydrate (79 mg, 0.21 mmol) was added to
a solution of ketone 42 (32 mg, 0.107 mmol) in methanol (2 mL).
After stirring for 30 min, the mixture was cooled to 0 °C, and
sodium borohydride (10 mg, 0.26 mmol) was added in one portion.
The reaction mixture was stirred for 20 min and water was added.
The mixture was extracted with CH2Cl2. The organic layer was
dried and concentrated in vacuo. Chromatographic purification on
silica gel (CH2Cl2/EtOH, 95:5) afforded 22 mg of an α-alcohol 43a
(Rf ϭ 0.46, 68%) and 7 mg of a β-alcohol 43b (Rf ϭ 0.37, 22%).
Ϫ1
˜
Compound 43a: Gum. Ϫ IR (neat): ν ϭ 3500Ϫ3300 cm (OH),
1653 (CϭO), 1504, 1485, 1447, 1034, and 930 (OCH2O). Ϫ 1H
NMR ([D6]benzene, 400 MHz): δ ϭ 1.20Ϫ1.40 (m, 3 H, 1-Hax, 1-
Heq, 2-Heq), 1.35 (dd, J ϭ 13.1, 10.0 Hz, 1 H, 4-Hax), 1.46Ϫ1.54
(m, 1 H, 2-H), 1.86 (dd, J ϭ 13.1, 3.2 Hz, 1 H, 4-Heq), 1.85Ϫ1.93
(m, 1 H, 6-H), 2.02 (dd, J ϭ 16.2, 8.4 Hz, 1 H, 7-H), 2.10 (dd, J ϭ
16.2, 5.5 Hz, 1 H, 1 H, 7-H), 2.18 (dt, J ϭ 16.1, 5.5 Hz, 1 H, 11-
Hα), 2.44 (ddd, J ϭ 16.1, 8.4, 6.9 Hz, 1 H, 11-Hβ), 3.02 (ddd, J ϭ
12.9, 8.4, 5.5 Hz, 1 H, 10-Hα), 3.46 (m, 1 H, 3-H), 3.87 (ddd, J ϭ
12.9, 6.9, 5.5 Hz, 1 H, 10-Hβ), 5.36 (s, 2 H, OCH2O), 6.29 (s, 1 H,
17-H), 6.57 (s, 1 H, 14-H). Ϫ 13C NMR ([D6]benzene, 100 MHz):
δ ϭ 24.6 (CH2, C-1), 27.9 (CH2, C-11), 30.0 (CH2, C-2), 35.3 (CH2,
C-10), 36.0 (CH2, C-7), 37.6 (CH, HCCH2CON), 45.0 (CH2, C-4),
63.2 (C, C-5), 65.9 (CH, C-3), 101.9 (OCH2O), 105.2 (CH, C-14),
109.5 (CH, C-17), 127.6 (C, C-12), 134.6 (C, C-13), 146.2 (C, C-15
or C-16), 146.7 (C, C-15 or C-16),171.7 (CO).
Acknowledgments
We gratefully acknowledge Dr. J. Mahuteau and Dr. M. Ourevitch
for the 2D NMR and NOE experiments, and Mrs. S. Mairesse-
Lebrun for the elemental analyses.
[1]
[1a]
For recent reviews see:
A. S. Chawla, V. K. Kapoor, in:
Alkaloids: Chemical and Biological Perspectives (Ed.: S. W. Pel-
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[1b]
Y.
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Eur. J. Org. Chem. 2001, 3631Ϫ3640
3639

C. Jousse-Karinthi, C. Riche, A. Chiaroni, D. Desmae¨le
FULL PAPER
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[14]
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[15]
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[5] [5a]
[5b]
V. Prelog, Angew. Chem. 1957, 69, 33Ϫ39. Ϫ
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[6]
For further examples featuring the formation of the C-5ϪC-15
[17]
[6a]
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[6b]
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[18]
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[6c]
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[19]
´
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