First asymmetric synthesis of boehmeriasin A

Article abstract of DOI:10.1002/ejoc.200901404

The first asymmetric synthesis of phenanthroquinolizidine alkaloid (R)-boehmeriasin A is described. Two alternative synthetic pathways to the key intermediate (RS,R)-4 were achieved through a combination of highly diastereoselective 1,2-nucleophilic addition on (-)-(S)-l-amino-2-(methoxy methyl)pyrrolidine hydrazones with a ring-closing metathesis to ensure the construction of the piperidine template. A subsequent acylation/oxidation/aldol condensation/radical cyclization sequence completed the assembly of the title (R)configured natural product.

Full text of DOI:10.1002/ejoc.200901404

FULL PAPER
DOI: 10.1002/ejoc.200901404
First Asymmetric Synthesis of Boehmeriasin A
David Dumoulin,[a,b,c] Stéphane Lebrun,[a,b,c] Axel Couture,*[a,b,c] Eric Deniau,[a,b,c] and
Pierre Grandclaudon[a,b,c]
Keywords: Nucleophilic addition / Diastereoselectivity / Cyclization / Ring-closing metathesis / Total synthesis
The first asymmetric synthesis of phenanthroquinolizidine
alkaloid (R)-boehmeriasin A is described. Two alternative
synthetic pathways to the key intermediate (RS,R)-4 were
achieved through a combination of highly diastereoselective
1,2-nucleophilic addition on (–)-(S)-1-amino-2-(methoxy-
methyl)pyrrolidine hydrazones with a ring-closing metathe-
sis to ensure the construction of the piperidine template. A
subsequent acylation/oxidation/aldol condensation/radical
cyclization sequence completed the assembly of the title (R)-
configured natural product.
Phenanthroizidines exhibit interesting biological proper-
ties, especially profound cytotoxic activity, and have been
shown to provide other medicinal benefits including mi-
totic, antileukemic, antimoebic, antibacterial and antibiotic
activities; such compounds have also been used as insecti-
cides and insect antifeedants.[2,3] In addition, analogues of
these natural products have been prepared and subjected to
various forms of biological screening.[2a,4]
Introduction
Since the first isolation of tylophorine in 1935 from the
perennial climbing plant Tylophoria indica,[1] the class of
phenanthroizidine alkaloids has grown considerably; it
presently encompasses close to 70 structurally related mod-
els.[2] The defining feature of these pentacyclic natural prod-
ucts, which are found primarily in plants belonging to the
Asclepiadaceae, Moraceae, Lauraceae and Urticaceae fami-
lies,[2a] is the presence of a highly oxygenated phenanthrene
ring fused to a saturated N-heterocycle (Figure 1).
As a consequence of their promising biological profile,
coupled with their low natural abundance and unusual
architecture, the phenanthrolizidine alkaloids have engen-
dered an impressive number of synthetic studies for the pur-
pose of fundamental research and drug development. How-
ever, most of these racemic and asymmetric synthetic stud-
ies[2a,2b,5] have been devoted to the indolizidines, which are
much more prevalent than the corresponding quinolizidines
in natural sources. Despite the fact that the closely related
phenanthroquinolizidine alkaloids exert interesting antivi-
ral, antifungal, antimicrobial and cancerostatic effects, as
well as inhibiting proteosynthesis in eukaryotic cells,[2a,5e]
they have received less attention as potential therapeutic
leads and have not elicited the same synthetic efforts.[2a,5a]
This is probably due to the fact that cryptopleurine (1a),
which was isolated as early as 1948 from the bark of Cryp-
tocarya pleurosperma,[6] was deemed for a long time to be
the sole example of this exceedingly rare class of alkaloids.
This family was later enriched by isolation of the hydroxy
derivatives cryptopleuridine (1b)[7] and 15-hydroxycrypto-
pleurine (1c),[8] and by the recent extraction of boehmeria-
sin A (1d) and B (1e) from the aqueous ethanolic extract of
Boehmeria siamensis Craib (Urticaceae) by bioassay-guided
fractionation.[9] In assays for cytotoxicity on a panel of
twelve cancer cell lines, which included leukemia and can-
cers of the kidney, prostate, lung and breast, boehmeria-
sin A proved to be more potent than Paclitaxel, with IC50
values in the low nanomolar range.[10] Whereas several syn-
thetic methodologies have been developed for the elabora-
Figure 1. Structures of phenanthroindolizidines and phenanthro-
quinolizidines.
[a] Université Lille Nord de France,
59000 Lille, France
Fax: +33-3-20336309
E-mail: axel.couture@univ-lille1.fr
[b] USTL, Laboratoire de Chimie Organique Physique, Bâtiment
C3(2),
59655 Villeneuve d’Ascq, France
[c] CNRS, UMR 8009 “COM”,
59655 Villeneuve d’Ascq, France
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D. Dumoulin, S. Lebrun, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
tion of cryptopleurine and its hydroxy derivatives in both ically pure hydrazine (–)-(S)-1-amino-2-(methoxymethyl)-
racemic and optically active forms[5] in order to determine pyrrolidine [(S)-8]. Hydrazone (S)-6 was submitted to an
chemical structure and stereochemistry, only one example addition reaction with allyllithium (9), and the intermediate
of a racemic approach to boehmeriasin A has been re- lithium hydrazide salt was intercepted with acryloyl chlo-
ported.[5a]
ride to give straightforward access to the desired diene
In this paper we wish, therefore, to describe for the first hydrazide (R,S)-5. This polyene compound was obtained
time a flexible, asymmetric synthesis of the representative with satisfactory yield; NMR spectroscopic investigations
phenanthroquinolizidine alkaloid boehmeriasin A (1d). Our after chromatographic separation indicated the presence of
main objective was to ensure that the synthetic methodol- a single diastereomer, thus confirming the high level of dia-
ogy allowed optimization of the pharmacological profiles stereoselectivity observed upon the initial 1,2-nucleophilic
of these potent cytotoxic agents through simple modifica- addition process on the C=N double bond.[11a] This pro-
tion of their basic skeleton to enable a range of analogues cedure allowed the absolute configuration at the C-14a car-
of this alkaloid to be prepared efficiently.
bon atom in the final compound 1d to be introduced in a
defined manner, which is one of the major challenges in the
total synthesis of the target alkaloid. Ring-closing metathe-
sis using first-generation Grubbs catalyst [Cl2Ru-
(=CHPh)(PCy3)2, 10 mol-%)] in refluxing CH2Cl2, pro-
ceeded smoothly to provide a satisfactory yield of the vir-
tually diastereochemically pure cyclic ene hydrazide (R,S)-
10. Catalytic hydrogenation with concomitant release of the
benzyl protection of the 2-hydroxyethyl group proceeded
uneventfully to afford the hydroxyalkylated hydrazide
(R,S)-11 in excellent yield and high diastereoselectivity
(deՆ96%). Subsequent Swern oxidation of 11 delivered the
cyclic hydrazide (R,S)-12 with the aldehyde functionality
necessary to secure the ultimate installation of the hy-
droxybenzyl appendage. Compound (R,S)-12 was then al-
lowed to react with the appropriate Grignard reagent 13
and standard workup delivered the hydroxylated hydrazide
14 in excellent yield as a 1:1 mixture of diastereomeric
(R,R,S)/(S,R,S) compounds.
Results and Discussion
The retrosynthetic analysis of 1d is shown in Scheme 1.
The pentacyclic skeleton of the (R)-configured alkaloid
could be constructed by radical-induced annulation of the
ortho-bromostilbene derivative 2, which could be assembled
by intramolecular aldol-type condensation of the oxo amide
3. The cyclization precursor should be accessible from the
amino alcohol 4, and this key intermediate was, in turn,
envisioned to arise from a strategic combination of the
highly diastereoselective nucleophilic 1,2-addition on chiral
(–)-(S)-1-amino-2-(methoxymethyl)pyrrolidine
(SAMP)
hydrazones[11] and subsequent acylation with acryloyl chlo-
ride with a ring-closing metathesis.[12]
At this stage, stereochemical considerations of the ben-
zylic carbon centre were not crucial for the outcome of the
synthetic process, because conversion of the benzylic hy-
droxy functionality into a carbonyl group was planned at a
later stage of the sequence. Finally, the reductive bond
cleavage of 14 with BH3·THF was accomplished through
simultaneous reduction of the lactam carbonyl function-
ality to complete the synthesis of the key intermediate
amino alcohol (RS,R)-4. The overall yield for the formation
of this piperidine derivative following the synthetic route
depicted in Scheme 2 was 17% over eight steps. We sur-
mised that the efficiency of the process could be signifi-
cantly improved by using an alternative strategy based upon
the incorporation of the aromatic unit prior to installation
of the stereodefined hydroxyalkyl appendage on the
Scheme 1. Retrosynthetic analysis.
For the elaboration of amino alcohol 4, we set out to piperidine template.
achieve alternative strategies to secure the stereochemistry
In this second approach, we embarked on the synthesis
of the hydroxyalkyl appendage on the piperidine template. of key intermediate 4 using the route depicted in Scheme 3,
The two approaches differed in the stage at which the chiral starting from aromatic oxo ester 15. Acetal protection, fol-
center is introduced. Initially, the synthetic route portrayed lowed by a reduction/oxidation sequence applied to 16 and
in Scheme 2 was developed. The first facet of the synthesis 17, respectively, delivered the protected carbaldehyde 18,
was the assembly of the highly conjugated precursor diene which was then coupled with enantiopure hydrazine (S)-8
hydrazide 5, which was performed as a single one-pot reac- to provide an excellent yield of hydrazone (S)-19. Sequen-
tion from chiral SAMP hydrazone 6. The synthesis started tial treatment with allyllithium (9) and trapping with acryl-
from the benzyl-protected 3-hydroxypropionaldehyde (7), oyl chloride, as described in Scheme 2, afforded diolefinic
which was quantitatively converted into the enantiopure hydrazide (R,S)-20 as a single diastereoisomer (deՆ96%),
SAMP hydrazone (S)-6 by simply mixing with enantiomer- which was characterized by its NMR spectra after chroma-
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First Asymmetric Synthesis of Boehmeriasin A
Scheme 2. Synthesis of key intermediate amino alcohol 4.
Scheme 3. Alternative synthesis of key amino alcohol 4.
Eur. J. Org. Chem. 2010, 1943–1950
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D. Dumoulin, S. Lebrun, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
Scheme 4. Asymmetric synthesis of (R)-boehmeriasin A.
tographic treatment. This bis(olefin) was then subjected to which contained a bromostilbene unit embedded in the
ring-closing metathesis, which delivered an excellent yield compact annulated compound framework. Construction of
of the diastereochemically pure cyclic ene hydrazide (R,S)- the phenanthrene nucleus was achieved by treatment with
21. Catalytic hydrogenation of the olefinic double bond Bu3SnH and AIBN, which effected a very efficient intramo-
proceeded smoothly to afford the corresponding saturated lecular radical cyclization.[14] Finally, reduction of pentacy-
hydrazide (R,S)-22 in excellent yield and high diastereo- clic lactam (R)-25 with LiAlH4 completed the synthesis of
selectivity. The choice of the acetal protection was rewarded the title compound boehmeriasin A [(R)-1d], which was ob-
here, because treatment of (R,S)-22 with the BH3·THF tained in 29% overall yield (over the last five steps). The
complex, followed by standard basic workup, triggered enantiopurity of the synthetic (R)-boehmeriasin A was
three simultaneous operations: release of the temporary chi- clearly established from the sign and value of the specific
ral auxiliary, reduction of the lactam carbonyl functionality optical rotation and from spectroscopic data, which
and stereocontrolled installation of the hydroxyalkyl ap- matched those reported for the natural product {[α]D25
=
pendage, to provide a 1:1 diastereomeric mixture of (R,R)- –80.2 (c = 0.15, CH3OH); ref.[9] [α]D25 = –80.4 (c = 0.1,
and (S,R)-4. This compound was obtained with an overall CH3OH)}. Furthermore, our asymmetric synthetic route al-
yield of 21% over eight steps, thus demonstrating that the lowed the assignment of the (R) absolute configuration to
second synthetic approach to key intermediate 4 shown in the recently isolated natural product.
Scheme 3 is more efficient and appealing than the former.
Interestingly, because the olefinic moieties of 10 and 21 and
the metalation sites in 11 and 22 are all present in interme-
diate compounds equipped with a stereocontrolling agent,
Conclusions
such compounds could serve as key branching points for
We have devised a new and flexible method for the first
alternative functionalization chemistries; this should enable asymmetric synthesis of (+)-(R)-boehmeriasin A. The key
the pharmacological profile of the target compounds to be step is the elaboration of a chiral building block, which was
optimized.
assembled following two synthetic routes based upon strate-
With amino alcohol 4 in hand, we set out to assemble gic combinations of a highly diastereoselective 1,2-nucleo-
the title compound 1d using Kibayashi’s method for the philic addition/acylation process applied to an enantiopure
synthesis of (–)-(R)-cryptopleurine[5g,5h] as depicted in SAMP hydrazone with a ring-closing metathesis reaction to
Scheme 4. Acylation of (RS,R)-4 with the appropriate bro- form the piperidine template. The main advantages of this
mobenzoyl chloride 23 produced an excellent yield of the synthetic method lie in the formation of chiral saturated or
hydroxy amide (RS,R)-24, which was subsequently oxidized unsaturated hydrazide intermediates that could be exploited
with pyridinium dichromate (PDC) to provide a fairly good for further synthetic use. Such compounds could be further
yield of virtually enantiopure oxo amide (R)-3 – a suitable functionalized, for example by epoxidation and di-
candidate for the elaboration of the quinolizidine scaffold. hydroxylation, which could have an impact on the bio-
Intramolecular aldol-type condensation under basic condi- logical profile of target models. Finally, the synthetic strat-
tions[13] led to the formation of quinolizidinone (R)-2, egy has significant potential for further extension to a range
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First Asymmetric Synthesis of Boehmeriasin A
fied by flash column chromatography on silica gel (ethyl acetate/
hexanes, 55:45) to afford the ene hydrazide 10 as a yellow oil
(971 mg, 75%). [α]2D5 = –32.5 (c = 0.50, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.44–1.52 (m, 1 H, CH2), 1.71–1.78 (m, 1
H, CH2), 1.97–2.22 (m, 4 H, 2ϫCH2), 2.34 (dd, J = 2.3, 3.5 Hz, 1
H, CH2), 2.68 (dd, J = 2.6, 6.8 Hz, 1 H, CH2), 3.12–3.16 (m, 1 H,
NCH2), 3.31 (s, 3 H, OCH3), 3.35–3.39 (m, 2 H, OCH2), 3.50 (t, J
= 6.1 Hz, 2 H, OCH2), 3.59–3.67 (m, 1 H, NCH), 3.75–3.88 [m, 2
H (1 H, NCH, 1 H, NCH2)], 4.42 (d, JAB = 11.8 Hz, 1 H,
OCH2Ph), 4.51 (d, JAB = 11.8 Hz, 1 H, OCH2Ph), 5.80 (dd, J =
2.6, 9.8 Hz, 1 H, CH=), 6.34 (t, J = 8.2 Hz, 1 H, CH=), 7.28–7.35
(m, 5 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.2 (CH2),
27.4 (CH2), 28.6 (CH2), 32.1 (CH2), 52.8 (NCH), 58.9 (OCH3),
59.9 (CH), 60.6 (CH), 67.4 (CH2), 72.9 (CH2), 76.5 (CH2), 125.9
(CH=), 127.4 (2ϫCH), 128.4 (2ϫCH), 129.1 (CH), 137.2 (CH=),
138.2 (C), 162.9 (CO) ppm. C20H28N2O3 (344.5): calcd. C 69.74, H
8.19, N 8.13; found C 69.78, H 8.45, N 7.99.
of analogues in this series and to the antipode of the natural
product owing to the availability of the RAMP chiral auxil-
iary.
Experimental Section
General Methods: Tetrahydrofuran (THF) was pre-dried with anhy-
drous Na2SO4 and distilled from sodium benzophenone ketyl un-
der argon before use. CH2Cl2, Et3N, and toluene were distilled from
CaH2. Dry glassware was obtained by oven-drying and assembly
under dry argon. The glassware was equipped with rubber septa,
and reagent transfer was performed by using syringe techniques.
Merck silica gel 60 (40–63 µm; 230–400 mesh ASTM) was used for
flash chromatography. Melting points were obtained with a Reich-
ert–Thermopan apparatus. Optical rotations were measured with a
Perkin–Elmer 343 polarimeter. Elemental analyses were obtained
with Carlo–Erba CHNS-11110 equipment. NMR spectra were re-
(6R)-6-(2-Hydroxyethyl)-1-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-
piperidin-2-one (11): A solution of ene hydrazide 10 (580 mg,
1.69 mmol) in EtOH (15 mL) was stirred with activated Pd/C (10%,
10 mg) at room temp. under H2 (1 atm) until TLC indicated com-
plete consumption of the starting material (12 h). The mixture was
filtered through a pad of Celite, which was further eluted with
EtOH (30 mL) and CH2Cl2 (30 mL). The filtrate was concentrated
under reduced pressure, and the resulting crude product was puri-
fied by flash column chromatography on silica gel (ethyl acetate)
to afford 11 as a colorless oil (429 mg, 99%). [α]2D5 = –74.6 (c =
2.20, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.48–1.80 (m, 6
H, 3ϫCH2), 1.84–2.13 (m, 4 H, 2ϫCH2), 2.35 (t, J = 6.8 Hz, 2
H, CH2CO), 3.08–3.19 (m, 1 H, NCH2), 3.29–3.35 (m, 5 H, OCH3,
OCH2), 3.52–3.63 [m, 2 H (1 H, NCH, 1 H, NCH2)], 3.70–3.85 (m,
3 H, OCH2, NCH) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.6
(CH2), 23.0 (CH2), 27.2 (CH2), 29.8 (CH2), 34.1 (CH2), 37.8 (CH2),
53.1 (NCH2), 58.7 (OCH3), 59.8 (CH), 60.2 (CH2OH), 60.8 (CH),
75.2 (CH2O), 169.2 (CO) ppm. C13H24N2O3 (256.4): calcd. C 69.39,
H 9.44, N 10.93; found C 69.49, H 9.27, N 10.74.
1
corded with a Bruker AM 300 (300 MHz and 75 MHz, for H and
13C, respectively) by using CDCl3 as solvent and TMS as internal
standard. Oxo ester 15 is commercially available. 3-(Benzyloxy)pro-
pionaldehyde (7)[15] and (3-benzyloxypropylidene)[(2S)-2-methoxy-
methylpyrrolidin-1-yl]amine (6)[16] were prepared according to re-
ported procedures. 2-Bromo-4,5-dimethoxyphenylacetyl chloride
(23)[17] was synthesized following literature methods.
N-[(1R)-1-(2-Benzyloxyethyl)but-3-enyl]-N-[(2S)-2-(methoxymeth-
yl)pyrrolidin-1-yl]acrylamide (5): Phenyllithium (1.8  in dibutyl
ether, 2 mL, 3.7 mmol) was added dropwise to a solution of allyltri-
phenyltin (1.46 g, 3.7 mmol) in dry THF (10 mL) under argon. Af-
ter stirring at room temp. for 30 min, the suspension was cooled to
–78 °C, and a solution of hydrazone 6 (500 mg, 1.81 mmol) in dry
THF (3 mL) was added dropwise by syringe. The mixture was
stirred at –78 °C for 30 min, then allowed to warm to room temp.
and stirred for an additional 12 h. The mixture was re-cooled to
–78 °C, and acryloyl chloride (524 mg, 0.47 mL, 5.79 mmol) was
added dropwise. After stirring at –78 °C for 30 min, the mixture
was allowed to warm to room temp. over 3 h. Water (10 mL) was
added dropwise, and the mixture was filtered and extracted with
CH2Cl2 (3ϫ30 mL). The combined organic extracts were dried
(MgSO4), the solvent was removed under vacuum, and the oily
residue was purified by flash column chromatography on silica gel
(ethyl acetate/hexanes, 30:70) to afford the diene hydrazide 5 as a
yellow oil (431 mg, 64%). [α]2D5 = –16.3 (c = 4.50, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.63–1.92 (m, 4 H, 2ϫCH2), 2.21–2.24 (m,
2 H, CH2), 2.72 (t, J = 7.2 Hz, 2 H, CH2), 2.88–2.93 (m, 2 H,
CH2), 3.19–3.34 [m, 6 H (1 H and 5 H), CH2OCH3], 3.41–3.48 (m,
{(2R)-1-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]-6-oxopiperidin-2-
yl}acetaldehyde (12): A solution of DMSO (368 mg, 0.33 mL,
4.72 mmol) in CH2Cl2 (2 mL) was slowly added to a stirred solu-
tion of oxalyl chloride (273 mg, 0.19 mL, 2.15 mmol) in CH2Cl2
(5 mL) at –78 °C. The mixture was stirred at –78 °C for 30 min,
and then a solution of alcohol 11 (550 mg, 2.15 mmol) in CH2Cl2
(2 mL) was added dropwise. After 30 min, Et3N (1.08 g, 1.5 mL,
10.7 mmol) was added, and the stirred mixture was allowed to
warm to room temp. over 2 h. Water (15 mL) was added, and the
aqueous layer was extracted with CH2Cl2 (3ϫ30 mL). The com-
bined organic layers were dried (MgSO4) and concentrated under
vacuum. The oily residue was purified by flash column chromatog-
raphy on silica gel (ethyl acetate) to afford aldehyde derivative 12
1 H, NCH), 3.52 (t, J = 5.7 Hz, 2 H, OCH2), 4.43 (d, JAB
=
11.8 Hz, 1 H, OCH2Ph), 4.54 (d, JAB = 11.8 Hz, 1 H, OCH2Ph),
4.98–5.12 (m, 2 H, CH2=), 5.55 (dd, J = 2.3, 10.5 Hz, 1 H, CH2=),
5.75–5.82 (m, 1 H, CH2=), 6.27 (dd, J = 2.3, 17.2 Hz, 1 H, CH2=),
7.15 (dd, J = 10.5, 17.2 Hz, 1 H, COCH=), 7.24–7.31 (m, 5 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH2), 26.3
(CH2), 33.3 (CH2), 37.4 (CH2), 52.1 (NCH2), 53.2 (CH), 58.1 (CH),
58.9 (OCH3), 67.4 (CH2), 72.7 (CH2), 74.2 (CH2), 117.1 (CH2=),
126.1 (CH2=), 127.5 (2ϫCH), 128.7 (2ϫCH), 129.4 (CH), 135.9
(CH), 137.2 (CH), 138.5 (C), 169.5 (CO) ppm. C22H32N2O3 (372.5):
calcd. C 70.94, H 8.66, N 7.32; found C 71.07, H 8.48, N 7.59.
1
as a yellow oil (448 mg, 82%). [α]2D5 = +1.7 (c = 0.70, CHCl3). H
NMR (300 MHz, CDCl3): δ = 1.18–1.29 (m, 1 H, CH2), 1.38–1.47
(m, 2 H, CH2), 1.53–1.59 (m, 1 H, CH2), 1.66–1.82 (m, 2 H, CH2),
1.87–1.98 (m, 2 H, CH2), 2.23–2.34 (m, 4 H, NCOCH2, CH2CO),
2.67 (dt, J = 4.1, 7.9 Hz, 1 H, NCH2), 3.23 (d, J = 5.4 Hz, 2 H,
CH2O), 3.26 (s, 3 H, OCH3), 3.29–3.34 (m, 1 H, NCH2), 3.85–3.88
(m, 1 H, NCH), 4.33–4.38 (m, 1 H, NCH), 9.53 (t, J = 3.1 Hz, 1
H, CHO) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.2 (CH2), 22.5
(CH2), 27.0 (CH2), 30.4 (CH2), 34.2 (CH2), 49.7 (CH2), 52.0
(NCH2), 58.4 (OCH3), 58.6 (CH), 59.8 (CH), 76.3 (OCH2), 168.7
(CO), 195.2 (CHO) ppm. C13H22N2O3 (254.3): calcd. C 61.43, H
8.72, N 11.01; found C 61.72, H 8.89, N 10.78.
(6R)-6-(2-Benzyloxyethyl)-1-[(2S)-2-(methoxymethyl)pyrrolidin-1-
yl]-5,6-dihydro-1H-pyridin-2-one (10): Grubbs first-generation cata-
lyst (0.3 g, 10 mol-%, 0.37 mmol) was added to a stirred solution
of diene hydrazide 5 (1.4 g, 3.76 mmol) in dry CH2Cl2 (80 mL), and
the resulting mixture was refluxed for 12 h. Then, the mixture was (6R)-6-[(2RS)-2-Hydroxy-2-(4-methoxyphenyl)ethyl]-1-[(2S)-2-(meth-
concentrated under reduced pressure, and the oily residue was puri- oxymethyl)pyrrolidin-1-yl]piperidin-2-one (14): A solution of p-
Eur. J. Org. Chem. 2010, 1943–1950
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D. Dumoulin, S. Lebrun, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
methoxybenzylmagnesium bromide (1  in THF, 1.73 mL,
1.73 mmol) was slowly added to a solution of aldehyde 12 (400 mg,
1.57 mmol) in dry THF (10 mL) at –78 °C under argon. After stir-
ring at –78 °C for 2 h, the reaction mixture was allowed to warm
to room temp. over 12 h and then quenched with saturated aqueous
[2-(4-Methoxyphenyl)[1,3]dioxan-2-yl]acetaldehyde (18): Pyridinium
dichromate (PDC; 23.7 g, 63 mmol) was added portionwise to a
solution of alcohol 17 (10 g, 42 mmol) in CH2Cl2 (200 mL). The
reaction mixture was stirred at room temp. for 12 h, then diluted
with Et2O (100 mL) and filtered through a pad of Celite. Evapora-
NaHCO3 (10 mL). The aqueous layer was extracted with CH2Cl2 tion of the solvents delivered a crude oily product, which was puri-
(3ϫ30 mL), and the combined organic layers were washed with
brine (10 mL) and dried (MgSO4). Evaporation of the solvent un-
der reduced pressure left a residue, which was purified by column
chromatography on silica gel (ethyl acetate) to afford 14 as an in-
separable 1:1 mixture of (R,R,S)/(S,R,S) isomers (423 mg, 77%).
The isomeric ratio was evaluated from the 1H NMR spectrum and
integration of the CHOH protons: δ = 4.68 (dd, J = 5.3, 7.6 Hz, 1
H) and 4.89 (dd, J = 2.5, 10.8 Hz, 1 H) ppm.
fied by flash column chromatography on silica gel (ethyl acetate/
hexanes, 45:55) to afford acetaldehyde derivative 18 as a yellowish
oil (9.0 g, 91%). 1H NMR (300 MHz, CDCl3): δ = 1.16–1.29 (m, 1
H, CH2), 2.05–2.18 (m, 1 H, CH2), 2.61 (d, J = 2.9 Hz, 2 H,
CH2CO), 3.83 (s, 3 H, OCH3), 3.86–3.95 (m, 4 H, 2ϫOCH2), 6.94
(d, J = 8.9 Hz, 2 H, ArH), 7.36 (d, J = 8.9 Hz, 2 H, ArH), 9.95 (t,
J = 2.9 Hz, 1 H, CHO) ppm. 13C NMR (75 MHz, CDCl3): δ =
25.4 (CH2), 55.3 (OCH3), 56.9 (CH2), 61.1 (2 ϫ OCH2), 100.4
(OCO), 114.3 (2ϫCH), 128.3 (2ϫCH), 130.8 (C), 159.5 (C), 201.3
(CHO) ppm. C13H16O4 (236.3): calcd. C 66.09, H 6.83; found C
65.97, H 6.95.
(1RS)-1-(4-Methoxyphenyl)-2-[(2R)-piperidin-2-yl]ethanol (4):
BH3·THF (1  in THF, 22.1 mL, 22.1 mmol) was slowly added to
a solution of 14 (400 mg, 1.1 mmol) in dry THF (15 mL) at 0 °C.
After refluxing for 48 h, the reaction mixture was cooled to room
temp. and quenched with aqueous NaOH (10%, 10 mL). The mix-
ture was concentrated under vacuum to one-third of its volume and
refluxed for 5 h. The aqueous layer was separated and extracted
with Et2O (3ϫ30 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to afford a 1:1
mixture of amino alcohols (R,R,S)-4/(S,R,S)-4 (combined yield:
202 mg, 78%), which was used directly in the next step without
[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]{2-[2-(4-methoxyphenyl)-
[1,3]dioxan-2-yl]ethylidene}amine (19): SAMP (4.86 g, 37 mmol)
and MgSO4 (2 g) were added to a solution of the aldehyde 18 (8 g,
34 mmol) in CH2Cl2 (50 mL), and the mixture was stirred at room
temp. for 12 h. After filtration and evaporation of the solvent under
reduced pressure, the crude product was purified by flash column
chromatography on silica gel (ethyl acetate/hexanes, 40:60) to af-
ford 19 as a pale-yellow oil (11.4 g, 96%). [α]2D5 = –66.6 (c = 1.30,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.18–1.29 (m, 1 H,
CH2), 1.71–1.93 (m, 4 H, 2ϫCH2), 2.02–2.13 (m, 1 H, CH2), 2.62
(t, J = 5.7 Hz, 2 H, CH2CN), 2.73–2.79 (m, 1 H, NCH2), 3.36–3.55
[m, 7 H (1 H, NCH2, OCH3, NCH, OCH2)], 3.78–3.91 (m, 7 H,
OCH3, 2ϫOCH2), 6.58 (t, J = 5.8 Hz, 1 H, CH=N), 6.93 (d, J =
8.9 Hz, 2 H, ArH), 7.33 (d, J = 8.9 Hz, 2 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 22.1 (CH2), 25.6 (CH2), 26.6 (CH2), 48.2
(NCH2), 50.3 (CH2), 55.2 (OCH3), 59.1 (OCH3), 61.0 (2ϫOCH2),
63.0 (CH), 74.7 (OCH2), 101.3 (OCO), 113.8 (2 ϫ CH), 128.7
(2ϫCH), 131.5 (C), 133.8 (C=N), 159.1 (C) ppm. C19H28N2O4
(348.5): calcd. C 65.49, H 8.10, N 8.04; found C 65.58, H 8.33, N
7.89.
1
further purification. The isomeric ratio was evaluated from the H
NMR spectrum and integration of the CHOH protons: δ = 4.84
(dd, J = 3.2, 9.8 Hz, 1 H) and 4.93 (dd, J = 4.2, 7.3 Hz, 1 H) ppm.
Methyl [2-(4-Methoxyphenyl)[1,3]dioxan-2-yl]acetate (16): A stirred
solution of β-oxo ester 15 (16.0 g, 77 mmol) in dry toluene (60 mL),
1,3-propanediol (17.6 g, 0.231 mmol) and a catalytic amount of p-
touenesulfonic acid was subjected to azeotropic distillation by
using a Dean–Stark trap for 5 h. The solvent was evaporated under
reduced pressure to give a crude oily product, which was purified
by flash column chromatography on silica gel (ethyl acetate/hex-
anes, 50:50) to afford methyl ester 16 as a yellow oil (16.4 g, 80%).
1H NMR (300 MHz, CDCl3): δ = 1.15–1.27 (m, 1 H, CH2), 2.02–
2.15 (m, 1 H, CH2), 2.99 (s, 2 H, CH2), 3.63 (s, 3 H, OCH3), 3.72–
3.87 (m, 7 H, 2ϫOCH2, OCH3), 6.91 (d, J = 8.8 Hz, 2 H, ArH),
7.30 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 25.3 (CH2), 45.6 (CH2), 51.8 (OCH3), 55.4 (OCH3), 61.8
(2ϫOCH2), 107.5 (OCO), 113.4 (2ϫCH), 127.1 (2ϫCH), 133.8
(C), 159.1 (C), 169.0 (CO) ppm. C14H18O5 (266.3): calcd. C 63.15,
H 6.81; found C 63.19, H 6.91.
N-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]-N-{(1R)-1-[2-(4-meth-
oxyphenyl)[1,3]dioxan-2-ylmethyl]but-3-enyl}acrylamide (20): Ob-
tained from 19 (1 g, 2.87 mmol) following the procedure reported
for the synthesis of compound 5. Purification by flash column
chromatography on silica gel (ethyl acetate/hexanes, 20:80) fur-
nished 20 as a yellow oil (829 mg, 65%). [α]2D5 = –35.8 (c = 1.00,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.22–1.29 (m, 1 H,
CH2), 1.64–1.86 (m, 4 H, 2ϫCH2), 2.03–2.11 (m, 1 H, CH2), 2.51–
2.63 (m, 2 H, CH2), 2.83–2.98 [m, 3 H (2 H, CH2, 1 H, NCH2)],
3.11–3.37 [m, 7 H (3 H, OCH3, OCH2, NCH, 1 H, NCH2)], 3.66–
3.78 [m, 8 H (3 H, OCH3, 2ϫOCH2, NCH)], 4.92–5.03 (m, 2 H,
CH2=), 5.49 (dd, J = 2.2, 10.4 Hz, 1 H, CH2=), 5.70–5.88 (m, 1 H,
CH=), 6.22 (dd, J = 2.2, 17.2 Hz, 1 H, CH2=), 6.91 (d, J = 8.6 Hz,
2 H, ArH), 7.03 (dd, J = 10.4, 17.2 Hz, 1 H, NCOCH=), 7.32 (d,
J = 8.6 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.2
(CH2), 25.8 (CH2), 26.2 (CH2), 38.0 (CH2), 50.8 (CH2), 51.6 (CH),
52.1 (CH2), 55.3 (OCH3), 57.5 (OCH3), 58.8 (CH), 60.75 (OCH2),
60.9 (OCH2), 73.6 (OCH2), 101.9 (OCO), 114.0 (2ϫCH), 116.3
(CH2=), 125.7 (CH2=), 128.6 (2ϫCH), 129.5 (CH=), 132.5 (C),
137.4 (CH=), 159.1 (C), 169.0 (CO) ppm. C25H36N2O5 (444.6):
calcd. C 67.54, H 8.16, N 6.30; found C 67.79, H 8.03, N 6.29.
2-[2-(4-Methoxyphenyl)[1,3]dioxan-2-yl]ethanol (17): A solution of
ester 16 (15 g, 56 mmol) in THF (40 mL) was slowly added to a
suspension of LiAlH4 (3.19 g, 84 mmol) in anhydrous THF
(150 mL) at 0 °C under argon. The resulting mixture was stirred
under reflux for 3 h. After cooling and addition of saturated aque-
ous NaOH (10%, 5 mL), CH2Cl2 (50 mL) was added and the or-
ganic layer was separated. The aqueous layer was extracted with
CH2Cl2 (2ϫ15 mL), and the combined organic layers were dried
(MgSO4), filtered and concentrated under vacuum. The crude resi-
due was purified by flash column chromatography on silica gel
(ethyl acetate/hexanes, 50:50) to afford alcohol 17 as a colorless oil
(11.3 g, 85%). 1H NMR (300 MHz, CDCl3): δ = 1.25–1.32 (m, 1
H, CH2), 1.96 (t, J = 5.3 Hz, 2 H, CH2), 2.06–2.18 (m, 1 H, CH2),
3.16 (br. s, 1 H, OH), 3.69–3.89 (m, 9 H, 3ϫCH2O, OCH3), 6.93
(d, J = 8.8 Hz, 2 H, ArH), 7.38 (d, J = 8.8 Hz, 2 H, ArH) ppm.
13C NMR (75 MHz, CDCl3): δ = 25.5 (CH2), 46.3 (CH2), 55.3
(OCH3), 58.6 (CH2OH), 61.0 (2 ϫ OCH2), 103.1 (OCO), 114.1
(6R)-1-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]-6-[2-(4-methoxy-
phenyl)[1,3]dioxan-2-ylmethyl]-5,6-dihydro-1H-pyridin-2-one (21):
(2 ϫ CH), 128.4 (2 ϫ CH), 131.5 (C), 159.3 (C) ppm. C13H18O4 Obtained by ring-closing metathesis of 20 (600 mg, 1.35 mmol) fol-
(238.3): calcd. C 63.53, H 7.61; found C 63.37, H 7.81. lowing the procedure reported for the synthesis of compound 10.
1948
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1943–1950

First Asymmetric Synthesis of Boehmeriasin A
Purification by column chromatography on silica gel (ethyl acetate/
and silica gel (2 g) were added to a solution of 24 (300 mg,
0.61 mmol) in CH2Cl2 (30 mL), and the mixture was stirred vigor-
hexanes, 40:60) to afford 21 as a yellow oil (388 mg, 69%). [α]2D5
=
1
–12.4 (c = 2.20, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.22– ously for 12 h. The reaction mixture was filtered through a pad of
1.29 (m, 1 H, CH2), 1.32–1.43 (m, 1 H, CH2), 1.53–1.65 (m, 1 H,
CH2), 1.83–2.19 [m, 5 H (4 H, 2ϫCH2, 1 H, CH2)], 2.57–2.68 (m,
1 H, CH2), 2.80 (ddd, J = 2.3, 6.0, 17.7 Hz, 1 H, CH2), 2.93–3.02
Celite, which was rinsed with CH2Cl2 (3ϫ100 mL). Concentration
of the filtrate under vacuum delivered the crude product, which
was purified by flash column chromatography on silica gel (ethyl
(m, 1 H, NCH2), 3.14–3.21 (m, 2 H, OCH2), 3.26 (s, 3 H, OCH3), acetate/hexanes, 45:55) to afford 3 as a yellow oil (212 mg, 71%).
3.38–3.47 (m, 1 H, NCH2), 3.62–3.71 (m, 1 H, NCH), 3.76–3.88
[α]2D5 = –2.4 (c = 2.10, CHCl3). 1H NMR (300 MHz, CDCl3, 1:1
[m, 8 H (OCH3, 2ϫOCH2, NCH)], 5.74 (dd, J = 2.5, 9.8 Hz, 1 H, amide rotamers): δ = 1.35–1.71 (m, 6 H, 3ϫCH2), 2.66 (td, J =
CH=), 6.33–6.42 (m, 1 H, CH=), 6.91 (d, J = 8.7 Hz, 2 H, ArH),
7.28 (d, J = 8.7 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 23.2 (CH2), 25.5 (CH2), 27.6 (CH2), 29.5 (CH2), 45.5 (CH2),
2.4–13.5 Hz, 0.5 H), 3.08–3.37 (m, 2.5 H), 3.66–3.89 (m, 11.5 H),
4.63–?? (m, 0.5 H), 4.76 (m, 0.5 H), 5.30 (m, 0.5 H), 6.82 (m, 1 H,
ArH), 6.91–7.03 (m, 3 H, ArH), 7.92 (d, J = 8.7 Hz, 1 H, ArH),
52.3 (CH2), 55.3 (OCH3, CH), 58.8 (OCH3), 60.4 (CH), 60.8 8.04 (d, J = 8.8 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3,
(2 ϫ OCH2), 76.7 (OCH2), 101.2 (OCO), 113.8 (2 ϫCH), 125.9 1:1 amide rotamers): δ = 18.7 (CH2), 19.3 (CH2), 25.5 (CH2), 25.6
(CH=), 128.5 (2ϫCH), 132.0 (C), 138.0 (CH=), 159.2 (C), 163.2
(CO) ppm. C23H32N2O5 (416.5): calcd. C 66.32, H 7.74, N 6.73;
found C 66.48, H 7.94, N 6.81.
(CH2), 27.3 (CH2), 29.3 (CH2), 37.6 (CH2), 38.5 (CH2), 38.9 (CH2),
40.5 (CH2), 40.9 (CH2), 42.0 (CH2), 46.6 (NCH), 49.6 (NCH), 55.5
(OCH3), 55.55 (OCH3), 56.0 (OCH3), 56.05 (2 ϫ OCH3), 56.1
(OCH3), 112.8 (CH), 113.2 (CH), 113.8 (2ϫCH), 113.9 (2ϫCH),
114.3 (C), 114.6 (C), 115.3 (2ϫCH), 127.1 (C), 127.5 (C), 129.6
(C), 129.8 (C), 130.3 (2ϫCH), 130.8 (2ϫCH), 130.9 (C), 130.95
(C), 148.3 (C), 148.4 (C), 163.6 (C), 163.8 (C), 169.2 (NCO), 169.5
(NCO), 195.8 (CO), 196.8 (CO) ppm. C24H28BrNO5 (490.4): calcd.
C 58.78, H 5.76, N 2.86; found C 58.57, H 5.69, N 2.81.
(6R)-1-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]-6-[2-(4-methoxy-
phenyl)[1,3]dioxan-2-ylmethyl]piperidin-2-one (22): Obtained as pre-
viously described for the synthesis of 11; catalytic hydrogenation of
21 (500 mg, 1.20 mmol) delivered 22 as a yellow oil (477 mg, 95%).
[α]2D5 = –24.9 (c = 0.51, CHCl3). H NMR (300 MHz, CDCl3): δ =
1
1.37–1.48 (m, 1 H, CH2), 1.52–1.81 (m, 1 H, CH2), 1.87–2.06 (m,
6 H, 3ϫCH2), 2.32 (t, J = 6.4 Hz, 2 H, CH2), 2.40–2.64 (m, 4 H,
2ϫCH2), 3.05–3.12 (m, 1 H, NCH2), 3.17–3.26 (m, 6 H, OCH2,
OCH3, NCH), 3.45–3.54 [m, 2 H (1 H, NCH, 1 H, NCH2)], 3.73–
3.85 (m, 7 H, OCH3, 2ϫOCH2), 6.82 (d, J = 8.6 Hz, 2 H, ArH),
7.11 (d, J = 8.6 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 17.4 (CH2), 23.1 (CH2), 27.2 (CH2), 27.6 (CH2), 31.3 (CH2),
33.9 (CH2), 34.6 (CH2), 53.2 (CH2), 55.3 (OCH3), 58.7 (CH), 59.8
(OCH3), 61.4 (CH), 62.3 (2ϫOCH2), 76.7 (OCH2), 101.5 (OCO),
113.8 (2ϫCH), 129.2 (2ϫCH), 133.6 (C), 157.8 (C), 169.4 (CO)
ppm. C23H34N2O5 (418.5): calcd. C 66.01, H 8.19, N 6.69; found
C 66.24, H 7.92, N 6.80.
(9aR)-3-(2-Bromo-4,5-dimethoxyphenyl)-2-(4-methoxyphenyl)-
1,6,7,8,9,9a-hexahydroquinolizin-4-one (2): A solution of 3 (250 mg,
0.51 mmol) in 5% ethanolic KOH (10 mL) was refluxed for 1 h.
The reaction mixture was then concentrated under reduced pres-
sure, diluted with water (15 mL) and extracted with CH2Cl2
(3ϫ30 mL). The combined organic layers were washed with water
(10 mL) and HCl (5%, 10 mL) and dried (MgSO4). After evapora-
tion of the solvent under vacuum, purification of the residue by
column chromatography on silica gel (ethyl acetate/hexanes, 40:60)
afforded 2 as a pale-yellow oil (155 mg, 69%). [α]2D5 = –37.3 (c =
0.50, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.36–1.95 (m, 6
H, 3ϫCH2), 2.61–2.82 [m, 3 H (1 H, NCH2, 2 H, CH2)], 3.64 (s,
3 H, OCH3), 3.65–3.71 (m, 1 H, NCH), 3.75 (s, 3 H, OCH3), 3.85
(s, 3 H, OCH3), 4.56 (br. d, 1 H, NCH2), 6.45 (s, 1 H, ArH), 6.69
(d, J = 8.7 Hz, 2 H, ArH), 7.00 (s, 1 H, ArH), 7.02 (d, J = 8.7 Hz,
2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.3 (CH2), 24.6
(CH2), 33.4 (CH2), 37.6 (CH2), 42.8 (NCH2), 53.4 (NCH), 55.2
(OCH3), 55.9 (OCH3), 56.0 (OCH3), 113.4 (2 ϫCH), 114.7 (C),
114.9 (CH), 115.5 (CH), 128.9 (2ϫCH), 130.4 (C), 130.6 (C), 131.5
(C), 145.7 (C), 148.0 (C), 148.6 (C), 159.1 (C), 166.2 (CO) ppm.
C24H26BrNO4 (472.4): calcd. C 61.02, H 5.55, N 2.97; found C
60.89, H 5.42, N 2.71.
(1RS)-1-(4-Methoxyphenyl)-2-[(2R)-piperidin-2-yl]ethanol (4):
Treatment of 22 (300 mg, 0.72 mmol) with BH3·THF complex (as
described previously for the conversion of 14 into 4) afforded 4 as
a mixture of (RS,R)-amino alcohols, which was used directly in the
next step without further purification (135 mg, 80%).
2-(2-Bromo-4,5-dimethoxyphenyl)-1-{(2R)-2-[(2RS)-2-hydroxy-2-(4-
methoxyphenyl)ethyl]piperidin-1-yl}ethanone (24): A solution of 2-
bromo-4,5-dimethoxyphenylacetyl chloride (23; 622 mg,
2.12 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred ice-
cooled mixture of amino alcohol 4 (250 mg, 1.06 mmol) and
K2CO3 (292 mg, 2.12 mmol) in CH2Cl2 (20 mL). The reaction mix-
ture was stirred at 0 °C for 6 h, then at room temp. for an ad-
ditional 2 h. The mixture was filtered, and the filtrate was washed
with water (15 mL), dried (MgSO4) and concentrated. The oily resi-
due was dissolved in a solution of K2CO3 (300 mg) in methanol/
water (40 mL, 2:1, v/v), and the mixture was refluxed for 1 h. Con-
centration under reduced pressure delivered a brown oil, which was
extracted with CH2Cl2 (3ϫ15 mL). The combined organic extracts
were washed with water (10 mL), aqueous NaOH (5 %, 10 mL)
then aqueous HCl (5%, 10 mL), dried (MgSO4), and the solvent
was evaporated under vacuum to give an oily residue. Purification
by column chromatography on silica gel (CHCl3) afforded 24 (1:1
mixture of two diastereoisomers) as a pale-yellow oil (464 mg,
89%). The isomeric ratio was evaluated from the 1H NMR spec-
trum and integration of the CHOH protons: δ = 4.77 (dd, J = 6.0,
8.2 Hz, 1 H) and 4.91 (br. d, J = 8.7 Hz, 1 H) ppm.
(9aR)-2,3,6-Trimethoxy-9,9a,10,11,12,13-hexahydro-13a-azabenzo-
[b]triphenylen-14-one (25): A solution of 2 (100 mg, 0.21 mmol),
AIBN (5 mg) and Bu3SnH (120 mg, 0.11 mL, 0.42 mmol) in freshly
distilled benzene (40 mL) was refluxed under argon for 3 h. After
cooling, the reaction mixture was concentrated under vacuum, and
the resulting mixture was purified by column chromatography on
silica gel (ethyl acetate/hexanes, 40:60) to afford 25 as a colorless
solid (75 mg, 91%); m.p. 199–200 °C. [α]2D5 = –102.3 (c = 0.53,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.41–1.68 (m, 4 H,
2ϫCH2), 1.87–2.09 (m, 2 H, CH2), 2.91 (td, J = 3.1, 13.0 Hz, 1 H,
CH2), 3.04 (dd, J = 11.0, 16.2 Hz, 1 H, NCH2), 3.43 (dd, J = 4.8,
16.2 Hz, 1 H, NCH2), 3.54–3.62 (m, 1 H, NCH), 4.06 (s, 3 H,
OCH3), 4.11 (s, 3 H, OCH3), 4.13 (s, 3 H, OCH3), 4.72 (br. d, J =
13.0 Hz, 1 H, CH2), 7.22 (dd, J = 2.4, 9.4 Hz, 1 H, ArH), 7.36 (s,
1 H, ArH), 7.84 (d, J = 2.4 Hz, 1 H, ArH), 8.05 (d, J = 9.4 Hz, 1
H, ArH), 9.41 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 22.9 (CH2), 24.7 (CH2), 32.7 (CH2), 32.9 (CH2), 42.8 (CH2), 52.8
(CH), 55.5 (OCH3), 55.7 (OCH3), 55.9 (OCH3), 102.9 (CH), 104.4
2-(2-Bromo-4,5-dimethoxyphenyl)-1-{(2R)-2-[2-(4-methoxyphenyl)-
2-oxoethyl]piperidin-1-yl}ethanone (3): PDC (275 mg, 0.73 mmol)
Eur. J. Org. Chem. 2010, 1943–1950
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1949

D. Dumoulin, S. Lebrun, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
A. Nam, Y.-H. Hea, Planta Med. 2003, 69, 21–25; h) J. P.
Michael, Nat. Prod. Rep. 2002, 19, 719–741; i) J. P. Michael,
Nat. Prod. Rep. 2001, 18, 520–542.
(CH), 108.7 (C), 115.5 (CH), 123.5 (C), 124.1 (CH), 125.5 (C),
126.6 (CH), 126.8 (C), 127.3 (C), 130.1 (C), 148.4 (C), 149.3 (C),
157.3 (C), 167.3 (CO) ppm. C24H25NO4 (391.5): calcd. C 73.64, H
6.44, N 3.58; found C 73.79, H 6.42, N 3.86.
[4] a) M. G. Banwell, A. Bezos, C. Burns, I. Kruszelnicki, C. R.
Parish, S. Su, M. O. Sydnes, Bioorg. Med. Chem. Lett. 2006,
16, 181–185 and references cited therein; b) L. Wei, Q. Shi,
K. F. Bastow, A. Brossi, S. L. Morris-Natschke, K. Nakagawa-
Goto, T.-S. Wu, S.-L. Pan, C.-M. Teng, K.-H. Lee, J. Med.
Chem. 2007, 50, 3674–3680.
(R)-Boehmeriasin A (1d): A solution of 25 (70 mg, 0.18 mmol) in
THF (2 mL) was added dropwise to an ice-cooled, stirred suspen-
sion of LiAlH4 (10 mg, 0.27 mmol) in dry THF (3 mL). The reac-
tion mixture was refluxed under argon for 3 h, then cooled to 0 °C
and carefully quenched by addition of an aqueous NaOH solution
(10%, 2 mL); CH2Cl2 (5 mL) was added, and the organic layer was
separated. The aqueous layer was extracted with CH2Cl2
(3ϫ5 mL), and the combined organic layers were dried (MgSO4),
filtered and concentrated under reduced pressure. The crude resi-
due was purified by flash column chromatography on silica gel
(CHCl3/CH3OH, 95:5) to yield boehmeriasin A (1d) as a colorless
[5] For representative recent examples, see: a) M. Cui, Q. Wang,
Eur. J. Org. Chem. 2009, 5445–5451; b) S. Yamashita, N. Ku-
rono, H. Senboku, M. Tokuda, K. Orito, Eur. J. Org. Chem.
2009, 1173–1180; c) S. Kim, Y. M. Lee, J. Lee, T. Lee, Y. Fu,
Y. Song, J. Cho, D. Kim, J. Org. Chem. 2007, 72, 4886–4891;
d) A. Fürstner, J. W. J. Kennedy, Chem. Eur. J. 2006, 12, 7398–
7410; e) S. Kim, T. Lee, E. Lee, J. Lee, G.-j. Fan, S. K. Lee, D.
Kim, J. Org. Chem. 2004, 69, 3144–3149; f) S. Lebrun, A. Cout-
ure, E. Deniau, P. Grandclaudon, Tetrahedron 1999, 55, 2659–
2670; g) H. Suzuki, S. Aoyagi, C. Kibayashi, J. Org. Chem.
1995, 60, 6114–6122; h) H. Suzuki, S. Aoyagi, C. Kibayashi,
Tetrahedron Lett. 1995, 36, 935–936.
solid (51 mg, 75%); m.p. 215–217 °C (ref.[9] 216–218 °C). [α]2D5
=
–80.2 (c = 0.15, CH3OH) {ref.[9] [α]2D5 = –80.4 (c = 0.1, CH3OH)}.
Analytical and spectroscopic data were in agreement with those
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Received: December 3, 2009
Published Online: February 16, 2010
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