First asymmetric synthesis and determination of the absolute configuration of a lignan isolated from virola sebifera

Article abstract of DOI:10.1002/ejoc.200400885

The first asymmetric synthesis of a lignan isolated from the seeds of Virola sebifera, one of the most widely spread Myristicaceae species in Brazil, in four steps (48 % overall yield) and with excellent stereoselectivity (de, ee ≥ 96%) is described. The key step is the asymmetric Michael addition of a lithiated enantiopure α-amino nitrile to an enone, followed by α-methylation and cleavage of the amino nitrile. The absolute configuration of the naturally occurring 1,4-diketone was determined by polarimetry as well as by CD spectroscopy and quantum chemical calculations. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400885

FULL PAPER
First Asymmetric Synthesis and Determination of the Absolute Configuration
of a Lignan Isolated from Virola sebifera
Dieter Enders,*[a] Mile Milovanovic,[a] Elena Voloshina,[a] Gerhard Raabe,[a] and
Jörg Fleischhauer[a]
Keywords: Lignans / Nucleophilic acylation / α-Amino nitriles / Michael addition / Circular dichroism
The first asymmetric synthesis of a lignan isolated from the
seeds of Virola sebifera, one of the most widely spread Myr-
isticaceae species in Brazil, in four steps (48% overall yield)
and with excellent stereoselectivity (de, ee Ն 96%) is de-
scribed. The key step is the asymmetric Michael addition of
a lithiated enantiopure α-amino nitrile to an enone, followed
by α-methylation and cleavage of the amino nitrile. The ab-
solute configuration of the naturally occurring 1,4-diketone
was determined by polarimetry as well as by CD spec-
troscopy and quantum chemical calculations.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
cleophilic acylation methodology (Umpolung) employing
enantiopure lithiated α-amino nitriles developed in our
group[5] and to determine the absolute configuration of the
natural product.
Introduction
Lignans are important secondary plant metabolites pro-
duced in nature by oxidative dimerization of phenylprope-
nes, such as ferulic acid, coniferyl alcohol or isoeugenol.[1]
This large class of natural products has been of great inter-
est to synthetic organic chemists, mainly because its mem-
bers possess a variety of different biological activities.[2] Re-
cently, Kato and Rezende[3] isolated the 2,3-dipiperonoylbu-
tane lignan 1 from the seed extract of Virola sebifera (Aub-
let.), one of the most widely spread Myristicaceae species
in Brazil. The absolute configuration of this new lignan re-
mained unknown, but the meso compound (meso-1) could
be excluded because of the optical activity of the isolated
natural lignan. Interestingly, the racemic diketone rac-1 had
already been synthesized much earlier, before its isolation
from a natural source, by Stevenson et al.[4] in the course of
the synthesis of other lignans. We decided to synthesize
both enantiomers of the title lignan by the asymmetric nu-
Results and Discussion
For the asymmetric synthesis of the title 1,4-diketone lig-
nan 1 we had a choice of two synthetic methods developed
in our group: oxidative coupling of metallated SAMP-hy-
drazones[6] and asymmetric nucleophilic acylation with
amino nitriles.[5] We choose the latter methodology, which
has already been shown to give excellent asymmetric induc-
tion with the chiral auxiliaries (R,R)-2 or (S,S)-2 in Michael
additions to enoates,[5c] cyclic enones[5e,5f] and buten-
olide.[5g–5j] For this approach the methodology needed to
be extended to acyclic enones as Michael acceptors, so we
planned to use the amino nitrile anion A as an enantiopure
synthetic equivalent of the piperonoyl anion d1-synthon B
in a 1,4-addition to the enone (E)-5, easily available by aldol
condensation.
[a] Institut für Organische Chemie, Rheinisch-Westfälische Techni-
sche Hochschule,
Starting from acetopiperone 3, the aldol adduct 4 was
obtained in 62% yield after metallation with lithium diiso-
propylamide (LDA) and trapping of the enolate with acetal-
Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax: +49-241-8092127
E-mail: enders@rwth-aachen.de
1984
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400885
Eur. J. Org. Chem. 2005, 1984–1990

First Asymmetric Synthesis of a Virola sebifera Lignan
FULL PAPER
dehyde, followed by condensation with mesyl chloride and of 8 after 1,4-addition with methyl iodide in situ, but unfor-
triethylamine to afford the enone (E)-5 in 92% yield tunately the de decreased from 96% to 68% under these
(Scheme 1).
conditions. While trying to improve the yield of the final
cleavage step we found that (R,R,S,S,S)-9 can be converted
into (S,S)-1 not only with aqueous silver nitrate solution
as reported earlier,[5e] but also under acidic conditions. The
cleavage of the amino nitrile 9 to provide the ketone 1 with
2 m hydrochloric acid at reflux in THF was complete after
15 min, was epimerization-free and gave a high yield (79%).
This method was more reliable than the silver nitrate cleav-
age, which required longer reaction times (Scheme 2).
1
The diastereomeric excesses were determined by H and
13C NMR spectroscopy. The ee value of the title lignan
(S,S)-1 is based on the de value of the precursor 9, because
no epimerization and racemization occurred during the
amino nitrile cleavage. The enantiomeric lignan (R,R)-1 was
prepared in the same manner by employing the chiral amine
auxiliary (S,S)-2, and a similar overall yield and stereoselec-
tivity was achieved (de, ee Ն 96%).
Scheme 1. Synthesis of the enone Michael acceptor (E)-5.
The α-amino nitrile (R,R,S/R)-7 was synthesized from
the enantiomerically pure secondary amine (R,R)-2, pipero-
nal (6) and sodium cyanide in methanol. The product was
obtained in 81% yield as a mixture of α-epimers. Deproton-
ation of 7 with LDA in THF and treatment with the enone
(E)-5 at –100 °C afforded the Michael adduct (R,R,S,S)-8
in high yield (83%) and with good diastereoselectivity (de
Ն 96%). The second stereogenic centre of the natural pro-
duct was introduced through subsequent metallation of the
Michael adduct 8 with potassium diisopropylamide (KDA)
in THF at –100 °C and trapping of the enolate with methyl
iodide at –78 °C. The resulting amino nitrile (R,R,S,S,S)-9
was obtained in excellent yield (90%) and high dia-
stereomeric purity (de Ն 96%). It is important to note that
KDA was necessary for the α-methylation of 8, all attempts
Determination of the Absolute Configuration by CD
Spectroscopy and Quantum Chemical Calculations
The experimentally measured spectra of the two enantio-
mers of 1 [(R,R) and (S,S)] are shown in Figure 1. For the
assignment of the absolute configuration we performed
quantum chemical calculations.
Conformational Search
Starting with the arbitrarily chosen (R,R) enantiomer of
to deprotonate 8 with LDA under a variety of conditions 1, we performed a Monte-Carlo conformational search
having failed. We also tried a tandem Michael addition/ using the semiempirical AM1[7] parametrization and the
methylation process by trapping of the intermediate enolate program SPARTAN.[8]
Scheme 2. First asymmetric synthesis of the Virola sebifera lignan (S,S)-1.
Eur. J. Org. Chem. 2005, 1984–1990
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1985

D. Enders, M. Milovanovic, E. Voloshina, G. Raabe, J. Fleischhauer
FULL PAPER
geometry optimizations and a TZVP (triple-ζ valence plus
polarization functions)[13] basis set. The rotational strengths
were calculated by use of the origin-independent dipole-
velocity formalism.[14] The CD spectra of all 20 conform-
ers[10] were obtained as sums of Gaussians, each centred at
the calculated wavelength of the corresponding transition
and multiplied with its rotational strength.[15] The
Gaussians were generated by use of the empirical formula
Γ = k·λ1.5 for the half bandwidth Γ at Δεmax/e with k =
0.00375 nm–1/2 [16]
The total CD curve shown in Figure 2
.
was then obtained as a Boltzmann-weighted superposition
of the individual CD spectra.
Figure 1. CD spectra of the two enantiomers [(R,R) and (S,S)] of
1. For the assignment of the absolute configuration see text.
Figure 2. CD spectrum of (R,R)-1 calculated at the B3LYP/TZVP
level of time-dependent density functional theory (TDDFT).
The following five dihedral angels were included in the
search: θ1 = ЄC4–C3–C2–C1 and θ5 = ЄC6–C8–C9–C10,
since the C2–C3(=O)C4– and the C9–C8(=O)C6 segment
might occur in two different orientations with values of θ1
and θ5 close to 0° or 180°, θ2 = ЄC5–C4–C3–C2 and θ4 = Є
C7–C6–C8–C9, because the methyl groups at C4 and C6
might be rotated around the C3–C4 and C6–C8 bonds,
respectively, and θ3 = ЄC3–C4–C6–C8, because the two
halves of the molecule can be rotated relative to each other
about the C4–C6 bond. The initial geometry was defined by
use of the following values: θ1 = 0, θ5 = 180, θ2 = 0, θ4 =
120 and θ3 = 240°. The energetically lowest 66 stable con-
formers lying within an energy range of 6 kcal mol–1 were
reoptimized at the DFT level by use of the B3LYP combi-
nation of functionals[9] and the 6–31+G* basis set. Only
those conformers with energies not more than about
3 kcal mol–1 above that of the energetically lowest structure
should contribute significantly to the overall CD spectrum.
By this criterion, only the 20 energetically lowest structures
for (R,R)-1 were considered further in the calculation of the
chiroptical properties.[10]
The four highest occupied and the two lowest unoccu-
pied Kohn–Sham orbitals (KSOs) of the most stable con-
former (Ψ90–Ψ95) are shown in Figure 3 (see part b). Our
TDDFT calculations predict 20 transitions in the range be-
tween 210 and 340 nm. The relevant configurations for
these states obtained for the most stable conformer are
listed in Table 1, together with the calculated rotational
strengths. In addition we list the angle Θ between the elec-
trical and the magnetic transition dipole moments. Note
that in cases in which this angle is close to 90° the sign of
the corresponding Cotton effect is not very reliable because
the cosine changes its sign at 90°.
Both the spectrum calculated for (R,R)-1 and the experi-
mentally obtained one in the upper part of Figure 1 show
a positive first Cotton effect. The first calculated CD band,
with λmax = 315.8 nm, is relatively broad (~275–350 nm)
with a tail in the long-wavelength region. It is governed by
two nǞπ* transitions with rotational strengths of 14 and
35·10–40 ergcm3 at 329 and 325 nm for the most stable con-
former. At 20.8 and 50.9° the corresponding angles Θ are
sufficiently different from 90°, so their signs can be consid-
Calculation of the CD Spectra
The CD spectra of all twenty conformers of (R,R)-1 were ered reliable. The first measured Cotton effect in the upper
calculated by the time-dependent DFT method (TDDFT)[11] spectrum in Figure 1 is a relatively weak positive band with
as implemented in the program TURBOMOLE[12] with use a maximum at 350 nm, followed by a shoulder at 340 nm.
of the same functional (B3LYP) as in the ground state We assign these two absorptions to the transitions calcu-
1986
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 1984–1990

First Asymmetric Synthesis of a Virola sebifera Lignan
FULL PAPER
Figure 3. a) Structure of the most stable conformer of 1 calculated at the B3LYP/6-31+G* level of density functional theory. b) Kohn–
Sham orbitals ψ90–ψ95.[10]
Table 1. The electronic configurations and rotational strengths for the exited states of the most stable conformer of 1 (Boltzmann factor:
0.198) calculated at the B3LYP/TZVP level of DFT. Θ is the angle between the electrical and the magnetic dipole moment.
Wavelength (nm)
Transition weight (%)
Θ (°)
Rotational strength (×10–40 ergcm3)
329.3
325.4
311.7
307.3
295.4
294.4
272.9
270.7
91 Ǟ 94 (65.3), 90 Ǟ 95 (24.3)
90 Ǟ 94 (48.5), 91 Ǟ 95 (41.9)
93 Ǟ 94 (91.9)
92 Ǟ 94 (88.8)
93 Ǟ 95 (87.8)
20.8
50.9
92.9
121.2
113.4
82.8
119.3
116.0
14.12
34.89
–24.37
–21.31
–11.89
31.28
92 Ǟ 95 (87.6)
91 Ǟ 95 (47.6), 90 Ǟ 94 (37.9)
90 Ǟ 95 (66.4), 91 Ǟ 94 (23.4)
89 Ǟ 94 (35.5), 88 Ǟ 94 (14.3),
92 Ǟ 96 (11.6), 93 Ǟ 97 (10.5)
88 Ǟ 94 (32.8), 89 Ǟ 94 (12.8),
93 Ǟ 97 (9.6), 89 Ǟ 95 (9.2)
89 Ǟ 95 (49.2), 89 Ǟ 94 (33.1)
88 Ǟ 95 (51.5), 88 Ǟ 94 (31.0)
93 Ǟ 96 (62.6), 92 Ǟ 96 (32.8)
92 Ǟ 97 (60.7), 93 Ǟ 97 (34.4)
88 Ǟ 95 (25.8), 92 Ǟ 96 (21.2),
93 Ǟ 97 (19.3), 89 Ǟ 95 (7.7)
89 Ǟ 95 (24.9), 92 Ǟ 97 (13.6),
92 Ǟ 96 (11.3), 93 Ǟ 96 (11.2)
91 Ǟ 97 (39.1), 91 Ǟ 96 (33.3)
91 Ǟ 96 (35.0), 91 Ǟ 97 (33.6)
90 Ǟ 96 (70.5)
–12.71
–2.03
262.6
91.6
–8.80
261.7
75.3
6.28
246.1
245.0
233.4
232.5
119.8
99.1
78.4
76.7
–1.92
–5.60
0.38
0.40
229.5
108.5
–347.95
227.4
60.1
339.82
222.8
222.7
210.9
210.2
111.1
75.8
175.4
144.9
–5.68
6.43
–1.18
–1.25
90 Ǟ 97 (76.4)
lated at 329 and 325 nm. The next transition calculated at is 92.9° its sign is uncertain. An incorrect sign calculated
311.7 nm is a πǞπ* excitation with a rotational strength for this transition will certainly influence the rest of the
of –24·10–40 ergcm3. Since the angle between the corre- spectrum, so we omit further discussion of its lower-wave-
sponding electrical and magnetic transition dipole moment lengths part. However, since the sign of the first calculated
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D. Enders, M. Milovanovic, E. Voloshina, G. Raabe, J. Fleischhauer
FULL PAPER
and the combined organic layers were washed with water and dried
with MgSO4, and the solvents were evaporated in vacuo. The crude
product was purified by flash chromatography (silica gel, pentane/
diethyl ether, 1:1) to give the aldol product 4 as a colourless solid
Cotton effect agrees with that of the observed CD spectrum
in the upper part of Figure 1 we conclude that this is the
spectrum of (R,R)-1, while that in the lower part is that of
the (S,S) isomer. This assignment correlates well with the
relative topicity observed in our previous amino nitrile
Michael additions.[5] Thus, from the CD data, calculations
and the polarimetric data of the synthetic and natural lig-
nan we can unambiguously assign the (S,S) configuration
to the Virola sebifera lignan.
1
(11.86 g, 62%), m.p. 85 °C. H NMR (300 MHz, CDCl3): δ = 1.28
(d, J = 6.3 Hz, 3 H, CHCH3), 2.95 (dd, J = 17.6, 8.8 Hz, 1 H,
COCHH), 3.10 (dd, J = 17.6, 2.8 Hz, 1 H, COCHH), 3.45 (brs, 1
H, OH), 4.37 (m, 1 H, CHOH), 6.05 (s, 2 H, OCH2O), 6.85 (d, J
= 8.2 Hz, 1 H, CHarom), 7.42 (d, J = 1.7 Hz, 1 H, CHarom), 7.55 (dd,
J = 8.2, 1.7 Hz, 1 H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ
= 22.4 (CHCH3), 46.2 (OCH2), 64.1 (CHOH), 102.0 (OCH2O),
107.7, 107.9, 124.6 (Ar-CH), 131.6, 148.3, 152.2 (Ar-Cq), 198.8
(CO) ppm. IR (KBr): ν = 3469 (s), 3084 (w), 2991 (w), 2970 (m),
˜
Conclusions
2898 (m), 2788 (w), 2723 (w), 2675 (w), 2346 (w), 2216 (w), 2046
(w), 2000 (w), 1853 (w), 1791 (w), 1671 (s), 1600 (s), 1501 (s),1447
(s), 1410 (w), 1381 (m), 1323 (m), 1253 (s), 1207 (m), 1148 (m),
1110 (s), 1037 (s), 931 (m), 892 (m), 852 (w), 804 (s), 780 (m), 723
(w), 655 (w), 627 (m), 587 (w), 539 (w), 512 (87), 477 (w) cm–1. MS
(EI): m/z (%) = 208 [M]+ (32), 164 (17), 151 (27), 150 (16), 149
(100), 122 (11), 121 (23), 65 (8) 63 (7). C11H12O4 (208.21): calcd. C
63.45, H 5.81; found C 63.88, H 6.06.
In summary, a very efficient and straightforward four-
step asymmetric synthesis (de, ee Ն 96%) of both enantio-
mers of the dibenzylbutane-type lignan of Virola sebifera
has been developed, and the absolute configuration of the
natural product was determined as (S,S). In addition, the
new approach demonstrates that acyclic enones can be em-
ployed as Michael acceptors in conjugate additions with
our metallated enantiopure amino nitriles as well. The title
compounds may be used as starting building block in the
asymmetric synthesis of other related lignans.[17]
(E)-1-(Benzo[d][1,3]dioxol-6-yl)but-2-en-1-one [(E)-5]: The aldol ad-
duct 4 (7.50 g, 36.02 mmol) was dissolved in dry CH2Cl2 (180 mL)
and the solution was cooled to 0 °C. Triethylamine (10.12 mL,
72.04 mmol) was added quickly, and the reaction mixture was
stirred for 10 min. Methanesulfonyl chloride (5.58 mL,
72.04 mmol) was added dropwise, and the resulting solution was
stirred at 0 °C for 30 min. The reaction mixture was diluted with
water, and the phases were separated. The aqueous phase was ex-
tracted with CH2Cl2. The combined organic layers were washed
with HCl (1 m) and saturated aqueous NaHCO3 and were dried
over MgSO4, and the solvents were evaporated in vacuo. The re-
sulting crude product was purified by flash chromatography (silica
gel, pentane/diethyl ether, 1:3) to give (E)-5 (6.31 g, 92%) as a
colourless solid. M.p. 60 °C. 1H NMR (300 MHz, CDCl3): δ = 1.98
(dd, J = 6.9, 1.6 Hz, 3 H, CH3), 6.03 (s, 2 H, OCH2O), 6.84 (d, J
= 8.2 Hz, 1 H, CHarom), 6.86 (dq, J = 15.1, 1.7 Hz, 1 H, COCH),
7.05 (dq, J = 15.1, 6.9 Hz, 1 H, CHCH3), 7.45 (d, J = 1.7 Hz, 1 H,
CHarom), 7.55 (dd, J = 8.2, 1.7 Hz, 1 H, CHarom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 18.6 (CH3), 101.8 (OCH2O), 107.8, 108.4,
124.6 (Ar-CH), 127.0 (COCH), 132.6 (Ar-Cq), 144.3 (CH3CH),
Experimental Section
General Remarks: All moisture-sensitive reactions were carried out
by use of standard Schlenk techniques. All reagents were of com-
mercial quality from freshly opened containers or were purified by
common methods. The chiral auxiliaries (S,S)-2 and (R,R)-2 were
prepared by the literature procedure.[5b] THF was freshly distilled
from sodium/lead alloy, CH2Cl2 from CaH2 under argon. nBuLi
(1.6 m in hexane) was purchased from Merck, Darmstadt. Prepara-
tive column chromatography: Merck silica gel 60, particle size
0.040–0.063 mm (230–240 mesh). Analytical TLC: silica gel 60 F254
plates from Merck, Darmstadt. Optical rotation values were mea-
sured on a Perkin–Elmer P241 polarimeter; solvents used were of
Merck UVASOL quality. Microanalyses were obtained with a
Heraeus CHN-O-RAPID or a Vario EL element analyzer. Mass
spectra were acquired on a Finnigan SSQ 7000 (CI, 100 eV. EI
70 eV) spectrometer. High resolution mass spectra were recorded
on a Finnigan MAT 95 spectrometer. IR spectra were recorded on
148.2, 151.5 (Ar-C ), 188.5 (CO) ppm. IR (KBr): ν = 3459 (w),
˜
q
3061 (w), 2978 (w), 2908 (w), 2790 (w), 2720 (w), 2681 (w), 2608
(w), 1839 (w), 1755 (w), 1663 (s), 1617 (s), 1597 (s), 1505 (m), 1486
(s), 1442 (s), 1362 (w), 1327 (m), 1299 (s), 1251 (s), 1141 (w), 1113
(m), 1036 (s), 969 (m), 933 (s), 885 (m), 833 (w), 794 (s), 724 (w),
687 (m), 662 (w), 583 (w), 514 (w) cm–1. MS (EI); m/z (%) = 192
(0.9), 191 (9), 190 [M]+ (80), 175 (22), 149 (8), 148 (100), 121 (20),
91 (5), 69 (13), 63 (7). C11H10O3 (190.20): calcd. C 69.46, H 5.30;
found C 69.44, H 5.48.
a Perkin–Elmer FT/IR 1760. 1H NMR (300 and 400 MHz) and 13
C
NMR (75 and 100 MHz) spectra were recorded on Gemini 300 or
Varian Inova 400 spectrometers with CDCl3 as solvent and TMS
as internal standard. The CD spectra were recorded at room tem-
perature with an AVIV circular dichroism spectrometer (Model
62DS). The solvent was CHCl3 and for both spectra the concentra-
tion was 2.12·10–3 molL–1.
(SR)-2-(Benzo[d][1,3]dioxol-6-yl)-2-{methyl[(4R,5R)-2,2-dimethyl-4-
phenyl-1,3-dioxan-5-yl]amino}acetonitrile [(R,R,S/R)-7]: NaCN
(1.35 g, 27.55 mmol) was stirred for 20 min at room temperature in
methanol (50 mL) according to the general procedure described by
Weinges.[18] Compound (R,R)-2 (5.53 g, 24.98 mmol) and piperonal
(3.75 g, 24.98 mmol) were added, and the reaction mixture was co-
oled to 0 °C. Glacial acetic acid (2.25 mL, 38.97 mmol) was then
added, and the reaction mixture was cooled to –5 °C with an ice/
NaCl mixture and then allowed to warm to room temperature. The
reaction was finished after 3 days and the precipitated crude pro-
duct was filtered off, washed with water and dried over MgSO4.
The amino nitrile (R,R,SR)-7 was obtained as a colourless solid
(7.69 g, 81% yield), m.p. 113 °C, de = 58%. [α]2D6 = –104.8 (c = 1.1,
1-(Benzo[d][1,3]dioxol-6-yl)-3-hydroxybutan-1-one (4): Diisopro-
pylamine (21.35 mL, 151.49 mmol) was placed in a dry Schlenk
flask and abs. THF (1 mL per mmol diisopropylamine) was added.
The reaction mixture was cooled to –78 °C and nBuLi (1.6 m,
72.58 mL, 116.13 mmol) was added dropwise. The mixture was
stirred for 30 min and acetopiperone (3) (15.0 g, 91.37 mmol) was
then added. After a further 30 min, freshly distilled acetaldehyde
(6.83 mL, 120.96 mmol) in THF (47 mL) was added by syringe
pump. The reaction mixture was stirred at –78 °C for 3 h, allowed
to warm up to –10 °C and was quenched by addition of sat. NH4Cl
solution with vigorous stirring. After addition of water the organic
phase was separated. The aqueous phase was extracted with Et2O
1988
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 1984–1990

First Asymmetric Synthesis of a Virola sebifera Lignan
FULL PAPER
CHCl3). 1H NMR (300 MHz, CDCl3) mixture of epimers: δ = 1.53/
1.57 (s, 3 H, CCH3), 1.58/1.57 (s, 3 H, CCH3), 2.29/2.41 (s, 3 H,
NCH3), 2.86/2,89 (td, J = 3.3, 1.4 Hz, 1 H, NCHCH2), 4.20/4.32
(CHCH3), 19.3 (CCH3), 28.8 (CCH3), 35.4 (NCH3), 36.5
(CHCH3), 42.5 (COCH2), 54.4 (NCH), 58.8 (OCH2CH), 73.1
(CCN), 76.0 (PhCH), 99.4 (OCCH3), 101.5 (OCH2O), 101.8
(dd, J = 13.0, 3.3 Hz, 1 H, OCHHCH), 4.40/5.50 (s, 1 H, CHCN), (OCH2O), 107.7, 107.8, 108.6 (Ar-CH), 121.1 (CCN), 121.8, 124.3
4.53/4.60 (dd, J = 13.0, 1.4 Hz, OCHHCH), 5.25/5.28 (d, J =
3.3 Hz, 1 H, OCHPh), 5.87–5,95 (m, 2 H, OCH2O and 1 H,
CHarom), 6.47 (m, 1 H, CHarom), 6.55–6.61 (m, 1 H, CHarom), 7.28–
7.43 (5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.4/18.8
(CCH3), 29.4/29.6 (CCH3), 33.2/37.5 (NCH3), 57.0/60.6 (NCH),
59.0/60.2 (CHCH2O), 57.3/62.5 (CHCN), 73.4/74.5 (CHPh), 98.9/
(Ar-CH), 127.6 (Ar-Cq), 127.7, 127.8, 127.9 (Ar-CH), 131.6, 138.9,
147.6, 147.9, 148.1, 151.7 (Ar-C ), 195.9 (CO) ppm IR (KBr): ν =
˜
q
3774 (w), 3450 (m), 3070 (w), 2987 (m), 2899 (m), 2813 (w), 2611
(w), 2370 (w), 2345 (w), 2216 (w), 2047 (w), 1676 (s), 1609 (m),
1489 (s), 1442 (s), 1380 (m), 1298 (m), 1248 (s), 1202 (m), 1169 (w),
1100 (m), 1037 (s), 935 (m), 895 (w), 854 (w), 813 (m), 746 (m),
99.2 (CCH3), 101.0/101.1 (OCH2O), 107.2/107.4, 107.5/107.6 (Ar- 701 (m), 669 (w), 642 (w), 574 (w), 533 (w) cm–1. MS (EI): m/z (%)
CH), 117.4/117.7 (CN), 120.3/120.4, 125.3/125.5, 126.9/127.0,
127.7/128.0 (Ar-CH), 128.0/128.6, 139.89/139.93, 147.2/147.4,
= 543 (3) [M– HCN]+·, 406 (6), 395 (13), 394 (34), 355 (11), 354
(45), 350 (10), 336 (7), 322 (8), 243 (5), 232 (7), 231 (21), 230 (100).
MS (CI, methane): m/z (%) = 570 (0.6) [M]+·, 546 (6), 545 (32), 544
(100) [M – CN]+, 543 (28), 542 (11), 487 (7), 486 (27), 395 (9), 394
147.5/147.7 (Ar-C ) ppm. IR (KBr): ν = 3464 (w), 3078 (w), 3031
˜
q
(w), 2993 (s), 2973 (m), 2937 (s), 2863 (s), 2794 (m), 2703 (w), 2670
(w), 2376 (w), 2343 (w), 2228 (w), 2043 (w), 1956 (w), 1842 (w), (20), 355 (9). C33H34N2O7 (570.24): calcd. C 69.46, H 6.01, N 4.91;
1810 (w), 1725 (w), 1607 (w), 1485 (s), 1439 (s), 1378 (s), 1316 (w), found C 69.38, H 6.04, N 4.58.
1263 (s), 1236 (s), 1202 (s), 1152 (m), 1123 (m), 1086 (s), 1041 (s),
997 (m), 957 (m), 936 (s), 894 (w), 858 (m), 829 (m), 809 (w), 782
(2R,3R)-2,5-Bis(benzo[d][1,3]dioxol-6-yl)-2-{methyl[(4S,5S)-2,2-
dimethyl-4-phenyl-1,3-dioxan-5-yl]amino}-3-methyl-5-oxopentane-
nitrile [(S,S,R,R)-8]: The Michael adduct (S,S,R,R)-8 was synthe-
sized by the same procedure as described for (R,R,S,S)-8 with use
(m), 733 (s), 697 (m), 657 (w), 595 (w), 556 (m), 528 (w), 466
(w) cm–1. MS (EI): m/z (%) = 354 (3) [M – CN]+, 217 (10), 216
(73), 215 (22), 185 (5), 176 (37), 175 (35), 161 (11), 160 (100), 91
of the amino nitrile (S,S,RS)-7. The product was obtained as a
(7), 77 (5). MS (CI, methane): m/z (%) = 380 (1.8) [M]+, 355 (19),
colourless solid, m.p. 115 °C, de Ն 96%. [α]2D4 = –43.7 (c = 1.0,
354 (100) [M – CN]+, 323 (10), 217 (10), 216 (57), 215 (5), 160 (31).
CHCl3). The spectroscopic data were identical with those of
(R,R,S,S)-8.
C
22H24N2O4 (380.44): calcd. C 69.46, H 6.36, N 7.36; found C
69.93, H 6.31, N 7.44.
(2S,3S,4S)-2,5-Bis(benzo[d][1,3]dioxol-6-yl)-2-{methyl[(4R,5R)-2,2-
dimethyl-4-phenyl-1,3-dioxan-5-yl]amino}-3,4-dimethyl-5-oxo-
pentanenitrile [(R,R,S,S,S)-9]: Potassium tert-butoxide (0.51 g,
4.53 mmol) was placed in a dry Schlenk flask and carefully heated
under vacuum to avoid sublimation. After cooling to room tem-
perature and addition of abs. THF (4.5 mL) and diisopropylamine
(0.63 mL, 4.53 mmol) the mixture was cooled to –78 °C and nBuLi
(1.6 m, 2.83 mL, 4.53 mmol) was added dropwise. The mixture was
stirred at –78 °C for 30 min, followed by addition of the Michael
(RS)-2-(Benzo[d][1,3]dioxol-6-yl)-2-{methyl[(4S,5S)-2,2-dimethyl-4-
phenyl-1,3-dioxan-5-yl]amino}acetonitrile [(S,S,R/S)-7]: The amino
nitrile (S,S,RS)-7 was synthesized by the same procedure as de-
scribed for (R,R,SR)-6 with use of the amine (S,S)-2 (ee Ͻ 99%)
as chiral auxiliary. The product was obtained as a colourless solid,
m.p. 114 °C, de = 63%. [α]2D6 = +105.0 (c = 1.1, CHCl3). The spec-
troscopic data (1H, 13C NMR, MS) were identical with those given
for (R,R,SR)-7.
(2S,3S)-2,5-Bis(benzo[d][1,3]dioxol-6-yl)-2-{methyl[(4R,5R)-2,2- adduct (R,R,S,S)-8 (2.35 g, 4.53 mmol) in THF (4.5 mL). After 4 h
dimethyl-4-phenyl-1,3-dioxan-5-yl]amino}-3-methyl-5-oxopentane- at –78 °C the reaction mixture was cooled to –100 °C and methyl
nitrile [(R,R,S,S)-8]: Diisopropylamine (1.77 mL, 12.59 mmol) was iodide (0.51 mL, 8.24 mmol) was added. The reaction mixture was
placed in a dry Schlenk flask, and abs. THF (10 mL per mmol
diisopropylamine) was added. The reaction mixture was cooled to
–78 °C and nBuLi (1.6 m, 7.88 mL, 12.61 mmol) was added drop-
wise. The mixture was stirred at 0 °C for 30 min and cooled to
–78 °C, and the amino nitrile (R,R,SR)-7 (4.0 g, 10.51 mmol) was
then added. After 1.5 h at –78 °C the reaction mixture was cooled
to –100 °C, followed by addition of the Michael acceptor (E)-5
(2.0 g, 10.51 mmol) in THF (1 mL per mmol) by syringe pump.
The reaction mixture was stirred overnight and allowed to warm
up to –10 °C. After quenching by addition of sat. NH4Cl solution
with vigorous stirring, H2O was added and the organic phase was
separated. The aqueous phase was extracted with Et2O and the
combined organic layers were washed with brine and dried with
MgSO4, and the solvents were evaporated in vacuo. The crude pro-
duct was purified by flash chromatography (silica gel, pentane/di-
ethyl ether, 1:1 with 3 % triethylamine) to give amino nitrile
stirred overnight, allowed to warm to –10 °C, and was then
quenched by addition of sat. NH4Cl solution and H2O. The aque-
ous phase was extracted with Et2O and the combined organic layers
were washed with brine, dried with MgSO4 and evaporated under
reduced pressure. Purification of the residue by flash chromatog-
raphy (silica gel, pentane/diethyl ether, 1:1 with 3% triethylamine)
afforded (R,R,S,S,S)-9 (2.19 g, 90 %), m.p. 120 °C, de = 96 %.
1
[α]2D6 = +85.2 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ =
0.20 (d, J = 6.9 Hz, 3 H, COCHCH3), 0.60 (d, J = 6.9 Hz, 3 H,
CHCH3), 1.44 (s, 3 H, CCH3), 1.50 (s, 3 H, CCH3), 2.75–2.85 (m,
2 H, NCH, CHCH3), 2.97 (s, 3 H, NCH3), 3.33 (qd, 1 H, J = 6.9,
2.5 Hz, COCHCH3), 3.96 (dd, J = 13.1, 4.5 Hz, 1 H, OCHHCH),
4.73 (dd, J = 13.1, 2.2 Hz, 1 H, OCHHCH), 4.97 (d, J = 4.2 Hz, 1
H, PhCH), 5.96–6.02 (m, 1 H, CHarom) 6.03 (s, 4 H, 2×OCH2O),
6.64 (d(br), J = 7.1 Hz, 1 H, CHarom), 6.85 (d, J = 8.2 Hz, 1 H,
CHarom), 7.25–7.46 (m, 7 H, CHarom), 7.58 (dd, J = 8.2, 1.7 Hz, 1
H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 8.0 (CHCH3),
12.3 (COCHCH3), 19.4 (CCH3), 28.7 (CCH3), 35.1 (NCH3), 39.8
(R,R,S,S)-8 (5.00 g, 83% yield), m.p. 115 °C. de Ն 96%. [α]2D6
=
+49.7 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.57 (d,
J = 6.4 Hz, 3 H, CHCH3), 1.45 (s, 3 H, CCH3), 1.52 (s, 3 H, CCH3), (CHCH3), 40.5 (COCHCH3), 54.2 (NCH), 58.6 (OCH2CH), 73.2
1.83 (dd, J = 16.1, 10.9 Hz, 1 H, COCHH), 2.77 (m, 1 H, NCH), (NCC), 76.0 (PhCH) 99.4 (OCO), 101.5 (OCH2O), 101.8
2.83 (m, 1 H, COCHH), 2.92–3.01 (m, 1H, CHCH3), 3.05 (s, 3 H,
NCH3), 3.99 (dd, J = 13.2, 4.2 Hz, 1 H, OCHHCH), 4.66 (dd, J =
13.2, 2.2 Hz, 1 H, OCHHCH), 5.00 (d, J = 4.2 Hz, 1 H, PhCH),
(OCH2O), 107.8, 107.9, 108.5, 109.0 (Ar-CH), 121.6 (CN), 122.0,
124.7, 127.7, 127.9 (Ar-CH), 130.5, 138.9, 147.6, 148.1, 148.3, 151.8
(Ar-Cq), 201.1 (CO) ppm, MS (EI): m/z (%) = 558 (1.2) [M – CN]+,
5.96–6.02 (m, 1 H, CHarom), 6.00 (s, 4 H, OCH2O), 6.65 (d(br), J 436 (9), 420 (12), 409 (26), 408 (100), 379 (15), 368 (14), 365 (18),
= 7.7 Hz, 1 H, CHarom), 6.77 (d, J = 8.2 Hz, 1 H, Ar-CH), 7.25– 364 (89), 338 (6), 337 (5), 336 (9), 245 (6), 244 (45), 243 (51), 218
7.45 (m, 7 H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.8 (5), 216 (18), 215 (25), 214 (5), 205 (21), 187 (8) ppm. IR (KBr):
Eur. J. Org. Chem. 2005, 1984–1990
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1989

D. Enders, M. Milovanovic, E. Voloshina, G. Raabe, J. Fleischhauer
FULL PAPER
Rep. 1997, 14, 43–74; d) R. S. Ward, Nat. Prod. Rep. 1999, 16,
75–96. For a review on neolignan synthesis, see: e) M. Sefkow,
Synthesis 2003, 2595–2625.
ν = 3452 (w), 3071 (w), 3988 (m), 3940 (m), 3881 (m), 2814 (w),
˜
2603 (w), 2216 (w), 2032 (w), 1956 (w), 1674 (m), 1609 (m), 1488
(s), 1440 (s), 1380 (m), 1246 (s), 1202 (m), 1168 (w), 1101 (m), 1076
(w), 813 (w), 782 (w), 744 (w), 701 (w), 669 (w), 645 (w), 612 (w),
577 (w), 533 (w) cm–1 MS (CI, methane): m/z (%) = 585 (2.7) [M
+1]·+, 559 (18), 558 (63), 557 (16), 500 (8), 420 (12), 500 (17), 409
(16), 408 (57), 379 (15), 365 (6), 379 (15), 368 (13), 365 (21), 364
(100), 337 (8), 336 (9), 244 (15), 243 (14), 215 (7), 205 (14), 164 (8),
149 (24), 114 (6), 105 (6) C34H36N2O7: (584.25): calcd. C 69.85, H
6.21, N 4.79; found C 69.46, H 6.52, N 4.94.
[3] K. R. Rezende, M. J. Kato, Phytochemistry 2002, 61, 427–432.
[4] T. Biftu, B. G. Hazara, R. Stevenson, J. Chem. Soc., Perkin
Trans. 1 1978, 1147–1150.
[5]
a) For a review on α-amino nitrile chemistry, see: D. Enders,
J. P. Shilvock, Chem. Soc. Rev. 2000, 29, 359–373; b) D. Enders,
H. Lotter, Nouv. J. Chim. 1984, 8, 747–750; c) D. Enders, P.
Gerdes, H. Kipphardt, Angew. Chem. 1990, 102, 226–228, An-
gew. Chem. Int. Ed. 1990, 29, 179–181; d) G. Raabe, E. Zobel,
J. Fleischhauer, P. Gerdes, D. Mannes, E. Müller, D. Enders,
Z. Naturforsch., Teil A 1991, 46, 275–288; e) D. Enders, D.
Mannes, G. Raabe, Synlett 1992, 837–839; f) D. Enders, J.
Kirchhoff, D. Mannes, G. Raabe, Synthesis 1995, 659–666; g)
D. Enders, J. Kirchhoff, V. Lausberg, Liebigs Ann. 1996, 1361–
1366; h) D. Enders, J. Kirchhoff, P. Gerdes, D. Mannes, G.
Raabe, J. Runsink, G. Boche, M. Marsch, H. Ahlbrecht, H.
Sommer, Eur. J. Org. Chem. 1998, 63–72. For previous lignan
syntheses from our group, see: i) D. Enders, V. Lausberg, G.
Del Signore, O. M. Berner, Synthesis 2002, 512–522; j) D. En-
ders, G. Del Signore, O. M. Berner, Chirality 2003, 15, 510–
513.
D. Enders, P. Müller, D. Klein, Synlett 1998, 43–44.
M. J. S. Dewar, E. G. Zoebisch, E. F. Healy, J. J. P. Stewart, J.
Am. Chem. Soc. 1985, 107, 3902–3909.
Spartan (Version 5.0), Wavefunction, Inc., 18401 Von Karman
Ave., Suite 370, Irvine, CA 92612, USA (1997).
a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) C. Lee,
W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789; c) B.
Miehlich, A. Savin, H. Stoll, H. Preuss, Chem. Phys. Lett. 1989,
157, 200–206.
A table containing the total and the relative energies and se-
lected structural parameters of the twenty most stable con-
formers, as well as plots of the individual CD spectra of these
structures and a complete figure with all Kohn–Sham orbitals
mentioned in Table 1, are available free of charge from the au-
thors upon request.
(2R,3R,4R)-2,5-Bis(benzo[d][1,3]dioxol-6-yl)2-{methyl[(4S,5S)-2,2-
dimethyl-4-phenyl-1,3-dioxan-5-yl]amino}-3,4-dimethyl-5-oxo-
pentanenitrile [(S,S,R,R,R)-9]: Compound (S,S,R,R,R)-9 was syn-
thesized by the same procedure as described for (R,R,S,S,S)-9. The
product was obtained as a colourless solid, m.p. 120 °C, de = 96%.
[α]2D6 = –83.3 (c = 1.0, CHCl3). The spectroscopic data were iden-
tical with those of (R,R,S,S,S)-9.
(2S,3S)-1,4-Bis(benzo[d][1,3]dioxol-6-yl)-2,3-dimethylbutane-1,4-
dione [(S,S)-1]: Compound (R,R,S,S,S)-9 (150 mg, 0.26 mmol) was
dissolved in THF (10 mL), hydrochloric acid (2 m, 15 mL) was
added, and the reaction mixture was heated at reflux for 30 min.
The phases were separated and the water phase was extracted with
CH2Cl2. The combined organic layers were dried over MgSO4, and
the solvent was removed under reduced pressure. The crude pro-
duct was purified by flash chromatography with CH2Cl2 as eluent
to afford (S,S)-1 (72 mg, 79%). The product was obtained as a
colourless solid, m.p. 212 °C, de = 96%. [α]2D4 = –149.0 (c = 0.1,
CHCl3), ref.[3] [α]2D5 = –125.0 (c = 0.1, MeOH). 1H NMR (300 MHz,
CDCl3): δ = 1.27 (d, J = 6.9 Hz, 6 H, CH3), 3.84 (m, 2 H, CHCH3),
6.02 (s, 4 H, OCH2O), 6.87 (d, J = 8.2 Hz, 2 H, CHarom), 7.43
(d, J = 1.7 Hz, 2 H, CHarom), 7.63 (dd, J = 8.2 Hz, 1.7 Hz, 2 H,
CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.9 (CHCH3),
43.6 (CHCH3), 101.8 (OCH2O), 107.9, 108.4, 124.7 (Ar-CH),
[6]
[7]
[8]
[9]
[10]
130.8, 148.2, 151.7 (Ar-C ), 202.4 (CO) ppm. IR (KBr): ν = 3949
˜
q
[11] R. Bauernschmitt, R. Ahlrichs, Chem. Phys. Lett. 1996, 256,
(w), 3884 (w), 3818 (w), 3777 (w), 3676 (w), 3465 (m), 3060 (w),
2980 (m), 2917 (m) 2786 (w), 2700 (w), 2609 (w), 2376 (w), 2345
(w), 2066 (w), 1910 (w), 1787 (w), 1670 (s), 1610 (s), 1503 (s), 1441
(s), 1380 (m), 1357 (s), 1264 (s), 1208 (m), 1165 (w), 1143 (w), 1095
(s), 1038 (s), 977 (s), 931 (m), 890 (w), 868 (m), 835 (m), 812 (w),
749 (m), 718 (w), 670 (w), 611 (w), 577 (w), 535 (w), 501 (w), 460
(w) cm–1. MS (EI): m/z (%) = 354 (16) [M]+·, 150 (9), 149 (100),
121 (9), 65 (5) HRMS: C20H18O6: calcd. 354.1103; found 354.1103.
454–464.
[12] a) R. Ahlrichs, in: Encyclopedia of Computational Chemistry
(Ed.: P. v. R. Schleyer) TURBOMOLE. Wiley: Chichester,
1998; vol. 5, pp. 3123–3129; b) TURBOMOLE (Version 5): R.
Ahlrichs, M. Bär, H. P. Baron, R. Bauernschmitt, S. Böcker, M.
Ehrig, K. Eichkorn, S. Elliot, F. Furche, F. Haase, M. Häser,
H. Horn, C. Huber, U. Huniar, M. Kattannek, C. Kölmel, M.
Kollwitz, K. May, C. Ochsenfeld, H. Öhm, A. Schäfer, U.
Schneider, O. Treutler, M. von Arnim, F. Weigend, P. Weis, H.
Weis, Quantum Chemistry Group: University of Karlsruhe,
Germany, 2004.
(2R,3R)-1,4-Bis(benzo[d][1,3]dioxol-6-yl)-2,3-dimethylbutane-1,4-di-
one [(R,R)-1]: Diketone (R,R,)-1 was synthesized in the same way
as (S,S)-1. The product was obtained as a colourless solid. m.p.
212 °C, de = 96%. [α]2D3 = +151.0 (c = 0.1, CHCl3). The spectro-
scopic data were identical with those of (S,S)-1.
[13] A. Schäfer, C. Huber, R. Ahlrichs, J. Chem. Phys. 1994, 100,
5829–5835.
[14] A. Moscowitz, in: Modern Quantum Chemistry (Ed.: O. Sinan-
oglu), John Wiley & Sons, Inc.: New York, 1965, 3, 21.
[15] J. A. Schellman, Chem. Rev. 1975, 75, 323–331.
[16] a) R. W. Woody, private communication. b) E. N. Voloshina,
G. Raabe, M. Estermeier, B. Steffan, J. Fleischhauer, Int. J.
Quantum Chem. 2004, 100, 1104–1113; c) In the present case
the band at 320 nm in the experimental spectrum has a half
bandwidth of approximately 28 nm at Δεmax/e while this for-
mula give a result of a value of about 22 nm at the same wave-
length.
Acknowledgments
This work was supported by the Fonds der Chemischen Industrie.
We thank BASF AG, Bayer AG and the former Boehringer
Mannheim GmbH for the donation of chemicals.
[1] D. C. Ayres, J. D. Loike, in: Lignans: Chemical, Biological and
Clinical Properties, Cambridge University Press, Cambridge,
1990.
[2] a) R. S. Ward, Nat. Prod. Rep. 1993, 10, 1–28; b) R. S. Ward,
Nat. Prod. Rep. 1995, 12, 183–205; c) R. S. Ward, Nat. Prod.
[17] T. Biftu, B. G. Hazara, R. Stevenson, J. Chem. Soc., Perkin
Trans. 1 1979, 2276–81.
[18] K. Weinges, H. Brachmann, P. Stahnecker, H. Rodewald, M.
Nixdorf, H. Irngatinger, Liebigs Ann. Chem. 1985, 566–578.
Received: December 16, 2004
1990
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1984–1990