A Novel 1,3-Central-to-Axial Chirality Induction Approach to Cyclooctadiene Lignans

Article abstract of DOI:10.1055/s-2003-42039

The catalytic asymmetric synthesis of an axially chiral biaryl, potentially useful intermediate in the synthesis of dibenzocyclooctadiene lignans, has been performed. The key step consisted of a diastereoselective Suzuki coupling between a chiral benzylic

Full text of DOI:10.1055/s-2003-42039

LETTER
2009
A Novel 1,3-Central-to-Axial Chirality Induction Approach to Cyclooctadiene
Lignans
N
ovel Chirality Ap
l
proach
i
to
C
yc
v
looctadiene
i
Lignan
e
s
r Baudoin,* Anne Décor, Michèle Cesario, Françoise Guéritte
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Fax +33(1)69077247; E-mail: baudoin@icsn.cnrs-gif.fr
Received 16 July 2003
chiral boronic acid in the Suzuki coupling step of the van-
Abstract: The catalytic asymmetric synthesis of an axially chiral
biaryl, potentially useful intermediate in the synthesis of dibenzocy-
clooctadiene lignans, has been performed. The key step consisted of
a diastereoselective Suzuki coupling between a chiral benzylic alco-
hol and a sterically hindered boronic ester. The 1,3-induction from
the benzylic stereocenter to the biaryl axis proceeded with very
good diastereoselectivity.
comycin total synthesis.11
Our own asymmetric approach to stegane lignans is illus-
trated in Scheme 1. (–)-Steganacin 1 could arise from a
non-bridged precursor 2, bearing a stereogenic benzylic
carbon atom, via construction of the B-D ring system, and
2 could be obtained by a diastereoselective Suzuki cou-
pling. According to our recent work on the palladium(0)-
catalyzed synthesis of antimitotic bridged biaryls,12 the
Suzuki coupling should be more efficient if the boronic
ester function is placed on the correct ring, presumably
ring C. In order to determine the optimal substitution pat-
tern (R1–R3) and Suzuki coupling conditions, several pre-
cursors were synthesized. With the choice of these
precursors, the chemical compatibility of functional
groups with the Suzuki coupling conditions and the steric
hindrance of ortho substituents (R1–R3) were taken into
account.
Keywords: axial chirality, Suzuki coupling, chirality induction, cy-
clooctadiene lignans
Axially chiral biaryls are found in a number of different
living organisms and exhibit a great variety of biological
activities.1 These activities are often restricted to one
atropisomeric form, and several atroposelective synthetic
methodologies have been proposed in order to obtain the
bioactive atropisomer.1,2 Dibenzocyclooctadiene lignans
are axially chiral biaryls bridged by a median ring pos-
sessing several stereocenters.3 Among these, (–)-stegana-
cin 1 (Scheme 1) shows antitumor properties originating
in the inhibition of microtubule assembly. Several
enantioselective syntheses of (–)-steganacin and the relat-
ed C-5 ketone (–)-steganone have been described via: (a)
enantioselective construction of the butyrolactone D-ring
and subsequent intramolecular oxidative4 or intermolecu-
lar reductive5 biaryl coupling; (b) intermolecular diastere-
oselective biaryl coupling, either following the Meyers
chiral oxazoline method,6 or using a Suzuki coupling with
a chiral chromium tricarbonyl-complexed aryl halide,7
followed by construction of B-D rings. In spite of their
efficiency and elegance, the intermolecular coupling
approaches necessitate the introduction and removal of a
stoichiometric chiral auxiliary. Diastereoselective8 and
enantioselective9 Suzuki biaryl couplings using chiral
phosphines, which have recently been used in other con-
texts, could provide a straightforward control of the axial
chirality in the stegane series. An alternative approach
would involve a diastereoselective Suzuki coupling using
achiral ligands through chirality induction of the axial
configuration by a pre-existing stereocenter such as C-5.
Such a method was employed by Lipschutz in his ap-
proach to korupensamine A, observing a complete 1,4-in-
duction from a stereocenter attached to a phosphine
ligand.10 In addition, Nicolaou obtained a 33% de using a
Scheme 1
The A-ring building block 313 was obtained from com-
mercially available 3,4-methylenedioxyacetophenone in
77% yield by NaBH4 reduction and regioselective iodina-
tion (I2, CF3CO2Ag)14 (Scheme 2). This secondary alco-
hol was protected with a MOM group and submitted to
our modified Pd(0)-catalyzed borylation conditions15 to
give the corresponding sterically hindered boronic ester 5
in good yield. Ketone 6 was obtained by PCC oxidation of
3.13 C-Ring building blocks were synthesized from the
known iodide 7 (Scheme 2).13 After introduction of a
SYNLETT 2003, No. 13, pp 2009–2012
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-42039; Art ID: D17603ST.pdf
© Georg Thieme Verlag Stuttgart · New York

2010
O. Baudoin et al.
LETTER
MOM (compound 8), TES (compound 9) or MEM (com- pound has a high atropisomerization energy barrier. The
pound 10) protecting group, the borylation was performed yield of the Suzuki coupling was improved using biphenyl
as above in good yield in spite of the steric hindrance, ligand L2 (entry 3), giving 2d in 53% isolated yield after
giving boronic esters 11–13.
benzylation, with identical diastereoselectivity. When
the more sterically hindered boronate 12 was coupled to
iodide 3 (entry 4) in the presence of ligand L1, the desired
biphenyl 2b was obtained in low yield (ca. 15%), together
with the protodeiodinated by-product. In order to resolve
this mixture, the TES group was removed with TBAF
giving diol 2e in 10% isolated yield from 3 and as a single
diastereoisomer. The use of ligand L2 instead of L1 (entry
5) again gave an improved yield of 31% for 2e, also with
complete diastereoselectivity. The coupling of MEM-pro-
tected boronate 13 with iodide 3 (entry 6) furnished, after
protection with BnBr, the corresponding biphenyl 2f in
31% yield and with a 70% de. This result indicates that a
subtle adjustment of the size of the R2 group is necessary
to combine a satisfying yield with a high diastereoselec-
tivity. Finally, the coupling between boronate 11 and ke-
tone 6 (entry 7) gave less than 10% yield of the
corresponding biphenyl, indicating that the presence of
the alcohol group is crucial. Other coupling trials with
O
O
O
O
O
O
a
O
OH
OMOM
(78%)
I
I
X
3
4: X=I
5: X=B(pin) (83%)
6
b
I
I
MeO
MeO
a or c
OH
OR
MeO
MeO
OMe
OMe
7
8: R=MOM (96%)
9: R=TES (98%)
10: R=MEM (77%)
B(pin)
MeO
MeO
b
OR
OMe
Table 1 Suzuki Coupling Study to Form the A-C Ring System of
11: R=MOM (79%)
12: R=TES (79%)
13: R=MEM (84%)
Steganesa
Scheme 2 Reagents and conditions: a. MOMCl or MEMCl (2
equiv), EtN(i-Pr)2 (3 equiv), CH2Cl2; 0 °C to 25 °C, 15 h; b. (pin)BH
(2 equiv), Et3N (3 equiv), Pd(OAc)2 (5 mol%), PCy2(o-biph) (10
mol%), dioxane, 80 °C, 30 min; c. TESOTf (1.2 equiv), 2,6-lutidine
(1.5 equiv), CH2Cl2, 0 °C to 25 °C, 30 min. pin = pinacol, PCy2(o-
biph) = 2-(dicyclohexylphosphino)biphenyl
The Suzuki coupling reaction between these A-ring and
C-ring synthons was subsequently examined (Table 1).
Boronic esters and iodides were initially coupled using
our standard conditions,12,15 in the presence of barium hy-
droxide, palladium acetate and biphenyl ligand L1 or L2,16
in dioxane–water. Indeed we found that the combination
of this particular base and catalyst gives good yields and
short reaction times with sterically hindered substrates.
Entry
Boronate Iodide
Ligand Product Yield
(%)b
de
(%)c
The coupling of ring A boronic ester 5 with ring C iodide
7 (entry 1) gave only protodeiodinated or protodeboronat-
ed products, as gave other coupling trials in this sense.
When the sense of the reaction was reversed, starting from
an A-ring iodide and a C-ring boronate, the desired biphe-
nyls were formed in low to moderate yields (entries 2–7).
The coupling of boronate 11 with iodide 3 in the presence
of ligand L1 (entry 2) gave the coupling product 2a in ca
50% yield, as an inseparable mixture with the pinacol. For
purification and analysis purposes, the less polar biphenyl
2d was synthesized by treatment with NaH and benzyl
bromide, in 38% isolated yield from iodide 3. Examina-
tion of the 1H NMR spectra of 2a,d indicated a 84:16 mix-
ture of two diastereoisomers (68% de), resulting from a
chirality induction from the benzylic position to the biaryl
axis. Heating 2d in DMSO-d6 up to 140 °C did not modify
the diastereomeric ratio, which indicates that this com-
1
2
3
4
5
6
7
5
11
11
12
12
13
11
7
3
3
3
3
3
6
L1
L1
L2
L1
L2
L2
L1
0
38
2d
2d
2e
2e
2f
68
68
53
10
>96
>96
70
31
31
<10
a Reagents and conditions: iodide (1 equiv), boronic ester (1.5 equiv),
Pd(OAc)2 (5 mol%), L1 or L2 (10 mol%), Ba(OH)2 (2 equiv), diox-
ane–water (9:1), 100 °C, 1 h.
b Isolated yield for 2 steps.
c Diastereomeric ratio, from 1H NMR.
Synlett 2003, No. 13, 2009–2012 © Thieme Stuttgart · New York

LETTER
Novel Chirality Approach to Cyclooctadiene Lignans
2011
alcohol (+)-14 which was converted to iodide (+)-3 in
59% overall yield and 90% ee as determined by chiral
HPLC.18 The absolute (R) configuration of (+)-14 was de-
duced from literature data.19 The Pd(0)-catalyzed cou-
pling of (+)-3 and 11 proceeded as before to give biphenyl
(–)-2d after benzyl protection in 45% yield and 68% de.
Crystallization from heptane afforded compound (–)-2d
in 92% de and 90% ee as measured by chiral HPLC.20
Crystals of (–)-2d suitable for X-ray analysis were ob-
tained after slow crystallization from EtOH. The analysis
of the X-ray diffraction data provided evidence for the (R,
aS) absolute configuration of the molecule (Figure 1).21 In
the crystal, proton H-19 eclipses the biaryl axis, which is
probably the more sterically favored arrangement for sub-
situents at C-19. ROESY correlations (Figure 1) were in
agreement with the solid-state structure. NOESY experi-
ments conducted with racemic diol 2e showed similar 2D
correlations, arguing for the same (R, aS) relative config-
uration.
Scheme 3 Reagents and conditions: a. (S)-2-Methyl-CBS-oxazabo-
rolidine (10 mol%), BH3·SMe2 (1.0 equiv), CH2Cl2, –20 °C, 5 h; b. I2
(1.05 equiv), CF3CO2Ag (1.05 equiv), CHCl3, 0 °C, 15 min; c. (+)-3
(1.0 equiv), 11 (1.5 equiv), Pd(OAc)2 (5 mol%), L2 (10 mol%),
Ba(OH)2 (2 equiv), dioxane–water 9:1, 100 °C, 1 h; d. NaH (1.5
equiv), BnBr (1.5 equiv), THF, 25 °C, 4 h; e. crystallization from hep-
tane
From this, it can be deduced that the enantiomer (–)-3
should be employed instead of (+)-3 in the Suzuki cou-
pling step in order to obtain the (aR) configuration of nat-
ural (–)-steganacin.
A tentative explanation for the diastereoselectivity ob-
served in the Suzuki coupling between 3 and 11–13 is il-
lustrated in Figure 2. The oxidative insertion of the
palladium complex in the C–I bond of 3 could give, under
basic reaction conditions, the oxapalladacycle complex
A.22 The transmetalation by the ‘ate’ complex B should
occur with the bulky C-16 substituent (R2 = MOM, MEM,
TES) taking position in the face opposite to the C-20 me-
thyl group. This would furnish trans-palladium complex
bulkier boronic acids and iodides failed, giving only pro-
todeiodinated or deboronated products.
At this stage, the question regarding the relative configu-
ration at both stereogenic elements had to be addressed.
The Suzuki coupling was repeated starting with alcohol 3
in an enantiomerically enriched form (Scheme 3). The
catalytic enantioselective reduction of 3,4-methylene-
dioxyacetophenone with (S)-CBS-oxazaborolidine17 gave
Figure 1 X-ray crystal structure (left) and selected ROESY correlations (right) of biphenyl (–)-2d
Synlett 2003, No. 13, 2009–2012 © Thieme Stuttgart · New York

2012
O. Baudoin et al.
LETTER
(6) Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc.
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Chem. Eur. J. 1999, 5, 2584.
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38, 3530.
C and, after isomerization to the cis complex and reduc-
tive elimination, biphenyls 2a–c having the (R, aS) rela-
tive configuration. The transmetalation of B in the
opposite orientation, i.e. with the C-16 substituent in the
same face as the C-20 methyl group, which would furnish
2a–c with the (R, aR) relative configuration, should be
disfavored. This model accounts in particular for the bet-
ter diastereoselectivity observed with boronate 12 having
a bulkier protecting group than 11.
(11) Nicolaou, K. C.; Natarajan, S.; Li, H.; Jain, N. F.; Hughes,
R.; Solomon, M. E.; Ramanjulu, J. M.; Boddy, C. N. C.;
Takayanagi, M. Angew. Chem. Int. Ed. 1998, 37, 2708.
(12) (a) Baudoin, O.; Cesario, M.; Guénard, D.; Guéritte, F. J.
Org. Chem. 2002, 67, 1199. (b) Baudoin, O.; Claveau, F.;
Thoret, S.; Herrbach, A.; Guénard, D.; Guéritte, F. Bioorg.
Med. Chem. 2002, 10, 3395.
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Wiley: New York, 1963, 547.
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65, 9268.
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1999, 38, 2413. (b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.;
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Figure 2 Proposed stereochemical course of the Suzuki coupling
In conclusion, a novel atropo-diastereoselective Suzuki
coupling has been discovered in the synthesis of biaryl
lignans. In this process, a 1,3-chirality induction was per-
formed from an oxygen-bearing benzylic stereogenic cen-
ter to the biaryl axis. This benzylic stereocenter was in
turn generated by a catalytic enantioselective reduction.
Therefore, this methodology provides a unique catalytic
asymmetric access to axially chiral molecules having a
benzylic stereocenter. The elaboration of stegane-type
dibenzocyclooctadiene lignans using these findings will
be reported in due course.
(18) (+)-3: [a]D23 +38.8 (c 1.1, CHCl3); HPLC (Chiracel OD,
hexane–EtOH, 95:5, 1.0 mL/min) tR 7.8 min (minor
enantiomer), 9.2 min (major enantiomer).
(19) Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, K.;
Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997,
36, 288.
(20) Compound (–)-2d: mp 70 °C; [a]D24 –21.4 (c 1.0, CHCl3);
HPLC (C18 Symmetry column, H2O–CH3CN, 35:65, 1.0
mL/min) tR 16.6 min (diastereoisomer 1, 4%), 17.9 min
(diastereoisomer 2, 96%); HPLC (Chiralpak AD, heptane–i-
PrOH, 98:2, 1.0 mL/min) diastereoisomer 2: tR 10.8 min
(enantiomer 1, 5%), 24.5 min (enantiomer 2, 95%),
diastereoisomer 1: tR 11.4 min (enantiomer 1, 95%), 13.0
min (enantiomer 2, 5%). 1H NMR [300 MHz, (CD3)2CO]
d = 1.15 (d, J = 6.3 Hz, 3 H), 3.23 (s, 3 H), 3.61 (s, 3 H), 3.74
(s, 3 H), 3.89 (s, 3 H), 4.15 (d, J = 12.0 Hz, 1 H), 4.21 (d,
J = 12.0 Hz, 1 H), 4.25 (q, J = 6.5 Hz, 1 H), 4.33 (d, J = 12.3
Hz, 1 H), 4.45 (d, J = 12.3 Hz, 1 H), 4.57 (s, 2 H), 6.04 (s,
1H), 6.06 (s, 1 H), 6.63 (s, 1 H), 6.98 (s, 1 H), 7.12 (s, 1 H),
7.20–7.32 (m, 5 H) (major diastereoisomer). 13C NMR [75.5
MHz, (CD3)2CO] d = 23.9, 55.3, 56.2, 60.9, 61.0, 67.7, 70.8,
74.9, 96.7, 102.1, 105.9, 108.7, 111.0, 126.6, 127.7, 127.9,
128.5, 128.9, 133.5, 138.4, 140.7, 142.5, 147.2, 148.6,
151.2, 154.1 (major diastereoisomer). HRMS (ESI): m/z for
[(M + Na)+] calcd for C28H32NaO8: 519.1995; found:
519.1982.
Acknowledgment
We thank M.-T. Adeline and B. Dumontet for HPLC analyses and
Dr. M.-T. Martin for NMR experiments. This work was financially
supported by the Centre National de la Recherche Scientifique
(CNRS).
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Synlett 2003, No. 13, 2009–2012 © Thieme Stuttgart · New York