Atroposelective heck macrocyclization: Enantioselective synthesis of bis(bibenzylic) natural products

Article abstract of DOI:10.1021/ol302132s

The Heck protocol was applied for the first time to the atroposelective synthesis of macrocyclic natural products. As ring closure to bis(bibenzyls) of the isoplagiochin type leads to a configurationally stable biaryl axis in the molecule, cyclization could be conducted atroposelectively in the presence of a chiral BINAP ligand.

Full text of DOI:10.1021/ol302132s

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4548–4551
Atroposelective Heck Macrocyclization:
Enantioselective Synthesis of
Bis(bibenzylic) Natural Products
Matthias Groh,† Daniel Meidlinger,† Gerhard Bringmann,‡ and Andreas Speicher*,†
Department of Organic Chemistry, Saarland University, Campus, 66123 Saarbru€cken,
Germany, and Institute of Organic Chemistry, University of Wu€rzburg, Am Hubland,
97074 Wu€rzburg, Germany
anspeich@mx.uni-saarland.de
Received July 19, 2012
ABSTRACT
The Heck protocol was applied for the first time to the atroposelective synthesis of macrocyclic natural products. As ring closure to bis(bibenzyls)
of the isoplagiochin type leads to a configurationally stable biaryl axis in the molecule, cyclization could be conducted atroposelectively in the pre-
sence of a chiral BINAP ligand.
“Bis(bibenzyls)” are phenolic natural products that
can be isolated with broad diversity from bryophytes.1
Regarding the biosynthesis, they originate from bibenzyl
units.2 The distribution in liverworts, their structure elucida-
tion, and their numerous biological activities are reviewed.3,4
A twofold CÀC connection of two bibenzyl units leads to
a subtype represented by isoplagiochin D (1)5 with two
biaryl axes A/B (Figure 1).
earlier6,7 and for the unique structure of cavicularin.8 The
existence of configurationally stable atropisomers as a
consequence of axial chirality (two biaryl axes and one
helical element) and ring strain for 1 was first discussed
in detail by us9 and especially for its dehydro analogue
isoplagiochinC (2), forwhich the absoluteconfiguration at
the stereochemicallystable biaryl axisA wasdetermined by
quantum chemical CD calculations for the natural com-
pound from Plagiochila deflexa10 (Figure 2).
The occurrence of axial and/or planar chirality in the
series of these macrocyclic bis(bibenzyls) was discussed
† Saarland University.
‡ University of W€urzburg.
(1) Asakawa, Y. In Progress in the Chemistry of Organic Natural
Products; Herz, E., Kirby, G. W., Moore, R. E., Steglich, W., Tamm, Ch.,
Eds.; Springer: Wien - New York, 1995, p 5.
(2) Friederich, S.; Rueffer, M.; Asakawa, Y.; Zenk, M. H. Phyto-
chemistry 1999, 52, 1195–1202.
(3) Asakawa, Y.; Toyota, M.; Tori, M.; Hashimoto, T. Spectroscopy
2000, 14, 149–175.
(4) Asakawa, Y.; Ludwiczuk, A.; Nagashima, F.; Toyota, M.;
Hashimoto, T.; Tori, M.; Fukuyama, Y.; Harinantenaina, L. Hetero-
cycles 2009, 77, 99–150.
(5) Hashimoto, T.; Kanayama, S.; Kan, Y.; Tori, M.; Asakawa, Y.
Chem. Lett. 1996, 741–742.
€
ꢀ
ꢀ ꢀ
(6) Keseru, G. M.; Kolossvary, I.; Nogradi, M. J. Mol. Struct. 1995,
356, 143–148.
Figure 1. Biogenetical origin of bis(bibenzyls).
(7) Hashimoto, T.; Irita, H.; Takaoka, S.; Tanaka, M.; Asakawa, Y.
Tetrahedron 2000, 56, 3153–3159.
r
10.1021/ol302132s
Published on Web 08/23/2012
2012 American Chemical Society

Scheme 1. Ring Closing Methods in the Syntheses of the Iso-
plagiochin C/D Framework
Figure 2. Absolute configuration of (À)-isoplagiochin D (1) and
(À)-isoplagiochin C (2); * = configurationally stable, o = con-
figurationally unstable (the most stable diastereomer is shown).
Many members of the bis(bibenzyl) family have been
synthesized; the routes and strategies have been reviewed
very recently.11 Ring closure proved to be the main chal-
lenge because efficiency, not surprisingly, depends on ring
strain, substitution pattern, and concomitant dimeriza-
tion. In the total syntheses yet described for isoplagiochins
C (2) and D (1) or derivatives, ring closure was realized
by (a) Wittig reaction,12 (b) McMurry reaction,13 both be-
tween ring moieties A and D, and (c) SuzukiÀMiyaura
coupling14 between C and D (Scheme 1).
Scheme 2. Synthesis of Precursor 13 for a Heck Coupling
We were now focused on alternative methods enabling
enantioselective routes to the isoplagiochin framework.
We had to consider that the biaryl axis between rings C and
D is configurationally stable only in the macrocyclic con-
text, so that general methods for the atroposelective synth-
esis of axially chiral biaryls15 could not be simply adopted.
The atropo-divergent step rather had to include or follow
the ring closure. The catalytic enantioselective Suzuki
coupling is yet not a generally approved method due to
the harsh required reaction conditions.14,16 Also, Wittig
and McMurry procedures lack enantioselective protocols.
For the first time in the field of macrocyclic bis(bibenzyls)
we attempted the Heck methodology17 for synthesis. In-
tramolecular variants have been broadly used in natural
(8) Toyota, M.; Yoshida, T.; Kan, Y.; Takaoka, S.; Asakawa, Y.
Tetrahedron Lett. 1996, 37, 4745–4748.
(9) Scher, J. M.; Zapp, J.; Becker, H.; Kather, N.; Kolz, J.; Speicher,
A.; Dreyer, M.; Maksimenka, K.; Bringmann, G. Tetrahedron 2004, 60,
9877–9881.
€
(10) Bringmann, G.; Muhlbacher, J.; Reichert, M.; Dreyer, M.; Kolz,
J.; Speicher, A. J. Am. Chem. Soc. 2004, 126, 9283–9290.
(11) Harrowven, D.C.;Kostiuk, S.L. Nat. Prod. Rep. 2012, 29, 223–242.
(12) Eicher, T.; Fey, S.; Puhl, W.; Buchel, E.; Speicher, A. Eur. J. Org.
Chem. 1998, 877–888.
(13) Speicher, A.; Kolz, J.; Sambanje, R. P. Synthesis 2002, 2503–
2512.
product syntheses;18 asymmetric intramolecular var-
iants using BINAP and DIOP ligands were developed
by Shibasaki19 and Overman,20 but only for the con-
struction of chiral carbon centers, not for axially chiral
compounds.
(14) Esumi, T.; Wada, M.; Mizushima, E.; Sato, N.; Kodama, M.;
Asakawa, Y.; Fukuyama, Y. Tetrahedron Lett. 2004, 45, 6941–6945.
(15) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.;
Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384–5427.
(16) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051–
12052.
(17) Oestreich, M., Ed. The MizorokiÀHeck Reaction; Wiley-VCH:
Weinheim, 2009.
(19) Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54,
4738–4739.
(20) Carpenter, N. E.; Kucera, D. J.; Overman, L. E. J. Org. Chem.
1989, 54, 5846–5848.
(18) (a) Link, J. T.; Overman, L. E. In Metal-Catalyzed Cross-
Coupling Reactions; Stang, P. J., Diederick, F., Eds.; VCH: Weinheim:
1998; pp 231À269. (b) de Meijere, A.; Meyer, F. E. Angew. Chem., Int.
Ed. 1994, 33, 2379–2411.
Org. Lett., Vol. 14, No. 17, 2012
4549

Table 1. Cyclization of 13 by Heck Reaction
entry
Pd(OAc)2 [equiv]/ligand [equiv]
solventa
base [equiv]a
time/temp
yieldb,c
ee (%)d
1
2
[0.1]/PPh3 [0.2]
toluene
toluene
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K2CO3 [5.0]
K2CO3 [5.0]
K2CO3 [5.0]
K2CO3 [5.0]
K2CO3 [5.0]
K2CO3 [5.0]
PMP [6.0]
18 h/120 °C
18 h/120 °C
18 h/120 °C
18 h/120 °C
18 h/120 °C
18 h/85 °C
18 h/85 °C
18 h/60 °C
72 h/45 °C
18 h/60 °C
À
À
[0.4]/PPh3 [0.8]
6
À
3
[0.1]/PPh3 [0.2]
13
16
12
À
À
4
[0.1]/PPh3 [0.2]
À
5
[0.4]/M-BINAP [0.8]
[0.3]/M-BINAP [0.6]
[0.3]/M-BINAP [0.6]
[0.4]/M-BINAP [0.8]
[0.3]/M-BINAP [0.6]
[0.3]/P-BINAP [0.5]
rac
6
À
7
18
25
trace
20
21 for M
27 for M
34 for M
31 for P
8
PMP [6.0]
9
PMP [6.0]
10
PMP [6.0]
Pd(M-BINAP)2 [equiv]
11
12
13
0.2
0.2
0.1
DMF
PMP [5.0]
18 h/70 °C
72 h/50 °C
18 h/70 °C
22
37 for M
n.d.
DMF
DMF
PMP [5.0]
PMP [5.0]
trace
À
À
a DMA = dimethyl acetamide; PMP = pentamethyl piperidine. b Conversion monitored by TLC (SiO2, CH2Cl2/n-hexane 1:1). c Yield of 14 after
chromatographical purification. d EE-value determined for 1 by HPLC on Chiracel-OD-H, i-PrOH/n-hexane 65:35 (1.0 mL/min, 275 nm); (M)-1 is
eluated before (P)-1.9
In principle, the Heck reaction could be used for the
formation of a stilbene bridge between the aromatic rings
A and D as well as B and C (Scheme 1). The latter route
Scheme 3. Synthesis of the Isoplagiochin Framework via Heck
Coupling
seemed to be more promising because (a) the reaction
center is, with respect to the enantioselective approach,
closer to the (still flexible) biaryl axis and (b) preliminary
modeling studies on the geometry of the isoplagiochin
framework21 clearly demonstrated that between rings
A and D, besides a saturated ethylene bridge, only a cis
double bond geometry is tolerable. This could be incom-
patible with palladacyclic intermediates (vide infra). By
contrast, for the double bond between rings B and C, cis-
and trans-geometries are acceptable.
The precursor 13 for a Heck-type cyclization was syn-
thesized according to Scheme 2 starting from the benzyl
alcohol 321 and the known12 monoprotected dialdehyde 5.
First, the nonenantioselective cyclization of the triflate
13 to the racemic dehydro isoplagiochin D tetramethy-
lether (14) using an intramolecular Heck protocol was
attempted using Pd(OAc)2/PPh3. The best, although still
moderate, results were obtained in DMF and K2CO3 as a
base (Table 1, entries 1À4).
first time for this type of reaction, resulted in an atropo-
enantioselective (21% ee) Heck cyclization (entries 6,7).
Due to additional conformational effects21 at the second
(only partially flexible) biaryl axis B in 14, the stereochemi-
cal analyses were performed for the natural compound 1.9
Increasing the catalyst loading from 0.3 to 0.4 equiv
slightly increased the yield and ee value (entry 8), but no
acceptable conversion was observed at temperatures lower
than 60 °C (entries 9 and 12). Replacing (M)-BINAP by
(P)-BINAP evidenced the atroposelective effect of the
ligand, now leading to the (P)-enantiomer of 14 (and 1)
(entry 10).
Replacing the PPh3 by (M)- or (P)-BINAP could give
rise to an atropo-enantioselective Heck reaction as the
ring closing step with dynamic kinetic resolution (DKR)
(Scheme 3): The biaryl axis A is flexible enough in the
precursor 13, but not in the macrocyclic biaryl 14
at moderate temperatures. Not surprisingly, at 120 °C
only a racemic product was observed (Table 1, entry 5).
Reducing the reaction temperature gave conversion and
moderate yields only by switching the base to the (less
nucleophilic22) pentamethyl piperidine (PMP) and, for the
To reduce a possible “ligand-free” background reaction,
the preprepared Pd(M-BINAP)2 complex23 was used di-
rectly giving the best results even with 0.2 equiv at 70 °C
(entry 11). Further reducing the reaction temperature
(21) Speicher, A.; Backes, T.; Hesidens, K.; Kolz, J. Beilstein J. Org.
Chem. 2009, 5, No. 71.
(22) Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org.
Chem. 1993, 58, 6949–6951.
(23) Alcazar-Roman, L. M.; Hartwig, J. F.; Rheingold, A. L.
Liable-Sands, L. M.; Guzei, I. A. J. Am. Chem. Soc. 2000, 122, 4618–4630.
4550
Org. Lett., Vol. 14, No. 17, 2012

Scheme 4. Possible Mechanism for the Heck Coupling with Atropo-Differentiation
(entry 12) or the catalyst amount (entry 13) did not allow
the reaction to proceed.
atropo-diastereoselective coordination to the double bond
(15 f 16), or (3) atropo-selective syn-addition (16 f 17)
(Scheme 4).
The product 14 of cyclization was always isolated with
an (E)-configuration at the double bond, meaning an (E)-
selective Heck reaction or Pd-induced isomerization. The
mechanism of the Heck cyclization may follow a cationic
route (no coordinating triflate anion) involving a syn-
endo-trig addition via a palladacyclic intermediate 15.24
The mode of the asymmetric induction using BINAP still
remains to be further investigated. In principle, we suggest
three modes of atropo-differentiation with dynamic kinetic
equilibration/resolution: (1) atropo-selective oxidative ad-
dition assuming that intermediate 15 could be configur-
ationally stable due to the large Pd ortho substituent, (2)
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (DFG Sp 498/2-1).
Dedicated to Prof. Dr. Dr. h.c. Theophil Eicher on the
occasion of his 80th birthday.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds; details of HPLC on a chiral phase. This
material is available free of charge via the Internet at
http://pubs.acs.org
(24) Dekker, G. P. C. M.; Elsevier, C. J.; Vrieze, K.; van Leeuwen, P.
W. N. M. Organometallics 1992, 11, 1598–1603.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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