Total synthesis of (±)-Vertine with Z-selective RCM as a key step

Article abstract of DOI:10.1039/c0cc01885f

A concise total synthesis of the strained pentacyclic alkaloid (±)-Vertine has been achieved in eleven steps with the key steps being pelletierine condensation, Suzuki-Miyaura coupling, and ring-closing metathesis.

Full text of DOI:10.1039/c0cc01885f

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Total synthesis of (Æ)-Vertine with Z-selective RCM as a key stepw
´
Laetitia Chausset-Boissarie, Roman Arvai, Graham R. Cumming, Celine Besnard and
E. Peter Kundig*
¨
Received 14th June 2010, Accepted 9th July 2010
DOI: 10.1039/c0cc01885f
A concise total synthesis of the strained pentacyclic alkaloid
(Æ)-Vertine has been achieved in eleven steps with the key steps
being pelletierine condensation, Suzuki–Miyaura coupling, and
ring-closing metathesis.
Vertine (also called Cryogenine) was first isolated in 1962 by
Ferris from Decodon verticillatus (L.) Ell and classified as a
member of the Lythraceae alkaloids.1 Vertine displays a wide
range of biological activities, including anti-inflammatory,
sedative, and antispasmodic properties. It also plays a role in
glucose level regulation in blood and lowers blood pressure.2
The strained 12-membered macrolactone structure incor-
porating three stereogenic centers, two of which are part of the
macrocycle, and an induced chiral biaryl axis, is synthetically
challenging and attracted our interest. Moreover, we had
previously synthesized Lasubine I3 and thus were interested
in the more challenging 1 (Fig. 1). To the best of our
knowledge, the syntheses of neither Vertine (1) nor structural
analogues possessing the Z-configured a,b-unsaturated
macrolactone (e.g. Verticillatine, Lythrine)4 have been reported
previously. Here we detail the first total synthesis of
(Æ)-Vertine.
Fig. 2 Left: ring closing strategies. Vertine is shown in the conformation
adopted in the solid state.9 Right: late stage intermediate in an
attempted synthesis via macrolactonisation.
While representing a strategy which has been used extensively
in the synthesis of natural products,10 the route via RCM was
not our first choice because of the lack of precedent for the
formation of a Z-alkene a to a carbonyl function. The synthesis
would include key intermediate 2, obtained from diastereo-
selective ketone reduction and acylation of the biaryl product
resulting from a Suzuki–Miyaura cross coupling between
quinolizidinone
4 and a boronate generated from the
bromo-arene 3. In contrast to the Cr(CO)3-mediated synthesis
of an analogue of 4 used in the Lasubine I synthesis,3 we saw
an opportunity to use a pelletierine condensation between
pelletierine (5) and aldehyde 6 to access 4 (Scheme 1).
Our first approach built on our synthesis of Lasubine I3
with macrolactonisation5 as ring-closing strategy. While
we succeeded in synthesizing an advanced intermediate
(Fig. 2), the route was not efficient and, worse, all attempts
to macrolactonise without isomerisation of the alkene failed.6
The strategy using a Suzuki–Miyaura aryl–aryl coupling7
for the macrolactone also ran into difficulties.8
Accordingly, 4 was synthesized via a condensation between
pelletierine11 (5) and aldehyde 6. The reaction, proposed to
proceed by an aldol condensation followed by a Michael addition,
afforded a mixture of two diastereomeric quinolizidinone
products.12,13 Using 1 M aq. NaOH in THF at room temperature
(rt) 4 and 10 were obtained in a 4 : 1 ratio. The desired
diastereomer 4 was isolated in 53% yield. Treatment of the
mixture with a base in protic media or longer reaction time
resulted in isomerisation of 4 into 10 via retro-Michael/
Michael addition. In order to increase the diastereomeric
ratio and the overall yield of the process, a two-step
procedure was developed (Scheme 2). This involved an aldol
This publication details our third, and finally successful,
approach to (Æ)-Vertine using ring closing metathesis (RCM).
Fig. 1 Two Lythraceae alkaloids.
Department of Organic Chemistry, University of Geneva, 30,
quai Ernest Ansermet, CH-1211 Geneva, Switzerland.
E-mail: peter.kundig@unige.ch; Fax: +41 223793215;
Tel: +41 223796093
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all new compounds along
with copies of 1H and 13C NMR spectra. CCDC 780761. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc01885f
Scheme 1 Retrosynthetic analysis.
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Scheme 2 Synthesis of 4. Reagents and conditions: (a) NaOH [1 M],
MeOH/H2O, reflux, 91%; (b) TFA, CH2Cl2, 0 1C, quantitative;
(c) NaOH [1 M], THF, rt, 72%, ratio 4 : 10 = 9 : 1.
Fig. 3 ORTEP diagram of intermediate 15 (in red: alkenes that are to
be involved in RCM to form the 12-membered macrolactone).
condensation between the Boc protected pelletierine 7 and
bromoveratraldehyde 6 leading to 8. Deprotection with
trifluoroacetic acid (TFA) and cyclisation under basic conditions
yielded 4 and 10 in a 9 : 1 ratio. Diastereomer 4 was isolated in
66% overall yield.
diastereomer in 62% yield. The relative configuration of the
secondary alcohol was assigned by analogy to Lasubine I.3
Next, aldehyde 13 was obtained by oxidation with MnO2 in
98% yield. Wittig reaction followed by acylation under
Mukaiyama’s conditions then afforded the ester 15. An
X-ray structure determination of 15 confirmed the relative
configuration of the molecule (Fig. 3).16
All attempts to cleave the MOM group by using HCl,17
TFA,18 TMSBr,19 p-TsOH,20 NaHSO4ÁSiO2,21 I2/MeOH,22 or
a Lewis acid23 either gave unidentified byproducts or incomplete
deprotection. To circumvent this problem RCM was attempted
before the MOM cleavage. This furnished cyclised product in
o10% yield. The presence of unidentified side products
prevented its isolation in pure form. The phenol protecting
group was therefore changed from MOM to TBS as shown in
Scheme 4 with the final step being carried out by the use of
Nysted reagent. This avoided problems due to the presence of
the acrylate group.24,25
The structures of 4 and 10 were assigned from their NMR
and IR spectra. Quinolizidinone 10 shows Bohlmann bands in
its IR spectrum.14 These are absent in 4. The position of the
NMR signal of the benzylic proton (C4) is also diagnostic: the
chemical shift is at 4.85 ppm in 4 but at d 3.82 ppm in 10.
Boronate 11 was synthesized in 2 steps in 85% yield from
commercial 3-bromo-4-hydroxybenzaldehyde (Scheme 3).
Suzuki–Miyaura coupling between 11 and 4 afforded biaryl
12 in 80% yield. The product was isolated as a mixture of two
apparent atropisomers in a ratio of 3 : 1 (1H NMR, 500 MHz,
298 K, d8-toluene). Variable temperature NMR (d8-toluene,
298 to 388 K) revealed a coalescence temperature of 353 K,
showing that we are dealing not with true atropoisomers, but
with rotamers, as expected for biaryls having only three
substituents in the ortho-position.15 Attempts to selectively
methylenate aldehyde 12 were not successful and we therefore
proceeded with a reduction of both carbonyl functions.
L-Selectride proved to be the best choice affording a single
RCM of 19 to form the strained macrolactone was not easy.
The RCM product was formed in low yield only in CH2Cl2
(Table 1, entry 1). The use of hexafluorobenzene was reported
to improve the yield in RCM reactions.26 However, in our case
this led to the degradation of 19 (Table 1, entry 2). By
switching to toluene we slightly increased the yield (Table 1,
entry 3). The use of toluene at 110 1C turned out to be best.
This gave the product with a moderate yield of 37%. The
addition of one equivalent of Ti(OiPr)4 did not improve the
yield of the reaction. The TBS protecting group was removed
quantitatively with TBAF (À30 1C, 20 min) affording
(Æ)-Vertine 1 in 37% yield from 19. The spectral data are in
good agreement with the literature data.9,27
Scheme 3 Synthesis of 15. Reagents and conditions: (a) MOMCl,
DIPEA, CH2Cl2, 0 1C to rt, 98%; (b) Pd(dppf)Cl2, (PinB)2, dioxane,
140 1C, MW, 87%; (c) 4, Pd(PPh3)4, CsF, DME, 110 1C, 80%;
(d) L-Selectride, THF, À78 1C, 62%; (e) MnO2, Et2O/acetone, rt,
30 min 98%; (f) nBuLi, [Ph3PCH3][Br], THF, 0 1C to rt, 65%;
(g) acrylic acid, Mukaiyama’s salt, Et3N, CH2Cl2, rt, 84%.
Scheme 4 Synthesis of 19. Reagents and conditions: (a) Et3N, acryloyl
chloride, 4-DMAP, CH2Cl2, 0 1C, 84%; (b) TFA, CH2Cl2, 0 1C, 87%;
(c) Et3N, TBSCl, 4-DMAP, CH2Cl2, 0 1C, 83%; (d) Nysted reagent,
TiCl4, THF, 0 1C, 60%.
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Table 1 RCM reaction: screening of conditions
7 (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457;
(b) N. Miyaura, J. Organomet. Chem., 2002, 653, 54;
(c) A. Suzuki, J. Organomet. Chem., 2002, 653, 83.
8 The aforementioned approaches will be detailed in a future full
paper.
9 C. S. Rumalla, A. N. Jadhav, T. Smillie, F. R. Fronczek and
I. A. Khan, Phytochemistry, 2008, 69, 1756.
10 (a) A. Furstner and K. Langemann, Synthesis, 1997, 792;
¨
(b) A. Deiters and S. F. Martin, Chem. Rev., 2004, 104, 2199;
(c) A. Gradillas and J. Perez-Castells, Angew. Chem., Int. Ed.,
2006, 45, 8086.
11 Pelletierine synthesis: (a) A. Rieker and H. Kessler, Tetrahedron
Lett., 1969, 10, 1227; (b) J. Quick and R. Oterson, Synthesis, 1976,
745.
12 (a) T. Matsunaga, I. Kawasaki and T. Kaneko, Tetrahedron Lett.,
1967, 8, 2471; (b) M. Hanaoka, N. Ogawa, K. Shimizu and
Y. Arata, Chem. Pharm. Bull., 1975, 23, 1573; (c) I. Lantos,
C. Razgaitis, H. Vanhoeven and B. Loev, J. Org. Chem., 1977,
42, 228.
13 (a) J. Quick and R. Oterson, Tetrahedron Lett., 1977, 18, 603;
(b) J. Quick and C. Meltz, J. Org. Chem., 1979, 44, 573.
14 (a) F. Bohlmann and P. Strehlke, Tetrahedron Lett., 1965, 6, 167;
(b) F. Bohlmann, D. Schumann and C. Arndt, Tetrahedron Lett.,
1965, 6, 2705.
Entry
Solvent
T/1C
Time/h
Yield (%)
1
2
3
CH2Cl2
45
65
70
110
110
72
72
72
16
16
15
Decomposition
20
37
35
Hexafluorobenzene
Toluene
Toluene
4
5a
Toluene
a
1 equivalent of Ti(OiPr)4 was added.
15 (a) H. Kessler, Angew. Chem., Int. Ed. Engl., 1970, 9, 219;
(b) M. Oki, Top. Stereochem., 1983, 14, 1.
16 CCDC 780761 contains the supplementary crystallographic data
for 15.
17 (a) H. Appel, A. Rother and A. E. Schwarti, Lloydia, 1965, 28, 84;
(b) A. I. Meyers, J. L. Durandetta and R. Munavu, J. Org. Chem.,
1975, 40, 2025.
18 R. B. Woodward, E. Logusch, K. P. Nambiar, K. Sakan,
D. E. Ward, B. W. Au-Yeung, P. Balaram, L. J. Browne,
P. J. Card and C. H. Chen, J. Am. Chem. Soc., 1981, 103,
3210.
19 J. W. Huffman, X. H. Zhang, M. J. Wu, H. H. Joyner and
W. T. Pennington, J. Org. Chem., 1991, 56, 1481.
20 (a) H. Monti, G. Leandri, M. Klosringuet and C. Corriol, Synth.
Commun., 1983, 13, 1021; (b) T. R. Boehlow, J. J. Harburn and
C. D. Spilling, J. Org. Chem., 2001, 66, 3111.
In conclusion we have completed the first total synthesis of
(Æ)-Vertine. The synthetic route proceeds in 11 linear steps
with an overall yield of 6%. It includes the first example of the
formation of a Z-configured a,b-unsaturated macrolactone by
RCM. The strategy is sufficiently general to allow the synthesis
of not only analogues of (Æ)-Vertine, but also of other
members of the Vertine family.
We are grateful to Prof. I. A. Khan and Dr C. S. Rumalla
(The University of Mississippi School of Pharmacy) for a
sample of Vertine. We thank the Swiss National Science
Foundation for financial support.
Notes and references
21 C. Ramesh, N. Ravindranath and B. Das, J. Org. Chem., 2003, 68,
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29, 348; (c) W. J. Lema, J. W. Blankenship and M. H. Malone,
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23 For ZrCl4: G. V. M. Sharma, K. L. Reddy, P. S. Lakshmi and
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J. H. Han, Y. E. Kwon, J. H. Sohn and D. H. Ryu, Tetrahedron,
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24 S. Matsubara, M. Sugihara and K. Utimoto, Synlett, 1998, 313.
25 RCM with 17 (free phenol) was not successful.
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27 Initial 1H and 13C NMR spectra differed from those reported in
ref. 9 and we feared that we may have isolated the product
containing opposite atropisomerism. Extensive NOE analyses
showed this not to be the case. The problem turned out to arise
from the presence of small quantities of tetrabutylammonium salts
from the desilylation step. Once removed by chromatography on
neutral alumina the spectral match was excellent.
4 E. Fujita and K. Fuji, Int. Rev. Sci.: Org. Chem., Ser. Two, 1976, 9,
119.
5 A. Parenty, X. Moreau and J. M. Campagne, Chem. Rev., 2006,
106, 911 and references cited therein.
6 H. Ratni, PhD thesis no 3249, University of Geneva, 2001;
R. Arvai, PhD thesis no 3721, University of Geneva, 2006.
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6266 Chem. Commun., 2010, 46, 6264–6266
This journal is The Royal Society of Chemistry 2010