Enantioselective total synthesis of (-)-trans-dendrochrysine via a ring-rearrangement metathesis approach

Article abstract of DOI:10.1055/s-2007-986672

The enantioselective total synthesis of the dipyrrolidine alkaloid (-)-trans-dendrochrysine was accomplished in 18 steps starting from tropone. The key step was a ring-rearrangement metathesis for the construction of the bisheterocyclic skeleton of the na

Full text of DOI:10.1055/s-2007-986672

LETTER
2599
Enantioselective Total Synthesis of (–)-trans-Dendrochrysine via a
Ring-Rearrangement Metathesis Approach
E
nantioselective Total
a
Synthesis
o
x
f
(
–)-trans-D
i
endroc
m
hrysine ilian Dochnahl, Sabrina Renate Schulz, Siegfried Blechert*
Fachgruppe Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 115, 10623 Berlin, Germany
Fax +49(30)31423619; E-mail: blechert@chem.tu-berlin.de
Received 21 June 2007
figuration. The cis-1,4-diol can be set up by a hetero-
Diels–Alder reaction of a suitable diene with singlet
oxygen.8 The latter can be prepared from tropone D by a
literature procedure.9
Abstract: The enantioselective total synthesis of the dipyrrolidine
alkaloid (–)-trans-dendrochrysine was accomplished in 18 steps
starting from tropone. The key step was a ring-rearrangement
metathesis for the construction of the bisheterocyclic skeleton of
the natural product in a single step.
O
Key words: total synthesis, olefin metathesis, ruthenium, hetero-
cycles, alkaloids
N
N
Me
O
(–)-trans-dendrochrysine
The natural product (–)-trans-dendrochrysine belongs to
the class of the dipyrrolidine alkaloids. It was isolated by
a Swedish research group in 1965 from Dendrobium
chrysanthum Wall,1 an orchid endemic in the eastern
Himalaya. Until the present day no information about its
physiological properties exist which is due to the scarce
appearance of this natural product. Only one nonstereo-
selective total synthesis has been reported until now.2
OPG3
OPG3
N
N
N
N
PG2
PG1
PG1
PG2
A
B
O
OPG3
Olefin metathesis has emerged as one of the most impor-
tant and reliable methods for C–C bond formation.3 Espe-
cially the development of the more stable ruthenium
catalysts by Grubbs has dramatically increased the scope
of this transformation.4 Different types of metathesis reac-
tions exist such as ring-closing metathesis (RCM), cross
metathesis (CM), ring-opening-metathesis polymeriza-
tion (ROMP) and others.5 The ring-rearrangement
metathesis (RRM) is a comparably new process being a
combination of a ring-opening metathesis and a ring-
closing metathesis.6
Based on a precedent from our group,7 we sought to con-
struct the dipyrrolidine skeleton of the natural product by
a RRM process (Scheme 1). Thus, double bonds have to
be attached to strategic positions of the molecule which
will be removed by hydrogenation at a later stage of the
total synthesis. Consequently, the target molecule can be
traced back to bis(dihydropyrrole) A, bearing three
orthogonal protection groups in order to differentiate be-
tween both nitrogen and the oxygen atoms. Diene A
should be accessible from triene B by the aforementioned
RRM process. Compound B most significantly consists of
a 2,3-unsaturated trans-1,4-diamine moiety. This motif
can in principle be constructed from a cis-1,4-diol C, by
introducing one nitrogen-connected side chain under
inversion and the other one under retention of the con-
HO
OH
D
C
Scheme 1 Retrosynthetic analysis of (–)-trans-dendrochrysine.
Our synthesis started hence with the conversion of
tropone D into the oxygenated cycloheptene derivative 1,
a task that was accomplished in four steps in an overall
yield of 51% (Scheme 2).9 This meso-diol was converted
into the corresponding diacetate which was subsequently
desymmetrized by treatment with solid-phase supported
candida antarctica lipase B (CALB) in a saturated
phosphate buffer solution (pH 7.4). This enzyme selec-
tively cleaved one of the ester groups leading to the chiral
alcohol 2 with an ee of greater than 95% (comparison with
ref. 9). The first allylamine side chain had to be introduced
under inversion which was accomplished by a Mitsunobu-
type alkylation.10 This reaction proceeded strictly under
inversion of the configuration (NMR analysis). The
second allylamine side chain had to be attached to the
cycloheptene ring under retention of the configuration.
However, the envisioned Tsuji–Trost allylation11 failed,
perhaps due to steric reasons. Thus, the acetate was de-
protected and the corresponding alcohol was transferred
into allylchloride 4. This was accomplished by treatment
of the alcohol with methanesulfonyl chloride in pyridine.
The hereby intermediately formed allylmesylate then
reacted with the pyridinium chloride to give compound 4
SYNLETT 2007, No. 16, pp 2599–2601
0
1
.1
0
.2
0
0
7
Advanced online publication: 12.09.2007
DOI: 10.1055/s-2007-986672; Art ID: G19407ST
© Georg Thieme Verlag Stuttgart · New York

2600
M. Dochnahl et al.
LETTER
and pyridinium methansulfonate which precipitated from using palladium on charcoal removed both the double
the reaction mixture. When allylchloride 4 was treated bonds and the Cbz protecting group in quantitative yield.
with a large excess of allylamine (9 equiv) it led to the The reduction of the methyl carbamate with LiAlH4 led to
smooth displacement of the chlorine atom. The resulting the formation of diamine 8 with an excellent yield of 98%
secondary amine was protected as the corresponding for both steps without purification of the crude product.
benzylcarbamate delivering the precursor 5 for the pivotal Acylation of the secondary amine with cinnamoyl chlo-
ring rearrangement event.
ride proved superior to standard peptide coupling methods
(DCC, HOBt) due to the simpler isolation of the product.
Finally, the silyl ether moiety was removed under acidic
conditions and the resulting secondary alcohol was
oxidized to the ketone. This was accomplished by the
reaction with sodium acetate buffered PCC15 leading to
(–)-trans-dendrochrysine in a good yield of 70% starting
from 9. It was necessary to heat the reaction mixture
during the oxidation step, otherwise little conversion was
observed. Other oxidizing agents like DMP16 or 2-iodoxy-
benzoic acid (IBX)17 proved unreactive while oxidation
under Jones conditions18 only led to the formation of
intractable mixtures. The optical rotation of –9.2° for syn-
thetic (–)-trans-dendrochrysine19 is in good agreement
with the literature value of –11°.1
O
OTBS
Lit. 9
51%
HO
OH
D
1
a, b
81%
OTBS
OTBS
c
84%
N
OAc
HO
OAc
Ns
3
2
d, e
78%
OTBS
OTBS
OTBS
MesN
NMes
f, g
a
5
Cl
Cl
N
N
N
Cl
79%
N
Ns
N
91%
Ru
O
Ns
Cbz
Ns
Cbz
6
4
5
b
90%
Scheme 2 Reagents and conditions: (a) Ac2O, 4-DMAP, Et3N,
CH2Cl2, 0 °C to r.t.; (b) CALB, phosphate buffer (pH 7.4), 40 °C; (c)
allylNHNs, PPh3, DEAD, THF, 0 °C to r.t.; (d) KCN (cat.), MeOH,
r.t.; (e) MsCl, pyridine, 0 °C to r.t.; (f) allylamine (excess), K2CO3,
MeCN, reflux; (g) CbzCl, K2CO3, THF. (Ns = 2-nitrobenzenesulfonyl,
Cbz = benzyloxycarbonyl, TBS = tert-butyldimethylsilyl).
I
OTBS
OTBS
c, d
N
N
N
N
98%
Me
H
CO2Me
Cbz
8
7
Different ruthenium catalysts were tested for the RRM
process, such as Grubbs’ first-12 and second-generation
catalysts4b and the Hoveyda–Blechert catalyst I.13 The
reaction with the first-generation Grubbs’ catalyst in re-
fluxing toluene delivered the rearranged product 6 in a
moderate yield of 65%, whereas performing the reaction
in refluxing CH2Cl2 with Grubbs’ second-generation cat-
alyst gave only a yield of 43%. It showed that catalyst I
gave the best results permitting the reaction to be per-
formed with a catalyst loading of 5 mol% (Scheme 3).
When the reaction was conducted in refluxing toluene
overnight using catalyst I, bicyclic compound 6 was
isolated in 91% yield. In all investigated cases it turned
out to be advantageous when the solvent was saturated
with ethylene prior to the reaction, a circumstance that
was first reported by Mori.14 This behavior is explained by
a faster initiation of the precatalyst by ethylene rendering
the catalyst to a more reactive form. It should also be men-
tioned that the catalyst and its decomposition products
were conveniently removed by chromatography on silica.
e
60%
OTBS
f, g
(–)-trans-dendrochrysine
N
N
Me
70%
Ph
O
9
Scheme 3 Reagents and conditions: (a) catalyst I (5 mol%), tolue-
ne, ethylene atmosphere, 110 °C, overnight; (b) PhSH, K2CO3, DMF,
70 °C, 2 h then ClCO2Me, 0 °C; (c) H2, Pd on charcoal, MeOH, r.t.;
(d) LiAlH4, Et2O, 0 °C to r.t.; (e) cinnamoyl chloride, Et3N, CH2Cl2,
0 °C to r.t.; (f) HCl, EtOH, r.t.; (g) PCC, NaOAc, CH2Cl2, 35 °C, 2 h.
In summary we have reported the first asymmetric total
synthesis of the dipyrrolidine alkaloid (–)-trans-dendro-
chrysine. The synthesis, starting from commercially
available tropone (D), gave the natural product in an over-
all yield of 5.9%. The key steps of the synthesis were an
enzymatic desymmetrization of a meso-diacetate and the
ring-rearrangement metathesis. The latter provided the
skeleton of the natural product in a single step from a
readily accessible precursor in high yield.
Further steps to complete the synthesis were the deprotec-
tion of nitrobenzenesulfonyl group under standard condi-
tions (PhSH in DMF at 70 °C) and the in situ conversion
into the mixed biscarbamate 7 by the addition of methyl
chloroformate. Hydrogenation of the latter substance
Supporting Information with analytical data of all com-
pounds is available upon request from the author.
Synlett 2007, No. 16, 2599–2601 © Thieme Stuttgart · New York

LETTER
Enantioselective Total Synthesis of (–)-trans-Dendrochrysine
2601
(13) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2000, 122, 8168. (b) Gessler, S.;
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(14) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998,
63, 6082.
Acknowledgment
M. D. gratefully acknowledges a fellowship from the Fonds der
Chemischen Industrie (K 174/11).
(15) Banfi, L.; Cabri, W.; Poli, G.; Potenza, D.; Scolastico, C.
J. Org. Chem. 1987, 52, 5452.
References and Notes
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42, 1900.
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18. (b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
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(5) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, 2003.
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(11) Trost, B. M.; Lee, C. In Catalytic Asymmetric Synthesis;
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(19) (–)-trans-Dendrochrysine: Rf 0.30 (SiO2, hexanes–CH2Cl2–
Et2NH, 10:4:1); [a]D20 –9.2° (c = 0.25, CHCl3). 1H NMR
(500 MHz, CDCl3, 323 K): d = 1.19–2.16 (m, 8 H), 2.34 (s,
3 H), 2.39–2.65 (m, 3 H), 2.69–2.89 (m, 2 H), 2.98–3.11 (m,
1 H), 3.31 (ddd, J = 3.2, 9.0, 16.7 Hz, 1 H), 3.60–3.75 (m, 2
H), 4.49–4.68 (m, 1 H), 6.72 (d, J = 15.5 Hz, 1 H), 7.35–7.42
(m, 3 H), 7.51–7.56 (m, 2 H), 7.69 (d, J = 15.5 Hz, 1 H). 13
C
NMR (125 MHz, CDCl3, 353 K): d = 22.3, 24.1 (br), 29.5,
31.4, 40.3, 45.5 (br), 46.9 (br), 47.8 (br), 53.9 (br), 56.6,
62.2, 119.4, 127.7, 128.7, 129.4, 135.7 (Cq), 141.8, 164.8
(Cq), 207.5 (Cq). IR (ATR): 2957 (m), 2927 (m), 2875 (m),
2852 (m), 2780 (m), 1708 (m), 1650 (s), 1605 (s), 1577 (m),
1497 (m), 1450 (m), 1415 (s), 1375 (m), 1347 (m), 1306 (m),
1259 (m), 1201 (m), 1185 (m), 764 (m) cm–1. MS (EI, 70
eV): m/z (%) = 340 [M+] (26), 279 (25), 278 (43), 277 (100),
209 (10), 201 (16), 199 (11), 183 (10), 167 (28), 150 (10),
149 (80), 140 (51), 131 (51), 126 (10), 124 (10), 103 (22), 98
(20), 97 (23), 85 (10), 84 (85), 83 (12). HRMS: m/z calcd for
C21H28N2O2: 340.2151; found: 340.2155.
Synlett 2007, No. 16, 2599–2601 © Thieme Stuttgart · New York