Highly enantioselective construction of fused pyrrolidine systems that contain a quaternary stereocenter: Concise formal synthesis of (+)-conessine

Article abstract of DOI:10.1002/anie.200353583

No protecting groups were required in a concise and atom-economical synthesis of the optically active tetracyclic pyrrolidine 3 under mild conditions. A highly diastereoselective Pauson-Khand reaction (1→2) was used to construct the compact tetracycle wit

Full text of DOI:10.1002/anie.200353583

Angewandte
Chemie
Alkaloid Synthesis
Highly Enantioselective Construction of Fused
Pyrrolidine Systems That Contain a Quaternary
Stereocenter: Concise Formal Synthesis of
(+)-Conessine**
Biao Jiang* and Min Xu
The construction of organic molecules with stereogenic
quaternary carbon centers by stereoselective reactions is a
very challenging task in organic synthesis.[1] A diverse array of
steroidal alkaloids and natural products derived from benzo-
hydrindan (21) feature quaternary stereocenters in the ring-
fused pyrrolidine system.[2] Although significant progress has
been made in the development of strategies for the enantio-
selective synthesis of such compounds, there remains a need
for alternative approaches.
Tetracyclic pyrrolidines C, which contain the key BCDE
ring system of (+)-conessine (Scheme 1), have four contig-
uous stereogenic centers, one of which is a quaternary carbon
atom. In early reports, the synthesis of racemic steroidal
alkaloids from racemic C was an efficient pathway.[3] The
[*] Prof. B. Jiang, M. Xu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P. R. China)
Fax: (+86)21-6416-6268
E-mail: jiangb@mail.sioc.ac.cn
[**] Thiswork wasfinancially supported by the Science & Technology
Commission of Shanghai Municipality and the National Natural
Science Foundation of China.
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 2543 –2546
DOI: 10.1002/anie.200353583
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2543

Communications
Scheme 2. Synthesis of the 1,6-enyne amino esters 4–6b.
Scheme 1. Structures of the conessine family and retrosynthetic
analysis of the BCDE ring system of (+)-conessine.
enantioselective synthesis of (+)-21 was demonstrated by the
Meyers research group from a chiral nonracemic lactam in
13 steps. The key transformation was a diastereoselective
[3+2] cycloaddition with an azomethine ylide under pressure
to construct the pyrrolidine ring system, followed by intra-
molecular addition of an aryl lithium and an aldol reaction to
afford the tetracyclic cyclopentenone skeleton of the tetracy-
clic pyrrolidine enantioselectively.[4] Based on our recent
studies towards the convergent assembly of the cyclopen-
ta[c]proline ring system in an efficient and stereoselective
manner by an intramolecular Pauson–Khand reaction of a
chiral enyne amino acid,[5] it was envisaged that the tetracyclic
pyrrolidine 21 of (+)-conessine could be accessed by an
asymmetric Pauson–Khand reaction in a single step. The
installation of the stereogenic quaternary carbon center
would also be possible if the substrates possessed a dihydro-
naphthalenyl group (Scheme 1).
To check the viability of intramolecular Pauson–Khand
reactions of N-propargyl dihydronaphthalenyl amino acid
derivatives, the model 1,6-enyne 4 was readily prepared in
92% yield by treating the dihydronaphthalenyl boronic acid 1
with the propargyl amine 2 and glyoxylic acid.[6] To study the
steric effects of the propargylic amine substituent on the
efficiency and stereoselectivity of the cyclization, the cis and
trans isomers 5a, 6a and 5b, 6b, respectively, were prepared
from N-methyl-N-(1-methyl-2-propynyl)amine (3) in a ratio
of 1:1, and separated by flash chromatography (Scheme 2).
With this series of enynes in hand, we proceeded to study their
reactivity under typical Pauson–Khand reaction conditions.
Initially, the Pauson–Khand reaction was carried out
under catalytic conditions, as described previously.[5] How-
ever, the reaction gave a complex mixture of products.
Gratifyingly, the treatment of the enyne 4 with [Co2(CO)8]
(1.1 equiv) at 658C for 6 h in the presence of DMSO (6 equiv)
as an oxidant afforded the desired compact tetracyclic
pyrrolidine in 41% yield (Scheme 3). Two diastereomers,
exo-7a and endo-7b, were isolated in a ratio of 2:1. To
Scheme 3. Studieson the stereochemical effectsof the a methyl group
in the propargylic moiety.
examine the influence of the substituent on the propargylic
moiety on the stereochemical outcome of the reaction, the
enynes 5 and 6 were treated under the same Pauson–Khand
reaction conditions. All the reactions proceeded in good
yields, and the ratio of diastereomers reached 6:1. It was
found that the methyl group a to the N atom in the
propargylic moiety played the main role in controlling the
stereochemistry of the product. Irrespective of the nature of
the ester group and of whether it was oriented cis or trans with
respect to the methyl group a to N, the exo products (8a, 9a,
10a, 11a) were isolated as the major diastereomers
(Scheme 3). The stereochemistry of the products was readily
established by NMR spectroscopic studies. The NOESY
spectrum of 8a showed an NOE between Ha and the methyl
group a to the N atom in the pyrrolidine ring, thus indicating
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a cis relationship between this methyl group and the
cyclohexyl ring, and confirming that the major product had
an exo configuration (Figure 1).[7]
Figure 2. X-ray crystal structure of compound 16a.
Complex I can form two plausible diastereomeric cis cobalta-
À
cycles II and III upon alkene insertion into the internal Co C
bond. Because of the bulky tetrahydronaphthalene group on
Figure 1. NOEsobserved for compound 8a.
the convex face, the upper side of newly formed cis cobalta-
Based on the above results, a practical synthesis of the cycle is quite congested. In the cis cobaltacycle III, which
tetracyclic pyrrolidine (+)-21 was attempted. Starting from would lead to the exo product, the steric interactions between
À
commercially available 6-methoxy-1-tetralone (12), the enyne the methyl group a to the N atom and the C16 C17 bond in
15 was readily prepared (Scheme 4). A direct methylene- the cobaltacycle might be minimized, whereas in II a strong
transfer reaction by a general synthetic method produced the steric interaction exists between the methyl group on the endo
À
face and the C16 C17 bond. Thus, exo selectivity is observed.
At this stage, the scaffold of the tetracyclic pyrrolidine
(+)-21 had been constructed, and the quaternary carbon
center had been generated with the desired configuration.
Emphasis was then given to the establishment of the correct
configuration at C14 and C20 (conessine numbering;
Scheme 6). The hydrogenation of the adduct 16a in the
presence of palladium on activated carbon gave the product
17 as a mixture of diastereomers in a ratio of 23:1. The
stereoselectivity of the reaction was governed by the relative
steric inaccessibility of the concave b face, thus leading to the
attack of hydrogen from the a face. We hoped to take
advantage of the carbonyl group adjacent to the C14 center
and initially attempted to invert the configuration at C14 by
the conventional method with DBU (1,8-diazabicy-
clo[5.4.0]undec-7-ene). However, the inversion product was
Scheme 4. Synthesis of the key intermediate exo-16a:
obtained in less than 35% yield, and a significant amount of
the starting material was recovered (> 50%). We then
attempted to obtain the desired product through hydro-
a) CF3CO2À Ph(CH3)NH2+, (HCHO)n, THF, 658C, 4 h, 73%; b) Al2O3/
toluene, room temperature, 24 h, 95%; c) NaBH4, MeOH, 08C, 1 h;
d) p-TsOH·H2O, benzene, reflux, 91% (two steps); e) [Co2(CO)8]
genation of the corresponding olefin 18. It was anticipated
that hydrogenation would occur from the a face on the basis
of molecular modeling analysis. The successive treatment of
(1.1 equiv), DMSO (6 equiv), THF, 658C, 6 h, 16a/16b (6:1), 67%.
DMSO=dimethyl sulfoxide, Ts=toluenesulfonyl.
a-methylene enone 13 from 12.[8] The Michael addition of the ketone 17 with sodium borohydride then methanesulfonyl
(R)-(+)-N-methyl-N-(1-methyl-2-propynyl)amine (3) to the chloride (MsCl) was followed by elimination of methanesul-
enone 13 catalyzed by activated alumina[9] gave the adduct 14 fonic acid by treatment with potassium tert-butoxide, to give
in 95% yield. Reduction of the ketone group in 14 with the olefin 18 in 79% yield. Unexpectedly, hydrogenation of
sodium borohydride, followed by dehydration,
delivered the required enyne 15 in 91% yield with
98.2% ee ([a]2D5 = +166.7 (c = 1.275, CHCl3)). The
treatment of the enyne 15 with [Co2(CO)8] in the
presence of DMSO as an oxidant at 658C for 6 h
afforded the desired fused cyclopentenones 16a
([a]2D5 = +252.6 (c = 0.67, CHCl3)) and 16b ([a]2D5
=
À306.7 (c = 0.60, CHCl3)) in a ratio of 6:1 in 67%
yield. The configuration of 16a was determined by
X-ray crystallographic analysis, which further sup-
ported the assignment of the exo configuration to
the major product of the Pauson–Khand reaction
(Figure 2).[10]
observed exo selectivity is shown in Scheme 5.
A possible mechanism for the
Scheme 5. A possible mechanism for the observed exo selectivity.
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the entire chiral tetracyclic framework was created in one step
by a Pauson–Khand reaction. Thus, the synthesis was efficient
in terms of atom economy.
Received: December 19, 2003 [Z53583]
Keywords: alkaloids· cyclization · enynes· Pauson–Khand
.
reaction · pyrrolidines
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[3] a) L. Velluz, G. Mathieu, G. Monine, Tetrahedron Suppl. 1966, 8,
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Am. Chem. Soc. 1962, 84, 2018; c) J. A. Marshall, W. S. Johnson,
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Scheme 6. Completion of the synthesis of the tetracyclic pyrrolidine
(+)-21: a) Pd/C (10%), MeOH, H2 (20 atm), 24 h, 92%; b) NaBH4,
MeOH, 08C, 1 h; c) MsCl (2 equiv), pyridine, 08C, 3 h; d) KOtBu
(10 equiv), THF, room temperature, 24 h, 79% (three steps); e) Et3SiH
(20 equiv), TFA, room temperature, 24 h, 88%; f) MCPBA (2 equiv),
CH2Cl2, 08C, 1 h; g) TFAA (2.5 equiv), À308C; then NaBH(OAc)3, 93%
(two steps); h) Pd/C (10%), H2 (1 atm), 2 h, 78%.
the olefin 18 in the presence of palladium on activated carbon
gave inseparable products in a ratio of 8:1. 1H NMR spectro-
scopic analysis revealed that the major product was the
undesired product 22 of addition to the b face. This disap-
pointing result led us to investigate other conditions for
alkene reduction. To our delight, the treatment of the olefin
18 with triethylsilane[11] in trifluoroacetic acid (TFA) as the
solvent afforded exclusively the required a adduct 19 in 88%
yield.
[4] M. E. Kopach, A. H. Fray, A. I. Meyers, J. Am. Chem. Soc. 1996,
118, 9876.
[5] B. Jiang, M. Xu, Org. Lett. 2002, 4, 4077.
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[7] a) P. Magnus, D. P. Becker, J. Am. Chem. Soc. 1987, 109, 7495;
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4851; d) P. Magnus, C. Exon, P. Albaugh-Robertson, Tetrahedron
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The last challenge was to invert the configuration of the
C20 center adjacent to the nitrogen atom. It is well-
documented that the Polonovski reaction[12] is suitable for
this transformation. The oxidation of 19 with m-chloroper-
benzoic acid (MCPBA) gave the N-oxide derivative 20, which
was treated directly with trifluoroacetic anhydride (TFAA) at
À308C. Reduction with sodium triacetoxyl borohydride then
provided (+)-21 as a single isomer in 93% yield ([a]2D5 = +51
(c = 0.21, benzene)). The optical rotation of the product was
in agreement with that reported by Meyers and co-workers
for the same compound,[4] and the configuration of the
product was further confirmed by X-ray crystallographic
analysis.[13] The steric hindrance at the concave a face of the
tetracyclic molecule 20 may explain the excellent stereo-
selectivity observed.
In summary, we have described a concise and efficient
synthesis of the optically active tetracyclic pyrrolidine (+)-21
under mild conditions. We have demonstrated a highly
diastereoselective method for the construction of the compact
tetracycle in the fused pyrrolidine system, which bears a
quaternary stereocenter. The stereochemistry of the product
was affected by the substituent on the starting propargylic
amine. No protecting groups were used in the synthesis, and
[8] J. L. Gras, Tetrahedron Lett. 1978, 19, 2111.
[9] S. W. Pelletier, A. P. Venkov, J. Finer-Moore, N. V. Mody,
Tetrahedron Lett. 1980, 21, 809.
[10] X-ray crystallographic data for compound 16a: C18H21NO2, Mr =
283.36, monoclinic, space group P2(1)/n, a = 15.5826(10), b =
10.7104(7), c = 19.0881(12) Š, V= 3008.7(3) Š3, a = 90.008, b =
109.1930(10)8, g = 90.008; T= 20.08C, Z = 8, m(MoKa) =
0.081 mmÀ1
,
reflections collected: 17600 (unique 6948),
number of data with I > 2.00s(I): 3824, parameters: 547, R1 =
0.0462, Rw = 0.0923, int = 0.0459. CCDC 230574 (16a) and
R
CCDC 230573 (21) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[11] N. M. Loim, Z. N. Parnes, N. D. Kursanov, Synthesis 1974, 633.
[12] D. Grierson, Org. React. 1990, 39, 85.
[13] X-ray crystallographic data for compound 21: C18H25NO, Mr =
271.39, monoclinic, space group P2(1)/n, a = 6.8893(7), b =
27.701(3), c = 16.2366(16) Š, V= 3086.7(5) Š3, a = 90.008, b =
95.013(2)8,
g = 90.008,
T= 20.08C,
Z = 8,
m(MoKa) =
0.071 mmÀ1
,
reflections collected: 18522 (unique 7106),
number of data with I > 2.00s(I): 3248, parameters: 561, R1 =
0.0553, Rw = 0.0884, Rint = 0.0908; see reference [10].
2546
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Angew. Chem. Int. Ed. 2004, 43, 2543 –2546