Heck arylation of endocyclic enecarbamates with diazonium salts. Improvements and a concise enantioselective synthesis of (-)-codonopsinine.

Article abstract of DOI:10.1021/ol005762d

Total enantioselective synthesis of the natural (-)-codonopsinine was accomplished in seven steps with an overall yield of approximately 16% starting from the five-membered endocyclic enecarbamate 4. The total synthesis features a highly efficient and ste

Full text of DOI:10.1021/ol005762d

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3039-3042
Heck Arylation of Endocyclic
Enecarbamates with Diazonium Salts.
Improvements and a Concise
Enantioselective Synthesis of
(−)-Codonopsinine
Elias A. Severino and Carlos Roque D. Correia*
Instituto de Qu´ımica, UniVersidade Estadual de Campinas, UNICAMP, C.P.6154,
CEP 13083-970, Campinas, Sa˜o Paulo, Brazil
roque@iqm.unicamp.br
Received March 6, 2000 (Revised Manuscript Received August 14, 2000 )
ABSTRACT
Total enantioselective synthesis of the natural (−)-codonopsinine was accomplished in seven steps with an overall yield of ∼16% starting
from the five-membered endocyclic enecarbamate 4. The total synthesis features a highly efficient and stereoselective Heck arylation of
endocyclic enecarbamate 4 with p-methoxybenzenediazonium tetrafluoroborate and a stereoselective epoxidation/epoxide opening sequence
as key steps.
(-)-Codonopsinine 1 and (-)-codonopsine 2 are rather
complex pyrrolidine alkaloids isolated from Codonopsis
clematidea that display antibiotic activity and hypotensive
activity without affecting the central nervous system in
animal tests.1 Interest in the synthesis of codonopsine and
codonopsinine stems mainly from their pharmacological
activity associated with the synthetic challenge they consti-
tutes in view of their 1,2,3,4,5-pentasubstituted molecular
structures bearing four contiguous stereogenic centers
(2R,3R,4R,5R) around a pyrrolidine ring in an all trans
arrangement.2
introduce the required phenyl ring adjacent to the pyrrolidine
nitrogen with the concomitant placement of a strategic double
bond, which would later provide access to the required trans-
diol functionality (Figure 1).3
We envisioned the synthesis of these alkaloids starting
from an enantiomerically pure five-membered endocyclic
enecarbamate by means of a stereoselective Heck arylation
as the key transformation. The Heck arylation would
Figure 1. Retrosynthetic analysis for the synthesis of (-)-
codonopsinine and (-)-codonopsine.
(1) Codonopsinine and codonopsine were isolated by Russian researchers
in 1969, who later on made incorrect stereostructural assignments based
1
on H NMR coupling constants. The correct stereochemistry of codonop-
sinine was established by C. Kibayashi in 1986. For details, see: Iida, H.;
Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1986, 27, 5393.
Recently, we reported a formal total synthesis of (-)-
codonopsine and (-)-codonopsinine employing a Heck
10.1021/ol005762d CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/07/2000

reaction of endocyclic enecarbamates with diazonium salts
as effective arylating agents.4 Herein we report a concise
total synthesis of the natural product (-)-codonopsinine, as
well as significant improvements on the key Heck arylation
of five-membered endocyclic enecarbamates with diazonium
salts which clearly demonstrates the generality and synthetic
potential of this arylation reaction.
Enantiomerically pure endocyclic enecarbamates 3 and 4
were obtained from L-pyroglutamic acid with overall yields
of 52-70% following procedures developed in our labora-
tory.5 As previously reported by us, Heck arylation of
enecarbamates using “traditional” conditions (aryl triflates
and/or aryl iodides in the presence of phosphine ligands)
provided the desired aryl-3-pyrrolines in very low yields
(10-20%).4 We were thus pleased to find out that benzene-
diazonium tetrafluoroborates could act as suitable arylating
agents for endocyclic enecarbamates, when the reaction was
carried out in methanol using 2,6-di-tert-butyl-4-methylpy-
ridine or 2,6-di-tert-butyl-pyridine (2 equiv) as base. Heck
arylation of enecarbamates 3 and 4 were then performed as
indicated in Scheme 1 to afford a diastereomeric mixture of
roline adduct.6 In our initial studies of the Heck arylation,
we kept the amount of the starting enecarbamate to a
maximum of 1.5-2 equiv with good results (Scheme 1).
Normally, excess enecarbamate could be recovered (60-
80% recovery) after column chromatography and recycled
into the synthetic scheme. By comparison, literature proce-
dures using aryl triflates usually require large excesses of
the olefin or enecarbamate undergoing Heck reaction (4-5
equiv).7
The Heck 3-pyrroline adducts 5a,b and 6a,b were con-
sistently obtained as an unseparable mixture of diastereo-
mers.8 Stereoselectivity of the Heck arylation was moderate
(4.5:1 for the tert-butyldiphenylsilyl ether protecting group
and 7.3:1 for the triphenylmethyl ether protecting group) as
determined by capillary gas chromatography of the corre-
sponding free alcohols (see discussion ahead).
During attempts to further improve yields with the
tritylated enecarbamate 4, we found out that the Heck
arylation can be performed in high yields and with good
stereoselectivity using only 1% of Pd2(dba)39 in acetonitrile
at room temperature, in the presence of sodium acetate as
base as described in Scheme 2. Using this protocol the aryl-
Scheme 1. Heck Arylation of Endocyclic Enecarbamate 3 and
4 with p-Methoxybenzenediazonium Tetrafluoroborate
Scheme 2. Improved Heck Arylation of Endocyclic
Enecarbamate 4 with p-Methoxybenzenediazonium
Tetrafluoroborate
3-pyrrolines 5a,b were obtained in yields ranging from 90
to 95%, with a diastereomeric ratio of 90:10 favoring the
anti aryl-3-pyrroline 5a. This procedure is simpler, milder,
and more economic than the one depicted in Scheme 1. It
also seems to be a general arylation procedure for moderate
electron rich olefins.10
aryl-3-pyrroline 5a,b and 6a,b in good to high yields (79-
96%). Arylation proceeded rapidly (within 10-15 min) with
moderate stereoselectivity without detection of regioisomeric
products resulting from isomerization of the primary 2-pyr-
Noteworthy in this reaction is that no excess of the
endocyclic enecarbamate or diazonium salts was required
to attain high yields of the Heck adduct. Arylations in
acetonitrile were exothermic and usually very fast (from less
than 5 min with 1 mol % of the palladium catalyst, to up to
30 min with 0.5 mol %).11 Reaction rates also seem to be
dependent on the solubility of NaOAc, so diluted reactions
(2) For previous syntheses of codonopsinine and codonopsine, see: (a)
Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996, 37, 5531. (b)
Wang, C. L. J.; Calabrese, J. C. J. Org. Chem. 1991, 56, 4341. (c) Iida, H.;
Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52, 1956. (d) Iida, H.;
Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1985, 26, 3255. This last
reference actually marks the first total synthesis of the unnatural (+)-
codonopsinine. However, the stereochemical representation for (+)-
codonopsinine made in this work was latter revised; see ref 1.
(3) Reviews on the Heck reaction: (a) Shibasaki, M.; Vogl, E. M. J.
Organomet. Chem. 1999, 576, 1. (c) Crisp, G. T. Chem. Soc. ReV. 1998,
27, 427. (c) Shibasaki, M.; Boden, D. J.; Kojima, A. Tetrahedron 1997,
53, 7371. (d) Negishi, E.; Coperet, C.; Ma, S; Liou, S. Y.; Liu, F. Chem.
ReV. 1996, 96, 365. (e) de Meijere, A.; Meyer, F. E. Angew. Chem., Int.
Ed. Engl. 1994, 36, 2379. (f) Cabri, W.; Candiani, E. Acc. Chem. Res. 1995,
28, 8.
(4) Oliveira, D. F.; Severino, E. A.; Correia, C. R. D. Tetrahedron Lett.
1999, 40, 2083.
(5) Oliveira, D. F.; Miranda, P. C. M. L.; Correia, C. R. D. J. Org. Chem.
1999, 64, 6646. In more recent experiments, the endocyclic enecarbamate
4 was obtained after three steps in 85% overall yield from the commercially
available (S)-(+)-5-(trityloxymethyl)-2-pyrrolidinone using the protocol
described therein.
(6) Recently, Tietze and Ferraccioli reported on a Heck reaction of a
five-membered endocyclic enecarbamate under Jeffrey conditions that
afforded a 1.2:1 ratio of regioisomeric Heck products in 63% yield. See:
Tietze, L. F.; Ferraccioli, R. Synlett 1998, 145.
(7) (a) Ozawa, F.; Hayashi, T. J. Organomet. Chem. 1992, 428, 267. (b)
Nilsson, K.; Hallberg, A. J. Org. Chem. 1990, 55, 2464. (c) Loiseleur, O.;
Meier, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1996, 35, 200.
(8) The Heck products are obtained as homogeneous material by TLC.
Capillary gas chromatography and HPLC were ineffective to resolve the
two diastereomers. Capillary GC led to significant decomposition, and HPLC
(hexanes/EtOAc) provided only partial resolution of the two diastereomers.
(9) Pd2(dba)3‚dba was obtained according to the procedure described in
Takahashi, Y.; Ito, Ts.; Ishii, Y. J. Chem. Soc. Chem. Commun. 1970, 1065.
3040
Org. Lett., Vol. 2, No. 20, 2000

(0.16 M) were faster than concentrated ones (0.30 M) in
which NaOAc is not entirely soluble.
Separation of the two diastereomers was easily ac-
complished after removal of the trityl (HCO2H, EtOAc, rt,
1 h, or ZnBr2, CH2Cl2/MeOH) or silyl (HF‚pyr, THF, rt, 72
h, ∼85%) protecting groups (Scheme 3). Removal of the
Introduction of the required trans diol functionality was
carried out by the intermediacy of an epoxide. Olefin 8
reacted slowly with 3-chloroperoxybenzoic acid (m-CPBA);
however, use of 5 equiv (toluene, rt, 24 h) afforded the R
-and â-epoxides 9a/9b in 70% yield in a diastereomeric ratio
of 93/07 as observed by capillary GC (Scheme 4).14
Scheme 3. Conversion of Heck Product 5 into Pyrroline 8
Scheme 4. Conversion of Pyrroline 8 into Epoxide 9
Epoxidation occurred mainly from the least congested face
of the double bond and provided the R-oriented epoxide 9a
as the major product. The stereochemistry for the major
product was assigned as due to the larger coupling constant
between H4 and H5 (3J4,5 = 1.5 Hz), when compared to that
found in the â-epoxide 9b (3J4,5 = 0). These coupling
constants are in agreement with those reported in the
literature for similar systems.15 Epoxide stereochemistry
played a decisive role for the total synthesis of (-)-
codonopsinine as concluded from the reactivity of the isolated
stereoisomers. Acidic hydrolysis of the major R-epoxide 9a
afforded the desired (2R,3R,4R,5R)-diol as the major product,
whereas exposure of the minor â-epoxides 9b to the same
conditions afforded none of the expected trans-diol (analysis
by TLC and capillary GC).
Although we did not perform any mechanistic studies, it
is conceivable that the â-epoxide 9b, which is more sterically
congested, undergoes epoxide ring opening, generating a
carbocation that disproportionates to other products. On the
other hand, R-epoxide 9a, being more stable, undergoes
attack by the incoming nucleophile at C4, minimizing steric
repulsion with the C2 aryl group and the C5 methyl group.
Acidic hydrolysis was performed on epoxides 9a to
provide the expected trans-diol 10 in 55% yield (Scheme
5).16 To conclude the total synthesis, the last step was a
straightforward reduction of the carbamate moiety with
lithium aluminum hydride that provided the natural product
protecting groups gave two isomeric hydroxymethyl pyrro-
lines whose TLC retention factors were quite distinct: ∼0.30
for the anti stereoisomer 7a and ∼0.60 for the syn stereo-
isomer 7b.12 The anti 3-arylpyrroline 7a was obtained in 70%
yield when employing zinc bromide for removal of the trityl
protecting group (the same yield was obtained when using
formic acid). Compound 7a was then submitted to deoxy-
genation, which was best carried out by mesylation of the
primary alcohol, followed by reduction with NaBH4 at 90°
C to yield the desired 5-methyl-3-pyrroline 8 in 88% yield
for the two steps (Scheme 3). The stereocontrolled synthesis
of the trans-pyrroline 8 provided an outstanding opportunity
for the total synthesis of (-)-codonopsinine.13
(10) After much experimentation, these were conditions we have found
optimum for the Heck arylation of endocyclic enecarbamates with diazonium
salts. These were conditions almost identical to those previously reported
by Matsuda to perform Heck arylation of cyclic olefins with diazonium
salts (see: Kikukawa, K.; Nagira, K.; Matsuda, T. Tetrahedron 1981, 37,
31). However, they reported that these conditions gave poor results when
applied to enamines and to some other cyclic olefins. Preliminary results
from our laboratory indicate that these conditions could be applied to six-
and seven-membered ring enecarbamates with good yields. Moreover, the
nature of the functional group at C5 of the five-membered enecarbamates
plays a critical role in the diastereoselectivity of the Heck arylation. These
results should be reported in due course.
(11) Typical experimental procedure: To a solution of 627 mg of
enecarbamate 4 (1.57 mmol) in 10 mL of anhydrous acetonitrile was added,
at once, a mixture of 340 mg of p-methoxybenzenediazonium tetrafluo-
roborate (1.57 mmol), 380 mg of sodium acetate (4.50 mmol), and 20 mg
of Pd2(dba)3‚dba (0.017 mmol). Upon addition, strong evolution of nitrogen
ensued with a noticeable warning of the reaction mixture. Evolution of gas
ceased after ∼5 min with a concomitant darkening of the reaction medium.
At this stage TLC indicated complete consumption of the starting enecar-
bamate. Then, ∼10 mL of saturated NaHCO3 was added to the reaction,
followed by addition of 30 mL of EtOAc. The organic layer was separated,
washed with saturated NaHCO3, dried over anhydrous sodium sulfate, and
concentrated in vacuo. The residue obtained was flash chromatographed
on silica gel (hexane:EtOAc; 2:1) to afford 734 mg (93% yield) of a
diastereomeric mixture of Heck adduct 5a,b (90:10 dr by capillary GC of
the free alcohols) as a single spot on TLC (Rf ) 0.22; hexane:EtOAc; 3:1).
(12) This large difference in retention factors led us to a previous incorrect
conclusion about the diastereoselectivity of the Heck arylation (see ref 4).
The Heck arylation, although stereoselective (90:10), gives a mixture of
two diastereomers. After deprotection, chromatography on silica gel
furnishes the trans aryl-3-pyrroline 7a as a pure compound as analyzed by
capillary GC and HPLC.
(13) The synthesis of codonopsine 2 by Wang and Calabrese relied on
a diastereomeric mixture (1.3:1 ratio) of 3-pyrrolines very similar to ours.
See: Wang, C. L. J.; Calabrese, J. C. J. Org. Chem. 1991, 56, 4341.
(14) Three epoxidizing agents were tested: m-CPBA, dimethyldioxirane
(DMD), and magnesium monperoxyphthalate (MMPP). A period of 24 h
was necessary for the epoxidation of 8 with 5 equiv of m-CPBA (90%
conversion). DMD epoxidation was much faster (10 equiv of DMD, acetone,
0 °C, 3.5 h or at room temperature for 2.5 h), resulting in the same
diastereomeric mixture (∼90:10), but in somewhat lower yields (55-61%).
MMPP provided results very similar to those obtained with m-CPBA.
(15) The presence of conformational isomers makes 1H NMR spectra
complex. Nevertheless, we have noticed in several instances a good
correlation between the vicinal coupling involving H4 and H5 and the
stereochemistry of substituted pyrrolidines and proline systems. Large
coupling constants are associated with cis H4-H5, whereas smaller coupling
constants (between 0 and 4 Hertz) are associated with trans H4-H5. For a
full analysis of related systems (3,4-epoxyprolines), see: Robinson, J. K.;
Lee, V.; Claridge, T. D. W.; Baldwin, J. E.; Schofield, C. J. Tetrahedron
1998, 54, 981.
Org. Lett., Vol. 2, No. 20, 2000
3041

proved to be very practical, economic, and stereoselective.
The characteristics of this novel protocol for the Heck
arylation of enecarbamates permitted a rather concise and
enantioselective total synthesis of (-)-codonopsinine 1 in
seven steps from enecarbamate 4 with good overall yield
(∼16%). Additionally, the synthetic strategy features a
stereoselective epoxidation/epoxide opening sequence that
was also key to the present synthesis and that should prove
valuable to other targets. A similar strategy can be also
applied to the total synthesis of (-)-codonopsine, although
we have not carried that through.
Scheme 5. Conversion of Epoxide 9a into (-)-Codonopsinine
1
Further studies applying this methodology to the synthesis
of other nitrogen-containing heterocycles are in progress and
should be reported in due course.
Acknowledgment. We thank FAPESP (Research Sup-
porting Foundation of the State of Sa˜o Paulo) for financial
support and CNPq (Brazilian National Research Council) for
fellowships.
(-)-codonopsinine 1 in 74% yield. Spectroscopic data
obtained for our synthetic (-)-codonopsinine 1 were in
excellent agreement with data reported in the literature.2c
In summary, the Heck arylation of endocyclic enecarbam-
ates was greatly improved by the use of 1% Pd2 (dba)3‚dba
in acetonitrile and sodium acetate as base without the need
of an excess of the valuable enecarbamate. This process
Supporting Information Available: Spectroscopic data
1
for compounds 3, 4, 5a,b, 7a, 7b, 8, 9a 10, and 1 and H
NMR and IR spectra of compounds 7a, 7b, 8, and 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) The amount of sulfuric acid employed for hydrolysis seems to be
critical. Best results were obtained with dioxane/H2O/H2SO4 concentrated
in a ratio of 3/2/0.2 mL. Higher concentrations of the acid (3/2/0.5 mL) led
to a diastereomeric diol whose structure was not determined yet. Basic
hydrolysis of epoxide 9a (DMSO/KOH 10% solution, 90-100 °C, 15 h)
provided trans diol 10 in ∼ 40% yield.
OL005762D
3042
Org. Lett., Vol. 2, No. 20, 2000