Domino Rh-catalyzed hydroformylation-double cyclization of o-amino cinnamyl derivatives: Applications to the formal total syntheses of physostigmine and physovenine

Article abstract of DOI:10.1039/c3cc43257b

A parallel, versatile and efficient route to synthesis of pyrrolidinoindoline and tetrahydrofuranoindoline alkaloids from cinnamyl derivatives has been developed, featuring a domino Rh-catalyzed hydroformylation-double cyclization sequence. This method can be applied to the syntheses of anti-Alzheimer drugs such as physostigmine and physovenine.

Full text of DOI:10.1039/c3cc43257b

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Domino Rh-catalyzed hydroformylation–double
cyclization of o-amino cinnamyl derivatives:
applications to the formal total syntheses of
physostigmine and physovenine†
Cite this: Chem. Commun., 2013,
49, 8232
Received 2nd May 2013,
Accepted 15th July 2013
DOI: 10.1039/c3cc43257b
Wen-Hua Chiou,* Chien-Lun Kao, Jui-Chi Tsai and Yun-Man Chang
www.rsc.org/chemcomm
A parallel, versatile and efficient route to synthesis of pyrrolidinoindo- double cyclization reaction, a general strategy to synthesize
line and tetrahydrofuranoindoline alkaloids from cinnamyl derivatives these alkaloids with flexibility for variation in pyrrolidinoindo-
has been developed, featuring a domino Rh-catalyzed hydro- lines and tetrahydrofuranoindolines. We take advantage of the
formylation–double cyclization sequence. This method can be applied special regio-selectivity found in hydroformylation of styrene
to the syntheses of anti-Alzheimer drugs such as physostigmine and derivatives, which produce exclusive a-formylated products due
physovenine.
to the coordination nature of the aromatic group.9 We have also
employed theoretical DFT calculations to explain the observed
The pyrrolidinoindoline alkaloid family possesses a wide range of selectivity.
important pharmacological activities (Fig. 1).1 For example, physo-
Our synthesis commenced with the preparation of carbamate
stigmine, a reversible inhibitor of acetyl- and butyryl-cholinesterase, derivatives 2, obtained by a series of functional group transforma-
has been used for treatment of glaucoma, myasthenia gravis and tions from o-nitro cinnamyl alcohol 1 (Scheme 1). Reduction of the
Alzheimer’s disease.2,3 Phenserine, a synthetic analogue of physo- aryl nitro group to the aryl amine with Fe(II), followed by protection
stigmine, is an effective and selective inhibitor of acetylcholinesterase, with methyl chloroformate provided carbamate 2a in 84% yield.
but with little effect on butyryl-cholinesterase.4 Moreover, phenserine Alcohol 2a was treated with PBr3 to provide the corresponding
has been recognized to inhibit b-amyloid plaque deposition, and bromide, followed by azide substitution to introduce the nitrogen
thus used for treatment of Alzheimer’s disease.3c,5 Eseroline exhibits functionality, and then reduction with PPh3 to a free amine. The
morphine-like potent analgesic properties.6 Pyrrolidinoindoline alka- resulting amine was treated with methyl chloroformate in the
loids bearing a trifluoromethylsulfanyl group (CF3S–), a group with presence of base to obtain dicarbamate 2b in 83% yield over 4 steps.
extremely large Hansch lipophilicity parameters, at the C-3a position It is noteworthy to point out that the crude products mentioned
show high cytotoxicity against three cancer cell lines.7 The physiolo- above could be used directly without further purification.
gical activities of 3a-substituted pyrrolidinoindoline derivatives have
prompted many synthetic chemists to develop various elegant hydroformylation–double cyclization reaction conditions, and the
approaches.7,8
results have been summarized in Table 1. Treatment of dicarbamate
With dicarbamate 2b in hand, we have investigated the key
Here we report an efficient and diverse synthesis of pyrroli- 2b under the cyclized conditions, i.e. 2 mol% of Rh(acac)(CO)2 and
dinoindolines using a domino Rh-catalyzed hydroformylation– 8 mol% of P(OPh)3 catalyst under 80 atm of CO and H2 (1 : 1) in
Fig. 1 Substituted pyrrolidinoindoline and tetrahydrofuranoindoline.
Department of Chemistry, National Chung Hsing University, Taichung, 402,
Taiwan, ROC. E-mail: wchiou@dragon.nchu.edu.tw; Fax: +886-4-22862547;
Scheme 1 Preparation of cinnamyl derivatives and the results of double cyclization.
(a) (i) FeSO4, NH4OH, MeOH. (ii) MeOCOCl, NaHCO3, acetone. (b) (i) PBr3, Et2O; (ii) NaN3,
acetone, H2O; (iii) PPh3, THF, H2O; (iv) MeOCOCl, K2CO3, acetone. (c) Rh(acac)(CO)2
(2 mol%), P(OPh)3 (8 mol%), CO (40 atm), H2 (40 atm), MeCN, 95 1C.
Tel: +886-4-22840411-420
† Electronic supplementary information (ESI) available: Experimental procedure,
1H, 13C NMR spectra, stereochemistry assignment and calculated geometry
coordinates. See DOI: 10.1039/c3cc43257b
c
8232 Chem. Commun., 2013, 49, 8232--8234
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Table 1 Optimization for the double cyclization of dicarbamate 2b
Entrya
Solvent
T (1C)
3b b (%)
4b b (%)
1
Toluene
Toluene
Dioxane
Dioxane
Dioxane
Dimethoxyethane
THF
CH3CN
CH3COOH
CH3OH
75
75
75
95
115
95
95
95
95
95
95
—
—
65
73
74
37
41
80
—
—
64
91
87
20
20
25
59
47
17
93
87
27
2c
3
4
5
6
7
8
9
10
11d
CH3CN
a
All reactions were run with 1.0 mmol of 2b (0.05 M in 20 mL solvent),
Rh(acac)(CO)2 (2 mol%), and P(OPh)3 (8 mol%) for 16–20 h, CO
Scheme 2 Four possible double cyclization pathways 1–4 from a-aldehyde A
b
c
(40 atm), H2 (40 atm). Isolated yield. Additives of PTSA (10 mol%)
and the corresponding transition state geometries in CH3CN.
d
used. Rh(acac)(CO)2 (0.5 mol%) and P(OPh)3 (2 mol%) used.
selectivity outcome, followed by deprotonation of these adducts to
give the final cis or trans tricyclic product and completes the whole
double cyclization process. Although it is known that cyclization to a
5,5-fused ring system prefers a cis fusion due to the highly strained
nature of trans fusion. We believe that these 4 transition state
geometries in the pathways 1–4 will provide more mechanistic
information about the cis selectivity. Thus, we have carried out the
DFT calculations to obtain four transition state geometries at the
level of B3LYP/6-31++G** in the gas phase, as well as those in
the acetonitrile solvent using the CPCM model (see ESI†). The
geometries have been shown in Scheme 2 and the results have been
summarized in Table 2.11
The results in Table 2 have disclosed that the stabilities of four
transition states appear to be concerned with a trajectory angle (i.e.
Bu¨rgi–Dunitz angle12), which is the angle of the nitrogen nucleophile
to the iminium bond. More precisely, the positions of the TSs are in
respect to the deviation of the angle from the typical Bu¨rgi–Dunitz
angle (B1051). A smaller angle difference also implies a smaller
activation energy barrier. There is a small difference in the Bu¨rgi–
Dunitz angle in the TS1, which implies that pathway 1 is preferred. In
addition, the calculations also display that the cis tricyclic product is
more stable than the trans tricyclic product by 23.0 kcal molꢀ1 (see
ESI†). Thus, the results provide substantial theoretical corroboration
to rationalize the cis selectivity. Since the cis product has been
thermodynamically and kinetically favored, it is anticipated that
products retain the cis configuration in the subsequent reactions.
Benzylic bromination of cyclized product 3b using 1,3-dibromo-
5,5-dimethylhydantoin/AIBN13 yielded bromide 5b in 59% yield,
accompanied by tryptamine 4b in 27% yield. Treatment of cyclized
toluene at 75 1C, did not afford the desired cyclized product 3b but
only tryptamine derivative 4b in 91% yield (entry 1). Addition of a
catalytic amount of PTSA (10 mol%) as a proton source did not yield
the desired product either (entry 2). Use of dioxane as the solvent led
to the formation of cyclized product 3b in 65% yield, as well as
tryptamine 4b in 20% yield (entry 3). A higher reaction temperature
of 95 1C improved the yield to 73%, while a reaction temperature of
115 1C did not bring significant change (entries 4 and 5). Thus, we
set the optimized reaction temperature to 95 1C. Moreover, employ-
ment of CH3CN slightly increased the yield to 80%, with appearance
of side product 4b in 17% yield (entry 8). Reaction in DME and
THF as solvents produced product 3b, but accompanied by more
tryptamine side product 4b (entries 6 and 7). Reaction in AcOH and
MeOH gave only tryptamine derivative 4b (entries 9 and 10). In
addition, reaction proceeded with lower catalytic loading (0.5 mol%,
entry 11), producing cyclized product 3b in 64% isolated yield. Thus,
we concluded that both dioxane and acetonitrile are used as suitable
solvents for the formation of cyclized product 3b, while acidic
conditions or a protic solvent favors the formation of tryptamine
product 4b.
Reaction of monocarbamate 2a under the same conditions
also yielded cyclized product 3a in 65% yield, as well as
tryptophol 4a in 20% yield. The relative configurations of both
tetrahydrofuranoindoline 3a and pyrrolidinoindoline 3b were
clearly assigned as a cis configuration due to nOe signals
observed between two methines (see ESI†).
To explain the observed cis selectivity, we have considered the
whole reaction process as follows: the double cyclization commences
with hydroformylation of the cinnamyl derivatives to yield a-aldehyde
A (Scheme 2). One of the two carbamates (i.e. N-1 and N-8) is able to
undergo intramolecular condensation with the aldehyde to afford
either indolinium intermediate I, or pyrrolinium intermediate II.
Subsequent intramolecular addition of the other carbamate to the
iminium intermediate furnishes the second cyclization to give either
cis (pathways 1 and 3) or trans (pathways 2 and 4) adducts, which
also dominates the diastereoselectivity.10 There are 4 possible transi-
tion states in the process to form the last ring and determine the
Table 2 Relative energies, Burgi–Dunitz angles in the 4 TS geometriesa
¨
Rel E
Imag n
y
TS 1 (cis)
TS 2 (trans)
TS 3 (cis)
0.0
+28.3
+1.2
211
295
202
251
109.8
131.7
113.9
129.4
TS 4 (trans)
+23.6
a
Energy in kcal molꢀ1, imaginary frequency in cmꢀ1, G = +N–CQN in TSs.
c
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active alkaloids such as esermethole, phenserine, physostigmine
and physovenine. Complete DFT calculations reveal that cis
products are both thermodynamically and kinetically favored,
and the stability guarantees a cis configuration in the subsequent
chemical transformations. Since many efficient asymmetric hydro-
formylations have been developed, the methodology provides a
practical way to synthesize chiral 3a-substituted alkaloids. Sub-
sequent investigation and extension of this methodology towards
other natural products of interest are currently underway.
This research was supported by the National Science Council,
Taiwan (NSC101-2113-M-005-009-MY3), and the National Center
for High-Performance Computing for computation facilities.
Notes and references
Scheme 3 Syntheses of desoxyeseroline, CPC-1 and tetrahydrofuranoindoline
analogues: (a) 1,3-dibromo-5,5-dimethylhydantoin, AIBN, CCl4, reflux. (b) ZnMe2,
toluene, reflux. (c) Ti(iOPr)4 (25 mol%), MeOH, reflux. (d) (i) NaOH, microwave.
(ii) HCHO, Pd/C, H2, EtOAc, rt. (e) Red-Al, toluene, reflux.
1 U. Anthoni, C. Christophersen and P. H. Nielsen, in Alkaloids:
Chemical and Biological Perspectives, ed. S. W. Pelletier, Wiley,
New York, 1999, vol. 13, p. 163.
2 (a) B. G. Katzung, S. B. Masters and A. J. Trevor, Basic And Clinical
Pharmacology, McGraw Hill, 12th edn, 2011; (b) A. Shafferman,
D. Barak, D. Stein, C. Kronman, B. Velan, N. H. Greig and
A. Ordentlich, Chem.–Biol. Interact., 2008, 175, 166.
3 (a) D. Barak, A. Ordentlich, D. Stein, Q.-S. Yu, N. H. Greig and
A. Shafferman, Biol. Chem., 2009, 417, 213; (b) X.-F. Pei, Q.-S. Yu,
B.-Y. Lu, N. H. Greig and A. Brossi, Heterocycles, 1996, 42, 229;
(c) N. H. Greig, X.-F. Pei, T. T. Soncrant, D. K. Ingram and A. Brossi,
Med. Res. Rev., 1995, 15, 3.
4 Q.-S. Yu, N. H. Greig, H. W. Holloway and A. Brossi, Heterocycles,
1999, 50, 95.
5 K. T. Shaw, T. Utsuki, J. Rogers, Q.-S. Yu, K. Sambamurti, A. Brossi,
Y.-W. Ge, D. K. Lahiri and N. H. Greig, Proc. Natl. Acad. Sci. U. S. A.,
2001, 98, 7605.
product 3a under the same conditions yielded bromide 5a in a better
yield of 74% and tryptamine 4a in 21% yield. Both bromides 5b and
5a have been versatile building blocks for syntheses of pyrrolidino-
indoline and tetrahydrofuranoindoline alkaloids. Four examples have
been demonstrated for the flexibility of the synthesis (Scheme 3).
Treatment of bromide 5b with ZnMe2 in toluene afforded a methyl-
ated product 6b in 74% yield, and the reaction of bromide 5a yielded
6a in 69% yield. Ti-mediated methanolysis of bromide 5b afforded
ether 6b0 in 81% yield, while that of bromide 5a took about 2 days to
produce 6a0 in 56% isolated yield and recovered bromide 5a in 35%
yield. Strong nOe signals have been observed between the methyl
group or the methoxy group and the methine proton (i.e. 8a) in
all the four cases, indicating that the cis configuration has been
retained. Desoxyeseroline 7b was achieved by Red-Al reduction of
both two carbamate groups to methyl groups in 78% yield. Red-Al
reduction of ether 6b0 provided CPC-1 7b0 in 71% yield, a new
pyrrolidinoindoline alkaloid isolated from Chimonanthus praecox (L.)
f. concolor Makino (Calycanthaceae) in 2006.14 However, Red-Al
reduction of tetrahydrofuranoindolines 6a and 6a0 to the N-methyl
products 7a and 7a0 resulted in the formation of a little amount of
desired product, only in 10% yield and 14% yield respectively. A two-
step procedure of protecting group removal–reductive methylation
has been carried out: microwave-assisted basic hydrolysis of 6a gave
free amine, which was immediately treated with formalin followed
by exposure to hydrogen with Pd/C to produce methyl product 7a in
64% yield. Following the same procedure, methyl product 7a0 was
obtained in 70% yield. The NMR data of 7b and 7b0 are identical
to those reported in the literature.8f,15 Desoxyeseroline 7b and
tetrahydrofuranoindoline 7a could be further converted into
esermethole, physostigmine and physovenine according to the
published reports.15
6 S. Fu¨rst, T. Friedmann, A. Bartolini, R. Bartolini, P. Aiello-
Malmberg, A. Galli, G. T. Somogyi and J. Knoll, Eur. J. Pharmacol.,
1982, 83, 233.
7 Y. Yang, X. Jiang and F.-L. Qing, J. Org. Chem., 2012, 77, 7538.
8 For an excellent review on pyrrolidinoindolines see (a) P. Ruiz-
Sanchis, S. A. Savina, F. Albericio and M. Alvarez, Chem.–Eur. J.,
2011, 17, 1388–1408; After the review, several papers referred, see
(b) Y. Zhou, Y. Zhao, X. Dai, J. Liu, L. Li and H. Zhang, Org. Biomol.
Chem., 2011, 9, 4091; (c) G. Ozuduru, T. Schubach and M. M. K.
Boysen, Org. Lett., 2012, 14, 4990; (d) A. W. Schammel, G. Chiou and
N. K. Garg, J. Org. Chem., 2012, 77, 725; (e) H. J. Lim and T. V.
RajanBabu, Org. Lett., 2011, 13, 6596; ( f ) A. Singh and G. P. Roth,
Org. Lett., 2011, 13, 2118; (g) B. M. Trost and Y. Zhang, Chem.–Eur. J.,
2011, 17, 2916.
9 P. W. N. M. v. Leeuwen and C. Claver, in Rh-catalyzed Hydroformyla-
tion, ed. P. W. N. M. v. Leeuwen and C. Claver, Kluwer Academic
Publishers, Dordrecht, 2002.
10 For heteroatom-mediated double cyclizations, see (a) R. Roggenbuck,
A. Schmidt and P. Eilbracht, Org. Lett., 2002, 4, 289; (b) N. Mizutani,
W.-H. Chiou and I. Ojima, Org. Lett., 2002, 4, 4575; (c) W.-H. Chiou,
N. Mizutani and I. Ojima, J. Org. Chem., 2007, 72, 1871.
11 The complete IRC calculation results and proton affinity values of
both cis and trans tricyclic adducts can be found in the ESI†.
12 H. B. Burgi, J. D. Dunitz, J. M. Lehn and G. Wipff, Tetrahedron, 1974,
30, 1563.
13 (a) D. Crich and A. Banerjee, Acc. Chem. Res., 2007, 40, 151;
(b) M. Movassaghi and M. A. Schmidt, Angew. Chem., Int. Ed.,
2007, 46, 3725.
14 M. Kitajima, I. Mori, K. Arai, N. Kogure and H. Takayama, Tetra-
hedron Lett., 2006, 47, 3199.
15 (a) M. Node, A. Itoh, Y. Masaki and K. Fuji, Heterocycles, 1991, 32, 1705;
(b) M. G. Kulkarni, A. P. Dhondge, A. S. Borhade, D. D. Gaikwad,
S. W. Chavhan, Y. B. Shaikh, V. B. Nigdale, M. P. Desai, D. R. Birhade
and M. P. Shinde, Eur. J. Org. Chem., 2009, 3875; (c) M. G. Kulkarni,
A. P. Dhondge, A. S. Borhade, D. D. Gaikwad, S. W. Chavhan,
Y. B. Shaikh, V. B. Ningdale, M. P. Desai, D. R. Birhade and
M. P. Shinde, Tetrahedron Lett., 2009, 50, 2411.
In conclusion, we have described a versatile synthesis of
3a-substituted pyrrolidinoindolines and tetrahydrofuranoindolines
featuring a domino Rh-catalyzed hydroformylation–double cycliza-
tion reaction. The methodology provides a flexible access to various
substituted alkaloids, demonstrated as syntheses of CPC-1 and
desoxyeseroline, and can be applied to synthesize pharmacological
c
8234 Chem. Commun., 2013, 49, 8232--8234
This journal is The Royal Society of Chemistry 2013