Total synthesis of (+)-eburnamonine

Article abstract of DOI:10.1055/s-0031-1291143

The enantiospecific total synthesis of vinca alkaloid (+)-eburnamonine is accomplished from l-ethyl lactate. Key feature of the synthesis is the construction of the chiral quaternary center involving a Johnson-Claisen rearrangement and assembly of the pentacyclic core by the Pictet-Spengler reaction and ring-closing metathesis. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291143

LETTER
▌1477
letter
Total Synthesis of (+)-Eburnamonine
Synthesis of (+)-Eburnamonine
Kavirayani R. Prasad,* John E. Nidhiry
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Fax +91(80)23600529; E-mail: prasad@orgchem.iisc.ernet.in
Received: 10.02.2012; Accepted after revision: 03.05.2012
main feature in the synthesis of (–)-1 by Schultz and
Pettus3e while Rh(II) carbenoid mediated asymmetric in-
sertion of a chiral lactone was the key step in the synthesis
reported by Wee and Yu.3f–g Very recently, MacMillan’s
Abstract: The enantiospecific total synthesis of vinca alkaloid (+)-
eburnamonine is accomplished from L-ethyl lactate. Key feature of
the synthesis is the construction of the chiral quaternary center in-
volving a Johnson–Claisen rearrangement and assembly of the pen-
tacyclic core by the Pictet–Spengler reaction and ring-closing group disclosed the synthesis of a variety of alkaloids
metathesis.
based on their organocatalysis strategy in combination
with a metal-mediated synthesis.3h The Pictet–Spengler or
Key words: eburnamonine, alkaloids, L-ethyl lactate
Bischler–Napieralski cyclization is the well-established
transformation for the construction of the C2–C3 bond in
the pentacyclic framework of eburnamonine. However,
Indole alkaloids isolated from a number of plant sources
the challenging aspect in asymmetric synthesis of the
have been a subject of synthetic investigation for several
decades because of their proven therapeutic significance.1
Indole alkaloids possess common structural features prob-
ably because of their common biogenetic origin. (–)-Ebur-
namonine (1, Figure 1) and structurally related alkaloids
vincamine (2), eburnamenine (3), and eburnamine (4) iso-
lated from several plants of Vinca species have attracted
considerable interest in recent years.
eburnamonine alkaloids is the construction of the chiral
quaternary center.
Synthesis of natural products using chiral pool com-
pounds is an attractive method, and we have recently dis-
closed the synthesis of a number of oxygenated bioactive
compounds from tartaric acid.4 In continuation of our ef-
forts herein, we report the synthesis of the (+)-eburnamo-
nine from L-ethyl lactate. Our approach for the synthesis
of (+)-eburnamonine is depicted in Scheme 1. The synthe-
sis of (+)-1 is envisaged by a ring-closing metathesis
(RCM) of the diene in 5 and futher lactamization. Al-
though there have been applications of RCM reaction in
alkaloids synthesis,5 interestingly, the assembly of the
eburnamonine alkaloid via RCM is not reported in the lit-
erature. Synthesis of 5 is anticipated by the Pictet–Spen-
gler reaction of N-allyl tryptamine with aldehyde 6, the
synthesis of which is planned from 7. Johnson–Claisen re-
arrangement of the allylic alcohol 8 derived from L-ethyl
H
N
H N
N
O
N
Et
Et
MeO2C
HO
(–)-eburnamonine (1)
(+)-vincamine (2)
H
N
H
N
N
N
Et
HO
Et
H
H
N
H N
(–)-eburnamenine (3)
(+)-eburnamine (4)
N
H
N
Figure 1 Vinca alkaloids
Et
Et
O
BnO
Although, there has been a plethora of publications over
six decades concerning the synthesis of eburnamonine,2
only a few approaches for the enantioselective synthesis
of 1 were reported.3 Ogasawara’s group reported the syn-
thesis of (–)-1 from L-glutamic acid3a while an enantiodi-
vergent synthesis of both enantiomers of eburnamonine
was accomplished by Winterfeldt’s group using a chiral
cyclopropane carboxaldehyde.3b Fuji’s group disclosed
the synthesis of (–)-1 from a chiral nitro olefin.3c,d The
asymmetric Birch reduction–alkylation protocol was the
5
(+)-eburnamonine (1)
Et CHO
Et
OMOM
BnO
BnO
7
6
OH
CO2Et
OH Et
OMOM
SYNLETT 2012, 23, 1477–1480
Advanced online publication: 14.05.2012
9
8
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1291143; Art ID: ST-2012-D0118-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthesis for (+)-eburnamonine (1)

1478
K. R. Prasad, J. E. Nidhiry
LETTER
lactate6 is chosen as the appropriate transformation for the the MOM ether in 7 with PPTS in refluxing EtOH afford-
assembly of 7 (Scheme 1). ed the primary alcohol 15 in 91% yield (Scheme 2).
Accordingly, the synthetic sequence commenced with the Dess–Martin periodinane8 oxidation of alcohol 15 pro-
homologation of the aldehyde obtained from the ester 10 duced aldehyde 6. To our surprise Pictet–Spengler reac-
by Wittig–Horner olefination with the ylide 117 to afford tion of the aldehyde 6 with N-allyl tryptamine did not
the α,β-unsaturated ester 12 in 73% yield. Reduction of proceed at all. However, reaction of aldehyde 6 with trypt-
the ester in 12 with DIBAL-H yielded the corresponding amine furnished a nonseparable mixture (dr = 3:2) of car-
alcohol (93% yield), which was protected as the MOM bolines 16 in 64% yield. Allylation of 16 yielded a
ether 13 in 97% yield. Deprotection of the silyl ether in 13 separable mixture of N-allyl carbolines in which the major
furnished the alcohol 8 in 88% yield. Treatment of 8 with isomer 5 was isolated in 56% yield.9 Treatment of the di-
triethylorthoacetate in the presence of a catalytic amount ene 5 with the Grubbs second-generation catalyst10 fur-
of propionic acid resulted in the formation of quaternary nished the product 17 in 83% yield. Hydrogenation of the
ester 14 in 79% yield. Reduction of the ester in 14 to the alkene and deprotection of the benzyl ether in 17 was ac-
alcohol (90% yield) and further reaction with NaH/BnBr complished by Pd/C-mediated hydrogenation to yield the
afforded the benzyl ether 7 in 93% yield. Deprotection of known alcohol 18 in 78% yield. Using the protocol de-
1) DIBAL-H, CH2Cl2
TBDMSO
TBDMSO
Et
1) DIBAL-H, CH2Cl2
–78 °C, 1 h (93%)
–78 °C, 0.5 h
O
O
Et
2) MOMCl, i-Pr2NEt
CH2Cl2, 0 °C to r.t., 6 h, (97%)
OEt
OEt
OEt
2)
Ph3P
10
12
O
11
toluene, Δ, 8 h
73% (for 2 steps)
triethylorthoacetate
EtCO2H (5 mol%)
TBDMSO
Et
HO
Et
TBAF, THF
OMOM
OMOM
toluene, 120 °C, 15 h
79%
r.t., 6 h
88%
8
13
OBn
O
OEt
OBn
1) LiAlH4, THF
0 °C, 0.5 h (90%)
Et
Et
Et
PPTS, EtOH
OH
Δ, 12 h
91%
2) NaH, BnBr
DMF, 0 °C to r.t.
2 h (93%)
OMOM
OMOM
15
14
7
Scheme 2 Synthesis of the chiral quaternary alcohol from L-ethyl lactate
NH2
OBn
OBn
O
N
Et
Et
H
Dess–Martin periodinane
TFA, CH2Cl2, –20 °C, 8 h
64% (for 2 steps)
(dr 3:2)
NaHCO3, CH2Cl2, 0 °C to r.t.
1.5 h
OH
6
15
H
N
Br
H
NH
Grubbs II cat. (5 mol%)
N
H
CH2Cl2, r.t., 5 h
83%
K2CO3, DMF
0 °C to r.t., 1 h
56%
N
H
Et
Et
16
BnO
BnO
5
H
N
H
N
H
N
TPAP, NMMO
H2, Pd/C, EtOH
r.t., 24 h
78%
CH2Cl2, r.t., 1 h
40%
N
O
N
H
N
H
Et
Et
Et
HO
BnO
17
18
(+)-eburnamonine (1)
Scheme 3 Total synthesis of (+)-eburnamonine (1)
Synlett 2012, 23, 1477–1480
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (+)-Eburnamonine
1479
Asymmetry 2011, 22, 499. (d) Prasad, K. R.; Penchalaiah, K.
Tetrahedron: Asymmetry 2011, 22, 1400. (e) Prasad, K. R.;
Swain, B. J. Org. Chem. 2011, 76, 2029. (f) Prasad, K. R.;
Pawar, A. B. Synlett 2010, 1093. (g) Prasad, K. R.; Pawar, A.
B. ARKIVOC 2010, (vi), 39. (h) Prasad, K. R.; Gandi, V. R.
Synlett 2009, 2593. (i) Prasad, K. R.; Gholap, S. L. J. Org.
Chem. 2008, 73, 2. (j) Prasad, K. R.; Gholap, S. L. J. Org.
Chem. 2008, 73, 2916. (k) Prasad, K. R.; Swain, B.
Tetrahedron: Asymmetry 2008, 19, 1134. (l) Prasad, K. R.;
Chandrakumar, A. J. Org. Chem. 2007, 72, 6312.
(m) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2006, 71,
3643.
scribed by Schultz and Pettus, oxidation of 18 with
TPAP/NMMO furnished (+)-eburnamonine (1) in 40%
yield.11 The spectral and physical data are in complete
agreement with that reported in literature (Scheme 3).3c
In conclusion, a linear strategy for the synthesis of indole
alkaloid (+)-eburnamonine is presented from L-ethyl lac-
tate in 15 steps and 3.2% overall yield. The synthetic se-
quence showcased the use of the Johnson–Claisen
rearrangement for the construction of the chiral quaterna-
ry center, Pictet–Spengler reaction and ring-closing me-
tathesis for the completion of the pentacyclic ring. Also,
construction of the chiral quaternary center possessing an
alkyl, alkenyl, and alcohol functionality makes it a viable
building block for the synthesis of other structurally relat-
ed alkaloids, which is in progress.
(5) Dieters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
(6) For a recent application of lactic acid in the synthesis of
chiral quaternary isocyanide, see: Ichikawa, Y.; Matsuda,
Y.; Okumura, K.; Nakamura, M.; Masuda, T.; Kotsuki, H.;
Nakano, K. Org. Lett. 2011, 13, 2520.
(7) Baldwin, J. E.; Moloney, M. G.; Parsons, A. F. Tetrahedron
1992, 48, 9373.
(8) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(9) The minor diastereomer was isolated in 38% yield.
(10) (a) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40,
45. (b) Grubbs, R. H. Angew. Chem. Int. Ed. 2006, 45, 3760.
(c) Grubbs, R. H. Tetrahedron 2004, 60, 7117. (d) Marco, J.
A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron 2007, 63,
2929.
Acknowledgment
We thank the Department of Science and Technology (DST), New
Delhi for funding. K.R.P. is a Swarnajayanthi fellow of DST, New
Delhi. J.E.N. thanks Council of Scientific and Industrial Research
(CSIR), New Delhi for a senior research fellowship.
(11) Preparation of 17
Supporting Information for this article is available online at
To a stirred solution of the diene 5 (24 mg, 0.06 mmol) in dry
CH2Cl2 (6 mL) was added Grubbs II catalyst (2 mg, 5 mol%)
under an argon atmosphere, and the reaction mixture was
stirred at r.t. for 5 h. After completion of the reaction (TLC),
most of the solvent was evaporated off, and the crude residue
thus obtained was purified by silica gel column chroma-
tography using PE–EtOAc (7:3) as eluent to afford 17 (18
mg, 83%) as a yellow foam. [α]D +179.2 (c 0.6, CHCl3). IR
(neat): νmax = 3371, 2960, 2930, 1458, 1048 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.78 (br s, 1 H), 7.49 (d, J = 7.5 Hz,
1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.34–7.06 (m, 7 H), 5.87 (dd,
J1 = 10.1 Hz, J2 = 4.6 Hz, 1 H), 5.44 (d, J = 10.1 Hz, 1 H),
4.36 (s, 2 H), 3.64 (s, 1 H), 3.58 (qd, J1 = 6.0 Hz, J2 = 2.9 Hz,
1 H), 3.52 (qd, J1 = 6.0 Hz, J2 = 3.0 Hz, 1 H), 3.33 (dd,
J1 = 16.4 Hz, J2 = 4.7 Hz, 1 H), 3.09 (dd, J1 = 10.9 Hz,
J2 = 4.8 Hz, 1 H), 3.01 (d, J = 16.4 Hz, 1 H), 2.98–2.80 (m,
1 H), 2.78 (d, J = 16.4 Hz, 1 H), 2.58 (td, J1 = 8.4 Hz,
J2 = 3.0 Hz, 1 H), 2.02–1.92 (m, 1 H), 1.87 (q, J = 7.7 Hz, 2
H), 1.46–1.36 (m, 1 H), 1.10 (t, J = 7.6 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 138.7, 136.2, 133.6, 132.9, 128.2 (2
C), 127.5 (2 C), 127.2, 126.8, 126.1, 121.5, 119.3, 117.9,
111.9, 110.7, 72.7, 68.0, 61.2, 55.1, 52.4, 43.0, 37.4, 32.5,
21.6, 8.9. HRMS: m/z calcd for [C26H30N2O + H]: 387.2436;
found: 387.2436.
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References and Notes
(1) (a) Zenk, M. H.; Juenger, M. Phytochemistry 2007, 68,
2757. (b) Leonard, J. Nat. Prod. Rep. 1999, 16, 319.
(c) Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559.
(2) For synthesis of (±)-eburnamonine, see: (a) Kalaus, G.;
Malkieh, M.; Katona, I.; Peredy, M.; Koritsanszky, T.;
Kalaman, A.; Szantay, C. J. Org. Chem. 1986, 50, 3760.
(b) Magnus, P.; Pappalardo, P.; Southwell, I. Tetrahedron
1986, 42, 3215. (c) Shono, T.; Matsumura, Y.; Ogaki, M.;
Onomura, O. Chem. Lett. 1987, 1447. (d) Wenkert, E.;
Hudlicky, T. J. Org. Chem. 1988, 53, 1953. (e) Wasserman,
H.; Kuo, G. Tetrahedron Lett. 1989, 30, 873. (f) Meyers, A.
I.; Romine, J.; Robichaud, A. J. Heterocycles 1990, 30, 339.
(g) Greiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.;
Rapoport, H. J. Org. Chem. 1990, 55, 3068. (h) Ihara, M.;
Takahashi, M.; Taniguchi, N.; Yasui, K.; Niitsuma, H.;
Fukumoto, J. J. Chem. Soc., Perkin Trans. 1 1991, 25.
(i) Karvinen, E.; Lounasmaa, M. Heterocycles 1992, 34,
1773. (j) Ghosh, A. K.; Kawahama, R. J. Org. Chem. 2000,
65, 5433.
(3) (a) Takano, S.; Yonaga, M.; Morimsto, M.; Ogasawara, K.
J. Chem. Soc., Perkin Trans. 1 1985, 305. (b) Hakam, K.;
Thielmann, M.; Thielmann, T.; Winterfeldt, E. Tetrahedron
1987, 43, 2035. (c) Node, M.; Nagasawa, H.; Fuji, K. J. Am.
Chem. Soc. 1987, 109, 7901. (d) Node, M.; Nagasawa, H.;
Fuji, K. J. Org. Chem. 1990, 55, 517. (e) Schultz, A. G.;
Pettus, L. J. Org. Chem. 1997, 62, 6855. (f) Wee, A. G. H.;
Yu, Q. Tetrahedron Lett. 2000, 41, 587. (g) Wee, A. G. H.;
Yu, Q. J. Org. Chem. 2001, 66, 8935. (h) Jones, S. B.;
Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature
(London) 2011, 475, 183. (i) For an enzymatic approach,
see: Palmisano, G.; D’Anniballe, P.; Santagostino, M.
Tetrahedron 1994, 50, 9487.
Preparation of 18
To a stirred solution of the alkene 17 (18 mg, 0.05 mmol) in
dry EtOH (2 mL) was added preactivated palladium on
charcoal (10% w/w, 20 mg) under a nitrogen atmosphere.
The reaction mixture was then subjected to hydrogenation
under a hydrogen balloon and stirred at r.t. for 24 h. After
completion of the reaction (TLC), it was filtered through a
short pad of Celite using CHCl3 (20 mL). The solvent was
evaporated off, and the crude residue thus obtained was
purified by silica gel column chromatography using EtOAc–
MeOH (19:1) as eluent to afford 18 (10 mg, 78%) as a white
solid. [α]D +85.8 (c 0.4, CHCl3); mp (165–168 °C). IR
(KBr): νmax = 3649, 3252, 2922, 1462, 1096 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.84 (br s, 1 H), 7.47 (d, J = 7.7 Hz,
1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.15 (t, J = 7.3 Hz, 1 H), 7.09
(t, J = 7.5 Hz, 1 H), 3.75 (td, J1 = 11.6 Hz, J2 = 2.4 Hz, 1 H),
(4) (a) Prasad, K. R.; Kumar, S. M. Synlett 2011, 1602.
(b) Prasad, K. R.; Penchalaiah, K. J. Org. Chem. 2011, 76,
6889. (c) Prasad, K. R.; Gandi, V. R. Tetrahedron:
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1477–1480

1480
K. R. Prasad, J. E. Nidhiry
LETTER
residue obtained after evaporation of the solvent was
3.44 (dt, J1 = 11.8 Hz, J2 = 4.4 Hz, 1 H), 3.36 (s, 1 H), 3.09
(d, J = 4.7 Hz, 1 H), 3.08 (s, 1 H), 3.07–2.97 (m, 1 H), 2.72–
2.62 (m, 1 H), 2.67 (s, 1 H), 2.45 (td, J1 = 11.7 Hz, J2 = 3.0
Hz, 1 H), 2.23–2.00 (m, 1 H), 1.89–1.54 (m, 6 H), 1.37 (d,
purified by rapid column chromatography using EtOAc as
eluent to afford (+)-1 (4 mg, 40%) as a white solid. [α]D +
87.5 (c 0.2, CHCl3) {lit3c [α]D –88 (c 0.09, CHCl3) for the
enantiomer}; mp (171–172 °C) {lit.3e mp 173–176 °C)}. IR
(KBr): νmax = 2926, 2854, 1696, 1452, 1370 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 8.37 (d, J = 7.8 Hz, 1 H), 7.43 (d,
J = 7.2 Hz, 1 H), 7.39–7.23 (m, 2 H), 3.99 (s, 1 H), 3.34 (dd,
J1 = 14.0 Hz, J2 = 6.7 Hz, 1 H), 3.31–3.21 (m, 1 H), 2.98–
2.84 (m, 1 H), 2.63 (Abq, J1 = J2 = 16.7 Hz, 2 H), 2.57–2.45
(m, 1 H), 2.53–2.40 (m, 1 H), 2.40 (dd, J1 = 11.2 Hz, J2 = 3.0
Hz, 1 H), 2.13–1.97 (m, 1 H), 1.83–1.58 (m, 4 H), 1.44 (q,
J = 13.7 Hz, 2 H), 1.03 (td, J1 = 13.7 Hz, J2 = 3.8 Hz, 1 H),
0.93 (t, J = 7.6 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ =
167.6, 134.2, 132.0, 130.1, 124.3, 123.8, 118.1, 116.3,
112.6, 57.7, 50.7, 44.4, 44.3, 38.5, 28.4, 27.0, 20.7, 16.6, 7.6.
HRMS: m/z calcd for [C19H22N2O + H]: 295.1810; found:
295.1811.
J = 15.0 Hz, 1 H), 1.26 (s, 1 H), 1.12 (t, J = 7.5 Hz, 3 H). 13
NMR (100 MHz, CDCl3): δ = 136.0, 132.2, 126.7, 121.7,
C
119.4, 118.2, 111.9, 110.6, 67.1, 58.7, 56.3, 54.0, 40.9, 38.8,
35.7, 32.3, 23.0, 21.3, 8.5. HRMS: m/z calcd for [C19H26N2O
+ H]: 299.2123; found: 299.2120.
Eburnamonine (+)-1
To a stirred solution of the alcohol 18 (10 mg, 0.03 mmol) in
CH2Cl2 (1 mL) were added a small amount of 4 Å MS and
NMO (7 mg, 0.06 mmol) under a nitrogen atmosphere at r.t.,
followed by TPAP (1 mg, 10 mol%) after 10 min. The
reaction mixture was stirred for 1 h at r.t. After completion
of the reaction, it was filtered through a small pad of Celite,
which was washed with CH2Cl2 (20 mL). The organic layer
was washed with sat. Na2SO3 (8 mL), brine (5 mL), sat.
CuSO4 (5 mL) and dried over anhyd Na2SO4. The crude
Synlett 2012, 23, 1477–1480
© Georg Thieme Verlag Stuttgart · New York

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