Total synthesis of echinopines A and B

Article abstract of DOI:10.1021/ja9093988

Eohinopines A and B [(+)-1 and (+)-2], two naturally occurring compounds characterized with a unique [3.5.5.7] carbon framework, have been synthesized In both enantiomeric and racemic forms. Their total synthesis Involves a novel intramolecular rhodium-catalyzed cyclopropanation (4 →16) and a samarium dilodide-medlated ring closure (3 → 37).

Full text of DOI:10.1021/ja9093988

Published on Web 02/25/2010
Total Synthesis of Echinopines A and B
K. C. Nicolaou,* Hanfeng Ding, Jean-Alexandre Richard, and David Y.-K. Chen*
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences
(ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way,
The Helios Block, #03-08, Singapore 138667
Received November 9, 2009; E-mail: kcn@scripps.edu; david_chen@ices.a-star.edu.sg
Abstract: Echinopines A and B [(+)-1 and (+)-2], two naturally occurring compounds characterized with
a unique [3.5.5.7] carbon framework, have been synthesized in both enantiomeric and racemic forms.
Their total synthesis involves a novel intramolecular rhodium-catalyzed cyclopropanation (4 f 16) and a
samarium diiodide-mediated ring closure (3 f 37).
Introduction
The root of Echinops spinosus has proven its richness in
bioactive secondary metabolites with considerable molecular
diversity, including polyacetylene thiophenes, alkaloids, flavone
glycosides, and benzothiophene glycosides.1 In 2008, and after
extensive chemical investigations of the constituents of E.
spinosus, two sesquiterpenes with unprecedented molecular
architectures were reported by Shi, Kiyota and co-workers.2
Designated as echinopines A and B (1 and 2, Figure 1), these
structures are characterized by a unique [3.5.5.7] carbon
framework onto which a methylene group and a carboxymethyl
group are appended. A total synthesis of these compounds has
recently been disclosed.3 Herein we report an asymmetric total
synthesis of natural echinopines A and B [(+)-1 and (+)-2]
and racemic echinopines A and B [(()-1 and (()-2].
Figure 1. Structures of echinopines A (1) and B (2).
Results and Discussion
Retrosynthetic Analysis. The devised synthetic strategy
toward echinopines A (1) and B (2) (Figure 2) was based on
the premise that a diazo-derived carbenoid intramolecular
addition to an exocyclic olefinic bond would form concurrently
the cyclopropane ring and one of the cyclopentane rings of the
molecule (see 4 f 3, Figure 2), while an intramolecular SmI2-
mediated4 pinacol coupling (see 3 f 1, 2, Figure 2) at a later
Figure 2. Retrosynthetic analysis of echinopines A (1) and B (2).
stage would generate the cycloheptane ring. Intermediate 4 was
traced back to cyclohexenone (5) as shown retrosynthetically
in Figure 2.
(1) (a) Shih, C. In Flora Sinica; Scientific Press: Beijing, China, 1987;
Vol. 78, p 1. (b) Guo, D.; Cui, Y.; Lou, Z.; Gao, C.; Huang, L. Chin.
Trad. Herb. Med. 1992, 23, 3–5. (c) Guo, D.; Cui, Y.; Lou, Z.; Wang,
D.; Huang, L. Chin. Trad. Herb. Med. 1992, 23, 512–514. (d) Lam,
J.; Christensen, L. P.; Thomasen, T. Phytochemistry 1991, 30, 1157–
1159. (e) Chaudhuri, P. K. J. Nat. Prod. 1992, 55, 249–259. (f) Ram,
S. N.; Roy, R.; Singh, B.; Singh, R. P.; Pandey, V. B. Planta Med.
1996, 62, 187. (g) Koike, K. K.; Jia, Z. H.; Nikaido, T.; Liu, Y.; Zhao,
Y. Y.; Guo, D. A. Org. Lett. 1999, 1, 197–198.
Construction of [5.5.3] Tricyclic Dialdehyde 3 via Diazo
Ketoester 4. The construction of [5.5.3] tricyclic dialdehyde 3
commenced from cyclohexenone (5) and proceeded through
diazo ketoester 4 as summarized in Schemes 1-3. Thus,
bromination of 5 afforded 2-bromocyclohexenone (6, 98%
yield), whose reduction under modified CBS conditions (see
Scheme 1) afforded 2-bromocyclohexenol (7) in 90% yield and
greater than 95% ee (by Mosher ester analysis). Treatment of
the latter with n-BuLi followed by aqueous workup furnished
enantioenriched 2-cyclohexenol (8) in 80% yield.5 Ring contrac-
(2) Dong, M.; Cong, B.; Yu, S.-H.; Sauriol, F.; Huo, C.-H.; Shi, Q.-W.;
Gu, Y.-C.; Zamir, L. O.; Kiyota, H. Org. Lett. 2008, 10, 701–704.
(3) Magauer, T.; Mulzer, J.; Tiefenbacher, K. Org. Lett. 2009, 11, 5306–
5309.
(4) For selected reviews on the use of samarium diiodide in chemical
synthesis, see: (a) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew.
Chem., Int. Ed. 2009, 48, 7140–7165. (b) Edmonds, D. J.; Johnston,
D.; Procter, D. J. Chem. ReV. 2004, 104, 3371–3403. (c) Kagan, H. B.
Tetrahedron 2003, 59, 10351–10372. (d) Molander, G. A.; Harris,
C. R. Chem. ReV. 1996, 96, 307–338.
(5) Holub, N.; Neidho¨fer, J.; Blechert, S. Org. Lett. 2005, 7, 1227–1229.
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Scheme 1. Synthesis of Tricyclic Allylic Alcohol 23a
Scheme 2. Homologation of Carboxylic Acids 13 and 5-epi-13 to
Ketoesters 15 and 5-epi-15
mixture was taken through the next three steps, at which stage
the undesired diastereoisomer was conveniently and completely
removed as we shall see below. Thus, conversion of carboxylic
acid 13 to R-diazo-ꢀ-ketoester 4 was carried out through a two-
step procedure8 involving reaction with methyl potassium
malonate (14) in the presence of carbonyl diimidazole (CDI)
and MgCl2, followed by exposure of the resulting ꢀ-ketoester
(15) to p-acetamidobenzenesulfenyl azide (p-ABSA),9 in 76%
overall yield. The modest enhancement in diastereoisomeric
purity from carboxylic acid 13 (dr ca. 1.5:1) to ꢀ-ketoester 15
(dr ca. 2.7:1) was noteworthy. Apparently, anti acid 13 was
converted exclusively to the corresponding ꢀ-ketoester 15,
whereas the conversion of syn acid 5-epi-13 to ꢀ-ketoester 5-epi-
15 was accompanied by significant amounts (15%) of acyl
imidazole byproduct 5-epi-15a, which was easily removed from
the mixture of ketoesters, as shown in Scheme 2. Pleasantly,
heating diazo compound 4 in the presence of Rh2(OAc)4 (cat.)
in benzene at 90 °C resulted in the formation of the expected
[5.5.3] tricyclic system 16 in 70% yield and as a single
diastereoisomer. No cyclization product corresponding to 5-epi-4
(not shown) was observed, presumably due to steric shielding
of the R-face of the olefin by the OTBS group. Although
consumed, the fate of this diastereoisomer was not determined.
With tricyclic intermediate 16 in hand in multigram quantities
we then proceeded to the next key intermediate, allylic alcohol
23. To this end, 16 was subjected to a protecting group exchange
(HF·py, 17; then p-MeOC6H4CH2OC(N)CCl3, PPTS, 18, 73%
overall yield) and triflate formation (LDA, PhNTf2, 77% yield)
to give vinyl triflate 19. The stability of triflate derivative 19
allowed its elaboration to the corresponding triflate TBS ether
(Dibal-H, 20; TBSOTf, 2,6-lut., 21, 89% overall yield), which
underwent palladium-catalyzed carboxymethylation [MeOH,
CO, Pd(PPh3)4 (cat.), 22] and subsequent reduction (Dibal-H)
to afford allylic alcohol 23 in 85% yield over the two steps.
Alternatively, Stille coupling of vinyl triflate 21 with hydroxym-
ethyl stannane 24 in the presence of Pd(PPh3)4 (cat.) directly
afforded allylic alcohol 23 in 82% yield as shown in Scheme
1.
a Reagents and conditions: (a) Br2 (1.02 equiv), CH2Cl2, 0 °C, 1 h; then
Et3N (1.7 equiv), 0 f 25 °C, 1.5 h, 98%; (b) (R)-R,R-diphenylprolinol
(0.10 equiv), B(OMe)3 (0.12 equiv), THF, 25 °C, 1 h; then BH3 ·N,N-
diethylaniline (1.0 equiv), 5, -5 f 25 °C, 16 h, 90%, g95% ee (Mosher
ester analysis); (c) n-BuLi (3.5 equiv), Et2O, -78 f -10 °C, 2.5 h, 80%;
(d) TBSCl (1.3 equiv), Et3N (1.5 equiv), DMAP (0.1 equiv), CH2Cl2,
25 °C, 6 h; (e) O3, CH2Cl2, -78 °C; then PPh3 (1.0 equiv), -78 f 25 °C,
16 h; (f) piperidine (0.04 equiv), AcOH (0.04 equiv), benzene, 90 °C, 1 h;
(g) NaBH4 (1.0 equiv), MeOH, 0 °C, 45 min, 84% for the four steps; (h)
CH3C(OEt)3 (10.0 equiv), o-nitrophenol (0.05 equiv), xylenes, 150 °C, 21 h,
86% [ca. 1.5:1 mixture of anti:syn isomers (anti isomer shown)]; (i) LiOH
(2.0 equiv), THF/MeOH/H2O (3:1:1), 25 °C, 16 h, 100%; (j) 14 (3.0 equiv),
MgCl2 (3.0 equiv), CDI (2.2 equiv), THF, 25 °C, 16 h, 78% [ca. 2.7:1
mixture of anti:syn isomers (anti isomer shown)]; (k) p-ABSA (1.5 equiv),
Et3N (2.0 equiv), MeCN, 25 °C, 4 h, 97% [ca. 2.7:1 mixture anti:syn isomers
(anti isomer shown)]; (l) Rh2(OAc)4 (0.01 equiv), benzene, 90 °C, 70 min,
70%; (m) HF · py (15 equiv), THF, 25 °C, 1.5 h; (n)
p-MeOC6H4CH2OC(N)CCl3 (2.5 equiv), PPTS (0.1 equiv), CH2Cl2, 25 °C,
24 h, 73% for the two steps; (o) LDA (0.51 M in THF, 2.0 equiv), THF,
-78 °C, 1 h; then PhNTf2 (1.5 equiv), -78 f 0 °C, 2 h, 77%; (p) Dibal-H
(1.0 M in toluene, 2.5 equiv), CH2Cl2, -78 °C, 1 h; (q) TBSOTf (2.0 equiv),
2,6-lutidine (4.0 equiv), CH2Cl2, 25 °C, 1 h, 89% for the two steps; (r)
Pd(PPh3)4 (0.05 equiv), Et3N (3.0 equiv), MeOH/DMF (1.8:1), CO (1 atm),
50 °C, 1 h, 85%; (s) Dibal-H (1.0 M in toluene, 2.5 equiv), CH2Cl2,
-78 °C, 0.5 h, 100%; (t) Pd(PPh3)4 (0.05 equiv), LiCl (3.0 equiv),
n-Bu3SnCH2OH (24, 3.0 equiv), THF, 70 °C, 2 h, 82%.
tion of TBS protected 2-cyclohexenol (TBSCl, Et3N, 9) was
carried out by a three-step sequence6 involving ozonolysis,
piperidine-catalyzed intramolecular aldol condensation, and
NaBH4-mediated reduction, to give cyclopentyl allylic alcohol
11 in 84% overall yield. Claisen rearrangement7 of 11 was
effected by heating with CH3C(OEt)3 in the presence of
o-nitrophenol (cat.) to afford, after saponification of the resulting
ethyl ester (12), γ,δ-unsaturated carboxylic acid 13 in 86%
overall yield as a mixture of C-5 diastereoisomers in which the
desired anti product was predominating (dr ca. 1.5:1). This
While the synthetic sequence outlined in Scheme 1 provided
sufficient supplies of allylic alcohol 23, the modest diastereo-
selectivity of the Claisen rearrangement (11 f 12, dr ca. 1.5:
1), albeit with slight enhancement in its conversion to ꢀ-ketoester
15 (dr ca. 2.7:1), left something to be desired and called for an
improvement. To this end, allylic alcohol 11 was converted to
stannane 25 (NaH, n-Bu3SnCH2I, 80% yield), a substrate for a
(6) (a) Kozikowski, A. P.; Tuckmantel, W. J. Org. Chem. 1991, 56, 2826–
2837. For an alternative synthesis of allylic alcohol 9, see: (b)
Fukuzaki, T.; Kobayashi, S.; Hibi, T.; Ikuma, Y.; Ishihara, J.; Kanoh,
N.; Murai, A. Org. Lett. 2002, 4, 2877–2880.
(8) Brooks, D. W.; Lu, D. L.; Masamune, S. Angew. Chem., Int. Ed. Engl.
1979, 18, 72–74.
(9) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, D. H. Synth.
Commun. 1987, 17, 1709–1716.
(7) Castro, A. M. M. Chem. ReV. 2004, 104, 2939–3002.
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Total Synthesis of Echinopines A and B
A R T I C L E S
Scheme 3. Alternative Construction of Alkenyl Carboxylic Acid 13
Scheme 5. Completion of the Total Synthesis of (+)-Echinopine A
(1) and (+)-Echinopine B (2)a
through [2,3]-Wittig Rearrangementa
a Reagents and conditions: (a) NaH (1.0 equiv), n-Bu3SnCH2I (0.5 equiv),
THF/HMPA (3:1), 25 °C, 16 h, 80%; (b) n-BuLi (1.5 equiv), THF,
-78 °C, 0.5 h, 49% [ca. 7:1 mixture of anti:syn isomers (anti isomer
shown)]; (c) TsCl (4.0 equiv), Et3N (8.0 equiv), DMAP (1.0 equiv), CH2Cl2,
8.5 h, 85%; (d) KCN (4.0 equiv), DMF, 60 °C, 12 h, 86%; (e) Dibal-H
(1.0 M in toluene, 3.0 equiv), CH2Cl2, -78 °C, 1.5 h, 90%; (f) NaClO2
(2.0 equiv), 2-methyl-2-butene (10.0 equiv), t-BuOH/pH 7 phosphate buffer
(1:1), 25 °C, 2 h, 94%.
Scheme 4. Synthesis of Tricyclic Diol 35a
a Reagents and conditions: (a) DMP (4.0 equiv), NaHCO3 (16 equiv),
CH2Cl2, 25 °C, 2 h, 81%; (b) SmI2 (0.1 M in THF, 5.0 equiv), HMPA (20
equiv), THF, -78 f 25 °C, 1.5 h, 50%; (c) DMP (1.5 equiv), NaHCO3
(6.0 equiv), CH2Cl2, 25 °C, 45 min; (d) CDI (6.0 equiv), benzene, 80 °C,
3 h, 87%; (e) Ac2O (20 equiv), Et3N (20 equiv), DMAP (1.0 equiv), CH2Cl2,
25 °C, 48 h, 81% for the two steps; (f) SmI2 (0.1 M in THF, 2.0 equiv),
MeOH (5.0 equiv), THF, -78 °C, 15 min, 92%; (g) TsOH ·H2O (1.0 equiv),
MeOH/CH2Cl2 (1:1), 25 °C, 1 h, 100%; (h) Tebbe reagent (0.5 M in toluene,
2.2 equiv), pyridine (4.4 equiv), THF, -78 f 0 °C, 50 min, 87%; (i)
(COCl)2 (5.0 equiv), DMSO (10.0 equiv), CH2Cl2, -78 °C, 1 h; then Et3N
(15 equiv), -78 f 25 °C, 35 min; (j) Ph3PCH2OMe (5.0 equiv), LHMDS
(4.7 equiv), THF, -5 °C, 45 min; (k) TsOH•H2O (1.5 equiv), acetone, 25
°C, 3.5 h, 58% for the three steps; (l) NaClO2 (2.0 equiv), 2-methyl-2-
butene (10.0 equiv), t-BuOH/phosphate buffer (pH 7) (1:1),
25 °C, 1 h, 94%; (m) TMSCHN2 (2.0 M in Et2O, 1.5 equiv), benzene/
MeOH (4:1), 25 °C, 0.5 h, 92%.
a Reagents and conditions: (a) PtO2 ·H2O (60 wt %/wt, 0.88 equiv), H2,
benzene, 25 °C, 2 h, 69%; (b) DMP (2.0 equiv), NaHCO3 (6.0 equiv),
CH2Cl2, 25 °C, 2 h, 93%; (c) (MeO)2P(O)CH2COOMe (3.0 equiv), n-BuLi
(2.5 equiv), THF, 0 f 25 °C, 2 h, 96%; (d) NaBH4 (2.0 equiv), NiCl2 ·6H2O
(0.3 equiv), MeOH, 0 f 25 °C, 1 h, 98%; (e) Dibal-H (1.0 M in toluene,
2.5 equiv), CH2Cl2, -78 f 0 °C, 50 min; (f) LiEt3BH (1.0 M in THF, 7.8
equiv), THF, -78 °C, 3 h, 63%; (g) DDQ (3.0 equiv), CH2Cl2/phosphate
buffer (pH 7) (10:1), 0 °C, 80 min, 96% over the two steps.
desired 3-carbon length. To this end, and as shown in Scheme
4, 23 was hydrogenated under optimized conditions, employing
platinum catalyst (PtO2, H2) to afford the desired alcohol (30,
69% yield) as a single product. The latter was oxidized with
DMP leading to aldehyde 31 (93% yield), whose HWE
olefination [(MeO)2P(O)CH2COOMe, n-BuLi] gave enoate 32
as an inconsequential mixture of geometrical isomers (96%
yield, E:Z ca. 4:1). Sequential reduction of 32 with NaBH4-
NiCl2 ·6H2O (98% yield) and Dibal-H, followed by DDQ-
mediated PMB deprotection (33, 96% yield over the two steps),
furnished primary alcohol 35 via PMB ether 34. Alternatively,
alcohol 34 could be accessed directly from enoate 32 through
LiEt3BH-facilitated reduction (63% yield).
The forging of the remaining seven-membered ring within
the growing molecule was carried out as shown in Scheme 5,
which also summarizes the final stages of the synthesis. Thus,
exposure of diol 35 to DMP led to keto aldehyde 3 (81% yield),
whose intramolecular pinacol coupling under SmI2-HMPA
conditions,4 as planned, smoothly furnished tetracyclic system
planned [2,3] Wittig rearrangement,10 as shown in Scheme 3.
Thus, treatment of alkenyl stannane 25 with n-BuLi furnished
homoallylic alcohol 26, through the corresponding lithio species,
in 49% yield as a mixture of C-5 diastereoisomers in which the
desired anti product was predominating (ca. 7:1 dr). Conversion
of alcohol 26 to the previously obtained carboxylic acid 13 was
carried out through a four-step sequence involving tosylate 27
(TsCl, Et3N, DMAP), cyanide 28 (KCN) and aldehyde 29
(Dibal-H, 66% yield over the three steps), which was subjected
to Pinnick oxidation11 (NaClO2, 94% yield). In this instance,
carboxylic acid 13 was obtained as a single diastereoisomer (by
1H and 13C NMR analysis), presumably due to chromatographic
enrichment during the sequence from alcohol 26.
The next task was to reduce the ∆6,7 double bond of allylic
alcohol 23 stereoselectively and extend the side chain to its
(10) Nakai, T.; Mikami, K. Org. React. 1994, 46, 105–209.
(11) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37,
2091–2096.
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A R T I C L E S
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(c ) 0.70, CHCl3);3 2: [R]D25 ) +21.5 (c ) 0.50, CHCl3), [R]2D2
) +21 (c ) 0.14, CHCl3)2 and Lit. [R]2D2 ) +21.6 (c ) 0.60,
CHCl3)3] and mass spectrometric data with those reported for
the natural products.2,3
In our initial studies, and by employing racemic allylic alcohol
8, we have also synthesized (()-echinopines A and B [(()-1
and (()-2]. Their spectroscopic (1H and 13C NMR) data were
in agreement with those of the published data.2,3
Figure 3. Key NOEs in support of the stereochemical assignment of
carbonate 37a and thereby diol 37.
Conclusion
37 in 50% yield as a single diastereoisomer. Supported by NOE
studies (see Figure 3) on the corresponding carbonate (37a,
prepared from 37 and CDI, Scheme 5), this stereochemical
outcome can be rationalized by postulating the cyclic chelated
transition state 36 as shown in Scheme 5. Oxidation of the
secondary hydroxyl group of 37 (DMP, 38), followed by
excision of the superfluous tertiary acetate (Ac2O, Et3N, DMAP,
39, 81% for the two steps; SmI2-MeOH, 92% yield), then led
to ketone 40. Removal of the TBS group from the latter (TsOH),
followed by Tebbe olefination of the resulting hydroxy ketone
41 (87% yield for the two steps) and Swern oxidation of the
resulting hydroxyl olefin (42), furnished aldehyde 43. Homolo-
gation of the latter through the standard procedure
(Ph3PCH2OMe-LHMDS, 44; TsOH) afforded aldehyde 45
(58% yield for the three steps), whose Pinnick oxidation led
first to echinopine A (1, NaClO2, 94% yield) and thence
echinopine B (2, TMSCHN2, 92% yield). Synthetic (+)-1 and
(+)-2 exhibited identical spectroscopic (1H and 13C NMR) data
and satisfactory optical rotations [1: [R]2D5 ) +27.6 (c ) 0.54,
CHCl3), [R]2D2 ) +23 (c ) 0.11, CHCl3)2 and Lit. [R]2D2 ) +26.1
In summary, an asymmetric total synthesis of the novel
natural products echinopines A (1) and B (2) has been achieved
through a highly stereoselective and efficient strategy that
highlights the growing importance of rhodium catalysis and
samarium redox chemistry in chemical synthesis.
Acknowledgment. Professor K. C. Nicolaou is also at the
Department of Chemistry and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037 (USA), and Department of
Chemistry and Biochemistry, University of California, San Diego,
9500 Gilman Drive, La Jolla, California 92093 (USA). We thank
Ms. Doris Tan (ICES) for high resolution mass spectrometric
(HRMS) assistance. Financial support for this work was provided
by A*STAR, Singapore.
Supporting Information Available: Experimental procedures
and compound characterization. This material is available free
of charge via Internet at http://pubs.acs.org.
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