Construction of the "left domain" of haplophytine

Article abstract of DOI:10.1002/anie.200701947

(Chemical Equation Presented) Left of the middle: Synthesis of the "left" structural domain (2) of haplophytine (1) features a stereoselective construction of its sterically congested carbon-carbon bond (C9′-C15) and an efficient cascade sequence involvin

Full text of DOI:10.1002/anie.200701947

Angewandte
Chemie
DOI: 10.1002/anie.200701947
Haplophytine
Construction of the “Left Domain” of Haplophytine**
K. C. Nicolaou,* Utpal Majumder, Stephane Philippe Roche, and David Y.-K. Chen*
Dedicated to Professor Madeleine M. JoulliØ on the occasion of her 80th birthday
Haplophytine (1, Figure 1) is an architecturally intriguing and
synthetically daunting heterodimeric alkaloid endowed with
insecticidal properties. Originally isolated in 1952 by Snyder
and co-workers[1a–d] from the Mexican plant Haplophyton
cimicidum, the structure of haplophytine was finally revealed
in 1973 as a result of the pioneering studies of the groups of
Cava,[1e,h] Yates,[1f,h] and Zacharias.[1f,g] The haplophytine
molecule consists of a central indole moiety onto which two
tetracyclic heterocycles are attached, the one on the “right”
fused onto the indole system, and the one on the “left”
bridged through a sterically demanding carbon–carbon bond
(C9’–C15) to the aromatic nucleus of the indole. The two
overlapping domains of the haplophytine molecule are
designated as truncated haplophytine (2, “left domain”,
Figure 1) and aspidophytine (3, “right domain”, Figure 1).
While four total syntheses have already been reported for the
naturally occurring aspidophytine (3),[2] beginning with
Coreyꢀs brilliant synthesis in 1999,[2a] the “left” domain of
haplophytine with its challenging connectivity to the indole
moiety remains to this day as a thorny synthetic problem.[3]
We now report the construction of compound 2 (Figure 1), a
truncated version of haplophytine (1) housing the entire “left
wing” skeleton of the natural product, including six of its rings
and its C9’–C15 bond.
Figure 1. Structures of haplophytine (1), truncatedhaplophytine ( 2),
andaspidophytine ( 3), andretrosynthetic analysis of 2.
On the basis of biosynthetic considerations and degrada-
tion studies,[1h] we envisioned indole derivatives 4 and 5
(Figure 1) to be potential key building blocks for constructing
the required haplophytine skeleton. A possible scenario for
their coupling to afford the desired but challenging carbon–
carbon bond between them (C15–C9’, haplophytine number-
ing) would be to activate one of them with a suitable reagent
towards nucleophilic attack and allow the other to act as an
incoming nucleophile. To test this hypothesis, we set out to
synthesize 4 and 5.
Scheme 1 summarizes the construction of tetrahydro-b-
carboline 4 starting with tryptamine (6). Thus, acylation of 6
with succinic anhydride, followed by methylation of the
resulting carboxylic acid (MeOH, amberlyst-15) afforded
methyl ester 7 in 80% overall yield. Dihydro-b-carboline
formation within 7 under Bischler–Napieralski[4] conditions
(POCl3) gave the corresponding imine, reduction of which
with NaBH4 furnished, after nitrogen protection (NCCO2Me)
of the resulting secondary amine 8, the desired tetrahydro-b-
carboline 4 in 21% overall yield (unoptimized).
[*] Prof. Dr. K. C. Nicolaou, Dr. U. Majumder, Dr. S. P. Roche,
Dr. D. Y.-K. Chen
Chemical Synthesis Laboratory@Biopolis
Institute of Chemical andEngineering Sciences (ICES)
Agency for Science, Technology andResearch (A*STAR)
11 Biopolis Way, The Helios Block, #03-08
Singapore 138667 (Singapore)
Fax: (+65)687-45870
E-mail: kcn@scripps.edu
david_chen@ices.a-star.edu.sg
Prof. Dr. K. C. Nicolaou
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
and
Department of Chemistry andBiochemistry
University of California
San Diego, 9500 Gilman Drive, La Jolla, CA 92093 (USA)
Scheme 2 depicts the synthesis of the other desired
building block, diphenol 5. Thus, the known phenol 9[3] was
benzylated (BnBr, K2CO3), and the resulting product was
subjected to a Henry[5] reaction (nitromethane, NaOH)
followed by elimination (Ac2O, NaOAc) to afford nitroalkene
10 in 88% overall yield for the three steps. Reduction of 10
[**] We thank Ms. Doris Tan (ICES) for assistance with high-resolution
mass spectrometry (HRMS) andDr. Tommy Wang Chern Hoe
(Institute of Molecular andCell Biology (IMCB), A*STAR) for X-ray
crystallographic analysis. Financial support for this work was
provided by A*STAR, Singapore.
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Scheme 1. Construction of tetrahydro-b-carboline 4. Reagents andcon-
ditions: a) succinic anhydride (1.1 equiv), CH2Cl2, 238C, 19 h, 82%;
b) amberlyst-15 (20% w/w), MeOH, reflux, 19 h, 98%; c) POCl3
(7.0 equiv), benzene, reflux, 1.5 h, d) NaBH4 (1.5 equiv), CH3OH, 08C,
30 min, 42% for two steps; e) NCCO2Me (1.3 equiv), CH2Cl2, 08C,
19 h, 51%.
Scheme 2. Construction of diphenol 5. Reagents andconditions:
a) BnBr (1.3 equiv), K2CO3 (1.6 equiv), DMF, 0!238C, 14 h, 96%;
b) CH3NO2 (1.8 equiv), NaOH (2.4 equiv), CH3OH/H2O (10:1), 08C,
30 min; c) NaOAc (2.1 equiv), Ac2O, 1408C, 30 min, 92% for two
steps; d) Fe (21 equiv), AcOH/toluene (1:2), 1108C, 30 min, 75%;
e) KHMDS (0.5m in toluene, 1.1 equiv), NCCO2Me (1.2 equiv), THF,
ꢀ788C, 3 h, 96%; f) Pd(10% on activatedcarbon, 0.05 equiv), H
,
2
CH3OH, 238C, 12 h, 95%; g) BBr3 (3.0 equiv), CH2Cl2, ꢀ78!08C, 2 h,
90%. Bn=benzyl, DMF=N,N’-dimethylformamide, KHMDS=potas-
sium hexamethyldisilazane.
Scheme 3. Total synthesis of the truncatedhaplophytine structure ( 2).
Reagents andconditions: a) 4 (2.0 equiv), PIFA (1.2 equiv), CH3CN/
CH2Cl2 (9:1), ꢀ40!ꢀ308C, 48 h, 25%; b) Cs2CO3 (4.0 equiv), MeI
(excess), DMF, 0!238C, 14 h, 60%; c) NaH (excess), THF, 0!238C,
14 h, 80%; d) mCPBA (1.4 equiv), NaHCO3 (excess), CH2Cl2, 08C, 7 h,
65%. mCPBA=meta-chloroperoxybenzoic acid, PIFA=PhI(CF3CO2)2.
(Fe, AcOH) led to the corresponding indole (75% yield),
whose exposed nitrogen atom was protected as a carbamate
(NCCO2Me) to furnish indole derivative 11 in 96% yield.
Reduction of indole 11 to its corresponding indoline with
concomitant cleavage of the benzyl ether was achieved under
catalytic hydrogenation conditions (95% yield), while cleav-
age of the methyl ether was performed with BBr3 (90%
yield), operations that led to the required diphenol 5.
With the required components (4 and 5) in hand, we
proceeded to find conditions for their coupling. After
considerable experimentation, we discovered that reacting 4
and 5 in the presence of PhI(CF3CO2)2 (PIFA) in acetonitrile/
dichloromethane (9:1) at ꢀ408C resulted in their union,
furnishing hexacyclic compound 12 in 25% yield
(Scheme 3).[6] The structure of 12 (m.p. = 131–1338C, from
acetonitrile) was based on its spectroscopic data and was
confirmed by X-ray crystallographic analysis (see ORTEP
drawing, Figure 2).[7] Apparently, after coupling of the two
partners through initial activation of the diphenolic substrate
followed by stereoselective nucleophilic attack from the
indole component, the closest phenolic group collapsed
upon the generated imine to form the observed oxygen
bridge between the two domains of the product 12. This
undesired bridge was then ruptured by exposure of 12 to
Cs2CO3 and MeI, conditions that also led to methylation of
the two phenolic oxygen atoms, furnishing the pentacyclic
imine 13 (60% overall yield). Treatment of the latter
compound with NaH in THF caused isomerization of the
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Angewandte
Chemie
imine double bond and concomitant ring closure, leading to
tetrasubstituted olefin 14 in 80% yield.
Substrate 14 was expected[8] from the outset to undergo,
upon epoxidation, a cascade reaction involving regioselective
epoxide opening and skeletal rearrangement to afford the
targeted “left” nucleus of haplophytine (2) as shown in
Scheme 3. Indeed, when 14 was treated with 1.4 equivalents
of mCPBA in CH2Cl2 at 08C, it was smoothly converted into 2
(65% yield), presumably through intermediates 15 and 16.
Although the anti stereochemistry is shown arbitrarily in
Scheme 3 for 15 and 16, no evidence exists as to their
stereochemistry, as these intermediates were neither charac-
terized nor detected.[9] The structure of compound 2 (m.p. =
255–2568C (decomp.), from benzene/acetonitrile) was based
on its spectroscopic data (Table 1) and was confirmed by X-
ray crystallographic analysis (see ORTEP drawing,
Figure 3).[7]
Figure 2. ORTEP drawing of 12. Thermal ellipsoids are shown at the
50% probability level. One molecule of CH3CN per molecule of 12
observedin the crystal lattice is omittedfor clarity.
The described chemistry provides a synthetic pathway to
the hitherto inaccessible “left domain” of haplophytine (1)
Table 1: Selected data for compounds 4, 5, 12, 13, 14, and 2.
4: Rf =0.70 (silica gel, EtOAc/hexane 1:1); m.p.=157–1598C (CH2Cl2/hexane); IR (film): nmax =3472, 2969, 2506, 1654, 1614, 1482, 1254 cmꢀ1
;
1H NMR (600 MHz, CD3CN): d=11.17 (s, 1H), 6.58 (d, J=8.7 Hz, 1H), 6.57 (d, J=8.7 Hz, 1H), 6.23 (s, 1H), 4.02 (t, J=8.1 Hz, 2H), 3.85 (s, 3H),
3.01 ppm (t, J=8.1 Hz, 2H); 13C NMR (150 MHz, CD3CN): d=156.2, 145.7, 132.6, 127.6, 124.7, 115.5, 110.9, 53.7, 49.1, 27.1 ppm; HRMS (ESI): calcd
for C10H12NO4 [M+H+]: 210.0761; found: 210.0775.
5: Rf =0.55 (silica gel, EtOAc/hexane 1:1); IR (film): nmax =3321, 2953, 1733, 1677, 1439, 1409, 1229 cmꢀ1; 1H NMR (600 MHz, CD3CN): d=9.05 (s,
1H), 7.45 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.13 (ddd, J=8.3, 7.2, 1.1 Hz, 1H), 7.06 (ddd, J=7.9, 7.2, 1.0 Hz, 1H), 5.31 (brs, 1H), 4.33
(brs, 1H), 3.71 (s, 3H), 3.67 (s, 3H), 3.23 (brt, J=12.4 Hz, 1H), 2.72–2.80 (m, 1H), 2.67–2.72 (m, 1H), 2.42–2.55 (m, 2H), 2.25 (dddd, J=14.3, 7.4,
7.4, 4.0 Hz, 1H), 2.10 ppm (dddd, J=14.2, 10.1, 7.4, 7.4 Hz, 1H); 13C NMR (150 MHz, CD3CN): d=173.3, 156.4, 136.4, 134.1, 126.9, 121.4, 119.1,
117.8, 111.0, 108.0, 52.1, 51.0, 51.0, 38.1, 30.4, 29.2, 20.9 ppm; HRMS (ESI): calcdfor C 17H21N2O4 [M+H+]: 317.1496; found: 317.1523.
1
12: Rf =0.33 (silica gel, EtOAc/hexane 1:1); m.p.=131–1338C (CH3CN); IR (film): nmax =3326, 2952, 1733, 1672, 1478, 1450, 1400 cmꢀ1; H NMR
(600 MHz, CD3CN): d=10.77 (s, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.04 (ddd, J=7.7, 7.7, 1.2 Hz, 1H), 6.73 (ddd, J=7.6, 7.6, 1.0 Hz, 1H), 6.69 (s, 1H),
6.62 (d, J=7.9 Hz, 1H), 5.71 (brs, 1H), 4.72–4.68 (m, 1H), 4.05–3.95 (m, 2H), 3.84 (s, 3H), 3.64 (s, 3H), 3.63 (s, 3H), 3.41–3.37 (m, 1H), 3.09–3.02
(m, 1H), 3.01–2.93 (m, 2H), 2.55 (dd, J=14.3, 4.0 Hz, 1H), 2.43–2.39 (m, 2H), 2.35 (ddd, J=14.1, 5.6, 5.6 Hz, 1H), 2.17 (dddd, J=14.4, 7.2, 7.2,
5.5 Hz, 1H), 1.74 ppm (dddd, J=14.3, 11.4, 7.1, 7.1 Hz, 1H); 13C NMR (150 MHz, CD3CN): d=173.3, 157.0, 156.1, 147.8, 147.1, 132.4, 130.5, 128.6,
128.2, 128.0, 127.2, 122.3, 118.7, 109.5, 109.5, 107.8, 55.9, 55.8, 53.6, 52.0, 51.0, 49.4, 38.6, 30.7, 29.0, 27.4, 27.3 ppm; HRMS (ESI): calcdfor
C27H30N3O8 [M+H+]: 524.2027 found: 524.2072.
13: Rf =0.40 (silica gel, EtOAc/hexane 2:1); IR (film): nmax =2952, 1728, 1702, 1582, 1444, 1405, 1384 cmꢀ1; 1H NMR (600 MHz, CD3CN): d=7.58 (d,
J=7.8 Hz, 1H), 7.34 (ddd, J=8.8, 7.3, 1.7 Hz, 1H), 7.29 (s, 1H), 7.19–7.15 (m, 2H), 5.34 (dd, J=10.0, 4.2 Hz, 1H), 4.12 (ddd, J=11.1, 8.5, 6.6 Hz,
1H), 4.07–3.99 (m, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 3.64 (s, 3H), 3.37 (s, 3H), 3.20 (ddd, J=14.3, 9.5, 2.9 Hz, 1H), 3.08–3.02 (m, 3H), 2.97 (brs, 3H),
2.62 (dddd, J=14.3, 7.6, 7.6, 4.3 Hz, 1H), 2.52–2.44 (m, 2H), 2.07–2.01 (m, 1H), 1.29 ppm (ddd, J=14.5, 8.9, 8.9 Hz, 1H); 13C NMR (150 MHz,
CD3CN): d=188.9, 173.3, 156.1, 156.0, 154.6, 149.9, 144.4, 143.4, 134.1, 131.2, 127.8, 127.5, 125.1, 122.4, 120.1, 117.3, 59.6, 58.7, 58.7, 55.2, 52.4,
51.9, 51.0, 50.9, 35.4, 31.3, 30.0, 29.0, 27.2 ppm; HRMS (ESI): calcdfor C 29H34N3O8 [M+H+]: 552.2340; found: 552.2393.
14: Rf =0.30 (silica gel, EtOAc/hexane 1:1); IR (film): nmax =2951, 1702, 1677, 1464, 1442, 1379, 1341 cmꢀ1; 1H NMR (600 MHz, CD3CN): d=8.12 (d,
J=8.4 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.26 (ddd, J=7.9, 7.9, 1.2 Hz, 1H), 7.18 (s, 1H), 7.05 (ddd, J=7.5, 7.5, 1.1 Hz, 1H), 4.10 (ddd, J=11.1, 9.0,
6.3 Hz, 1H), 4.03 (ddd, J=11.0, 8.9, 7.3 Hz, 1H), 3.74 (s, 3H), 3.64 (s, 3H), 3.64 (s, 3H), 3.57 (s, 3H), 3.52–3.49 (m, 1H), 3.44–3.38 (m, 2H), 3.27
(dd, J=13.7, 5.7 Hz, 1H), 3.08–2.94 (m, 3H), 2.68 (ddd, J=16.3, 5.7, 2.3 Hz, 1H), 2.48 (ddd, J=15.8, 15.8, 5.8 Hz, 1H), 1.79 ppm (ddd, J=13.2,
13.2, 7.2 Hz, 1H); 13C NMR (150 MHz, CD3CN): d=165.8, 155.2, 154.6, 151.1, 144.1, 140.3, 136.6, 134.5, 130.8, 130.3, 128.0, 124.1, 123.9, 117.2,
115.0, 59.8, 58.3, 52.4, 52.2, 51.2, 48.6, 41.3, 34.4, 32.7, 28.9, 23.8 ppm; HRMS (ESI): calcdfor C 28H29N3O7Na [M+Na: 542.1898; found: 542.1910.
2: Rf =0.25 (silica gel, EtOAc/hexane 1:1); m.p.=255–2568C (decomp) (C6H6/CH3CN); IR (film): nmax =2950, 1754, 1705, 1443, 1379, 1128 cmꢀ1
;
1H NMR (600 MHz, CD3CN): d=8.14 (dd, J=8.2, 1.3 Hz, 1H), 7.28 (ddd, J=7.3, 7.3, 1.5 Hz, 1H), 7.14 (s, 1H), 7.12 (ddd, J=7.9, 7.9, 1.2 Hz, 1H),
6.91 (dd, J=7.9, 1.4 Hz, 1H), 4.17–4.08 (m, 2H), 3.76 (s, 3H), 3.67–3.62 (m, 1H), 3.64 (s, 3H), 3.62 (s, 3H), 3.36 (ddd, J=13.9, 7.0, 7.0 Hz, 1H), 3.25
(ddd, J=14.0, 11.2, 6.3 Hz, 1H), 3.08 (dd, J=7.8, 7.8 Hz, 2H) , 2.95 (ddd, J=17.5, 11.3, 6.3 Hz, 1H), 2.87 (s, 3H), 2.84 (ddd, J=12.9, 8.2, 6.8 Hz,
1H), 2.61 (ddd, J=13.2, 6.6, 6.6 Hz, 1H), 2.52 (ddd, J=15.6, 11.1, 4.6 Hz, 1H), 2.28 ppm (ddd, J=14.0, 11.1, 4.5 Hz, 1H); 13C NMR (150 MHz,
CD3CN): d=196.3, 172.3, 155.4, 154.7, 149.4, 143.6, 135.9, 135.0, 133.6, 131.2, 130.5, 127.7, 127.1, 125.3, 120.0, 117.5, 81.6, 58.3, 58.2, 52.8, 52.6,
52.5, 51.3, 39.5, 36.6, 30.7, 29.0, 20.9 ppm; HRMS (ESI): calcdfor C 28H30N3O8 [M+H+]: 536.2027; found: 536.2075.
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Communications
h) P. Yates, F. N. MacLachlan, I. D. Rae, M. Rosenberger, A. G.
Szabo, C. R. Willis, M. P. Cava, M. Behforouz, M. V. Lakshmi-
kantham, W. Zeiger, J. Am. Chem. Soc. 1973, 95, 7842 – 7850.
[2] a) F. He, Y. Bo, J. D. Altom, E. J. Corey, J. Am. Chem. Soc. 1999,
121, 6771 – 6772; b) S. Sumi, K. Matsumoto, H. Tokuyama, T.
Fukuyama, Org. Lett. 2003, 5, 1891 – 1893; c) J. M. Mejia-Oneto,
A. Padwa, Org. Lett. 2006, 8, 3275 – 3278; d) J. P. Marino, C.
Ganfeng, Tetrahedron Lett. 2006, 47, 7711 – 7713.
[3] P. D. Rege, Y. Tian, E. J. Corey, Org. Lett. 2006, 8, 3117 – 3120.
[4] A. Bischler, B. Napieralski, Ber. Dtsch. Chem. Ges. 1893, 26,
1903 – 1908.
Figure 3. ORTEP drawing of 2. Thermal ellipsoids are shown at the
50% probability level.
[5] a) L. Henry, C. R. Hebd. SeancesAcad. Sci. Ser. C. 1895, 120,
1265 – 1268; b) F. A. Luzzio, Tetrahedron 2001, 57, 915 – 945.
[6] Similar reactions were reported by Danishefsky and co-workers,
who observed, as an unintentional product and in unspecified
yield, a similar product in their work towards phalarine (C. Chan,
C. Li, Z. Fei, S. J. Danishefsky, Tetrahedron Lett. 2006, 47, 4839 –
4841), and by Harran and co-workers, who constructed a similarly
and should facilitate the total synthesis of this long-sought
synthetic target.
Received: May 3, 2007
ꢀ
crowded C C bond between a phenol and an oxazole in their
synthesis of diazonamide A (A. W. G. Burgett, Q. Li, Q. Wei, P. G.
Harran, Angew. Chem. 2003, 115, 5111 – 5116; Angew. Chem. Int.
Ed. 2003, 42, 4961 – 4966).
Keywords: alkaloids · natural products · nitrogen heterocycles ·
.
rearrangement · total synthesis
[7] CCDC 645294 and 645295 contain the supplementary crystallo-
graphic data for compounds 12 and 2, respectively. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[8] This expectation was based on the elegant work of Cava and
Yates who, in 1973, converted reversibly haplophytine to hap-
lophytine dihydrobromide, a hydroxyiminium species.[1h]
[9] It should be noted that haplophytine dihydrobromide[1h,8] (corre-
sponding to 16) was proven by X-ray crystallographic analysis to
display syn stereochemistry. Molecular models, however, appear
to favor an anti approach on 14 suggesting formation of the anti
epoxide. On the other hand, the anti epoxide corresponding to 15
appears to be more strained than its syn counterpart.
[1] a) E. F. Rogers, H. R. Snyder, R. F. Fischer, J. Am. Chem. Soc.
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