π-allyl cation cyclisations initiated by electrocyclic ring-opening of gem-dihalocyclopropanes: Application to the first total syntheses of the crinine-type alkaloids maritinamine and epi-maritinamine

Article abstract of DOI:10.1039/b106369n

The πallyl cation cyclisation initiated by electrocyclic ring-opening of gem-dihalocyclopropanes was presented. The application to the first total syntheses of the crinine-type alkaloids maritinamine and epi-maritinamine was discussed. The racemic modific

Full text of DOI:10.1039/b106369n

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ꢀ-Allyl cation cyclisations initiated by electrocyclic ring-opening
of gem-dihalocyclopropanes: application to the first total syntheses
of the crinine-type alkaloids maritinamine and epi-maritinamine
1
Martin G. Banwell,* Joanne E. Harvey and Katrina A. Jolliffe
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 0200, Australia
Received (in Cambridge, UK) 17th July 2001, Accepted 30th July 2001
First published as an Advance Article on the web 13th August 2001
The racemic modifications of the crinine alkaloids 1 and 2
have been synthesized for the first time and by a pathway
that involves silver(I)-promoted electrocyclic ring-opening
of the ring-fused gem-dichlorocyclopropane 3 and trapping
of the resulting π-allyl cation by the tethered carbamate
moiety so as to form the pivotal C3a-arylated hexahydro-
indole 14.
heterocyclic compounds7 and now describe the application
of this protocol to a new synthesis of C3a-arylhexahydro-
indoles. We also report on the exploitation of this methodology
in the first total syntheses of the racemic modifications of
maritinamine (1) and epi-maritinamine (2), two crinine alkal-
8
oids isolated by Shamma and co-workers from Sternbergia
lutea found in Turkey. Natural products 1 and 2 differ from
most other members of the crinine alkaloid class in that they
possess a C9-methoxy and a C8-hydroxy group rather than the
usual (and less synthetically demanding) methylenedioxy unit
spanning these positions.9
The crinine alkaloids1,2 embody the 2,3,4,4a-tetrahydro-1H,
6H-5,10b-ethanophenanthridine skeleton and represent an
important sub-class within the large family of Amaryllidaceae
alkaloids. Many members of this sub-class display interesting
biological properties including immuno-stimulatory, cytotoxic
and anti-malarial activities. As a consequence, these natural
products have been the subject of numerous synthetic studies.3–6
Broadly speaking, two major routes have been developed. One
of these, reported by Schwartz and Holton,3 employs an intra-
molecular oxidative coupling of linked aryls (to form the C10a–
C10b bond of the crinine skeleton – see structure 1) followed by
an intramolecular hetero-Michael addition reaction (to form
the C4a–N5 bond) and may be regarded as a biomimetic syn-
thesis. Variations on this basic approach have been exploited
by a number of workers4 and even executed using polymer-
supported reagents.5 The second and more common route
employs an appropriate C3a-arylperhydroindole that is subject
to a Pictet–Spengler reaction so as to install C6 of the target
framework with accompanying formation of the N5–C6 and
C6–C6a bonds. The requisite C3a-arylperhydroindoles have
been prepared in a remarkably diverse number of ways.6 In all
of these approaches, construction of the sterically congested
quaternary carbon centre (C10b) carrying the aryl group has
proved especially challenging.
The early stages of the synthesis leading to the pivotal gem-
dichlorocyclopropane 3 (Scheme 1) rely upon a similar strategy
to that employed by Keck and Webb6e for construction of
the quaternary carbon centre associated with ( )-dihydro-
maritidine. Thus, β-ethoxycyclopentenone (4)10 was treated
with the lithio-species
6 derived from metallation of
bromoarene 511 with t-BuLi at Ϫ78 ЊC. The resulting alkoxide
was subjected to acidic work-up thereby providing the
β-arylcyclopentenone 7† (67%). Smooth and selective 1,2-
reduction of this last compound could be effected with the
Luche reagent12 but the reaction had to be carried out in
the presence of 2,6-lutidine because of the exceptional
acid-sensitivity of the product alcohol 8 (99%). The readily
derived acetate 9 (98%) then underwent an Ireland–Claisen
rearrangement13 so as to provide, after acidic work-up, the
γ,δ-unsaturated acid 10 (83%) embodying the pivotal quater-
nary carbon centre associated with targets 1 and 2. The methyl
and ethyl ester derivatives of compound 10 failed to undergo
effective reaction with dibromocarbene (generated under phase
transfer conditions)14 and such outcomes are attributed to the
high level of steric congestion at the cyclopentenyl double-bond
resulting from the presence of the adjacent quaternary carbon
center. In an effort to relieve such congestion, the acid moiety
within compound 10 was converted, via the intermediate amide
11, into the corresponding nitrile 12 (76% from 10). Whilst
compound 12 also failed to engage in reaction with dibromo-
carbene, on prolonged exposure to dichlorocarbene a ca. 2 : 1
mixture of the epimeric adducts 13a–b (50% combined yield)
was obtained.‡ These chromatographically separable adducts
were each subjected to hydrogenation in the presence of chloro-
form and PtO2 and the ensuing amine hydrochlorides were
immediately treated with Boc2O in the presence of triethyl-
amine so as to deliver the corresponding carbamates 3a and 3b
(75% in each case).
Independent subjection of each of the epimeric forms of
compound 3 to reaction with silver tetrafluoroborate in THF at
40 ЊC resulted in smooth electrocyclic ring-opening of the
cyclopropane and accompanying π-allyl cation cyclisation. The
ensuing mixture of the C3a-arylhexahydroindole 14 and the
corresponding free amine (arising from loss of the Boc-group)
was treated with Boc2O and in this manner clean samples of
compound 14 could be obtained in yields of 65–75%. Interest-
ingly, the epimeric forms of the gem-dichlorocyclopropane 3
react at rather different rates in the electrocyclic ring-opening–
For some time we have been interested in exploiting π-allyl
cation cyclisations initiated by electrocyclic ring-opening
of gem-dihalocyclopropanes as a method for the assembly of
2002
J. Chem. Soc., Perkin Trans. 1, 2001, 2002–2005
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DOI: 10.1039/b106369n

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Scheme 1 Reagents and conditions: (i) t-BuLi (2.0 mol equiv.), THF, Ϫ78 ЊC, 10 min then compound 4 (0.84 mol equiv.), 1.5 h; (ii) p-TsOH (cat.),
THF, 25 ЊC, 14 h; (iii) NaBH4 (2.5 mol equiv.), CeCl3ؒ7H2O (2.5 mol equiv.), 2,6-lutidine (10 mol equiv.), MeOH, 0–25 ЊC, 10 min; (iv) Ac2O (4 mol
equiv.), pyridine, 25 ЊC, 24 h; (v) LDA (1.2 mol equiv.), THF, DMPU, Ϫ78 ЊC, 0.5 h then TBDMSCl (2.7 mol equiv.), Ϫ78 ЊC, 10 min then heat at
66 ЊC, 3.5 h then H3Oϩ; (vi) NH4Cl (4 mol equiv.), EDCI (1.6 mol equiv.), HOBt (1.6 mol equiv.), DMF, 0–25 ЊC, 18 h; (vii) Cl3CCOCl (1.2 mol
equiv.), Et3N (2 mol equiv.), CH2Cl2, 0 ЊC, 0.66 h; (viii) CHCl3, 50 % aq. NaOH, TEBAC (cat.), 18 ЊC, 24 d; (ix) H2 (3 atm), PtO2 (cat.), EtOH–
CHCl3, 25 ЊC, 12 h then (Boc)2O (2 mol equiv.), Et3N (5 mol equiv.), THF, 25 ЊC, 15 h; (x) AgBF4 (6 mol equiv.), THF, 40 ЊC, 21 h, then (Boc)2O
(2 mol equiv.), Et3N (5 mol equiv.), THF, 25 ЊC, 15 h; (xi) (CH2O)n (11 mol equiv.), HCO2H, 80 ЊC, 18 h; (xii) Na (6 g atom equiv.), t-BuOH (14 mol
equiv.), THF, 66 ЊC, 3 h. EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and TEBAC = triethylbenzylammonium chloride.
π-allyl cation cyclisation sequence with the major isomer, 3a,
being completely consumed within 8 hours and the minor
isomer taking three times longer. Subjection of compound 14
to a Pictet–Spengler reaction,15 involving its treatment with a
mixture of formic acid and paraformaldehyde at 80 ЊC for 18 h,
resulted in the smooth formation of compound 15 (76%)
incorporating the crinine framework and with seemingly
appropriate functionality for elaboration to the target com-
pounds 1 and 2. However, whilst the chloroalkene 15 readily
underwent reductive dechlorination reaction under Bouveault–
Blanc conditions, the ensuing non-chlorinated alkene 16
(98%) could not be manipulated (e.g. via attempted oxy-
mercuration or hydroboration–oxidation of the double bond)
in any useful manner. On the basis that such difficulties may
arise because of steric congestion within the rigid crinine
framework, a re-ordering of the reaction sequence, wherein the
Pictet–Spengler cyclisation was delayed, seemed appropriate.
To such ends, the C3a-arylated hexahydroindole 14 (see Scheme
2) was subject to reductive dechlorination under the same con-
ditions as used earlier and in this manner alkene 17 (98%) was
obtained. Subjection of the latter material to oxymercuration
with Hg(OAc)2 under conditions described by Burk and
Overman6j gave, after reductive work-up with alkaline sodium
borohydride, a chromatographically separable mixture of
the epimeric alcohols 18 (25%) and 19 (71%). Independent
subjection of each of these products to a Pictet–Spengler
reaction (using formic acid and paraformaldehyde as before)
gave, after hydrolytic work-up with methanolic potassium
carbonate, the corresponding crinines 20 (72%) and 21 (58%),
respectively. Whilst selective de-isopropylation of compounds
20 and 21 could not be effected with AlCl3 in dichloro-
methane,16 such conversions could be achieved with BCl3 in
dichloromethane at 0 ЊC. Under these conditions compound
20 afforded ( )-maritinamine 1§ (70%) and congener 21 led to
( )-epi-maritinamine 2¶ (70%). The spectroscopic data derived
from the synthetic samples of ( )-1 and ( )-2 are completely
consistent with the assigned structures. Further, there is reason-
able agreement between these data and those reported by
Shamma et al.8 for the corresponding natural materials. The
consistent ca. 0.1 ppm difference in chemical shifts between the
appropriate sets of 1H NMR data is attributed to variations in
both solvent acidity and sample concentration. Related differ-
1
ences have been observed between the H NMR spectroscopic
data sets obtained for 4a-dehydroxycrinamabine.17
Since the C3a-arylperhydroindole moiety is also a basic
structural element associated with Sceletium alkaloids such as
mesembrine and pretazettine,6l the strategy described here
could also serve as a useful means of accessing these interest-
ing types of compounds. In addition, any capacity to effect
enantioselective 1,2-reduction of the prochiral enone 7 should
enable ready adaptation of the chemistry described above to the
synthesis of the (ϩ)- and (Ϫ)-forms of the title alkaloids.18
Experimental
Compound 14
A magnetically stirred solution of carbamate 3a (90 mg, 0.20
mmol) in THF (5 mL) was treated with silver tetrafluoroborate
(0.23 g, 1.2 mmol). The resulting solution was protected from
light and heated at 40 ЊC under an atmosphere of nitrogen for
21 h then cooled and poured into H2O (20 mL). After the
addition of aq. NH3 (2 mL) the mixture was extracted with
ethyl acetate (3 × 20 mL). The combined organic fractions were
then dried (MgSO4), filtered and concentrated under reduced
pressure. The resulting pale-yellow oil was re-dissolved in THF
(2 mL) and triethylamine (0.19 mL, 1.4 mmol) added. The
ensuing mixture was stirred for 10 min, treated with di-tert-
butyl dicarbonate (0.12 g, 0.54 mmol), stirred at 18 ЊC for
15 h then poured into H2O (20 mL) and extracted with ethyl
acetate (3 × 15 mL). The combined organic fractions were dried
J. Chem. Soc., Perkin Trans. 1, 2001, 2002–2005
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Scheme 2 Reagents and conditions: (i) Na (6 g atom equiv.), t-BuOH (14 mol equiv.), THF, 66 ЊC, 3 h; (ii) Hg(OAc)2 (2 mol equiv.), 1 : 1 v/v
THF–H2O, 25 ЊC, 24 h then NaBH4 (2 mol equiv.), 3 M aq. NaOH, 25 ЊC, 0.5 h; (iii) (CH2O)n (10 mol equiv.), HCO2H, 80 ЊC, 18 h then K2CO3
(6 mol equiv.), MeOH, 25 ЊC, 1 h; (iv) BCl3 (5 mol equiv.), CH2Cl2, 0 ЊC, 0.25 h.
(d, J 16.6 Hz, 1H), 3.64 (m, 1H), 3.47 (m, 1H), 3.11 (dd, J 12.0 and 5.1
Hz, 1H), 2.93 (m, 1H), 2.45 (dt, J 13.8 and 3.3 Hz, 1H), 2.31 (m, 1H),
2.24 (m, 1H), 2.03 (m, 1H), 1.84–1.74 (complex m, 2H), 1.60 (m, 1H),
1.35 (app. q, J 12.0 Hz, 1H), signals due to hydroxy group protons not
observed; 13C NMR (150 MHz, CD3OD) δ 148.5 (C), 146.8 (C), 138.3
(C), 122.2 (C), 114.0 (CH), 107.7 (CH), 68.9 (CH), 68.2 (CH), 60.9
(CH2), 56.5 (CH3), 52.6 (CH2), 43.7 (C), 37.3 (CH2), 36.0 (CH2), 31.3
(CH2), 27.1 (CH2); IR (neat, NaCl plates) 3306, 2920, 1562, 1509, 1447,
1277, 1128, 1071, 1029 cmϪ1; MS (EI) m/z 275.1519 (C16H21NO3
(MgSO4), filtered and concentrated under reduced pressure to
afford a pale-yellow oil. Subjection of this material to flash
chromatography (1 : 4 v/v ethyl acetate–hexane elution) gave,
after concentration of the appropriate fractions (Rf1 0.3), the
carbamate 14 (60 mg, 72%) as a clear, colorless oil. H NMR
(300 MHz, CDCl3) δ 6.84 (s, 1H), 6.83 (s, 2H), 5.91 (m, 1H),
4.92 (broad m, 1H), 4.50 (septet, J 6.1 Hz, 1H), 3.85 (s, 3H),
3.38–3.02 (complex m, 2H), 2.40–1.80 (complex m, 6H), 1.42
(broad s, 9H), 1.35 (d, J 6.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 155.4 (C), 150.1 (C), 145.8 (C), 138.4 (C), 133.6 (C),
125.6 (CH), 117.8 (CH), 115.5 (CH), 109.9 (CH), 79.6 (C), 71.3
(CH), 56.0 (CH3), 49.7 (C), 43.7 (CH2), 31.3 (CH2), 28.4 (CH3),
23.3 (CH2), 22.1 (CH3), two signals obscured or overlapping; IR
requires 275.1521, Mϩ , 100%), 258 (18), 247 (16), 246 (21), 228 (16),
ؒ
204 (39), 203 (37), 202 (18), 187 (19), 79 (46).
1 S. F. Martin, in The Alkaloids, ed. A. Brossi, Academic Press,
New York, 1987; vol. 30, pp. 251–376.
2 J. R. Lewis, Nat. Prod. Rep., 1998, 15, 107.
3 M. A. Schwartz and R. A. Holton, J. Am. Chem. Soc., 1970, 92,
1090.
4 (a) H. Irie, S. Uyeo and A. Yoshitake, J. Chem. Soc. C, 1968, 1802;
(b) T. Fushimi, H. Ikuta, H. Irie, K. Nakadachi and S. Uyeo,
Heterocycles, 1979, 12, 1311; (c) I. H. Sánchez, F. J. López, J. J.
Soria, M. I. Larraza and H. J. Flores, J. Am. Chem. Soc., 1983, 105,
7640.
(KBr) 2975, 2931, 1693, 1517, 1389, 1262, 1174, 1111 cmϪ1; MS
(EI) m/z 421.2019 (C23H32 35ClNO4 requires 421.2020, Mϩ
,
ؒ
65%), 367 (6), 365 (18), 325 (39), 323 (71), 288 (23), 235 (53), 57
(100).
Acknowledgements
5 S. V. Ley, O. Schucht, A. W. Thomas and P. J. Murray, J. Chem. Soc.,
Perkin Trans. 1, 1999, 1251.
We thank the Institute of Advanced Studies for financial
support including the provision of an IAS post-Doctoral
Fellowship to KAJ and a PhD Scholarship to JEH.
6 For representative examples see (a) H. Muxfeldt, R. S. Schneider
and J. B. Mooberry, J. Am. Chem. Soc., 1966, 88, 3670; (b) H. W.
Whitlock Jr. and G. L. Smith, J. Am. Chem. Soc., 1967, 89, 3600;
(c) R. V. Stevens, Acc. Chem. Res., 1977, 10, 193; (d ) J. B. P. A.
Wijnberg and W. N. Speckamp, Tetrahedron, 1978, 34, 2579;
(e) G. E. Keck and R. R. Webb II, J. Org. Chem., 1982, 47,
1302; ( f ) I. H. Sánchez, F. J. López, H. J. Flores and M. I.
Larraza, Heterocycles, 1983, 20, 247; (g) O. Hoshino, S. Sawaki,
N. Shimamura, A. Onodera and B. Umezawa, Chem. Pharm. Bull.,
1987, 35, 2734; (h) S. F. Martin and C. L. Campbell, J. Org. Chem.,
1988, 53, 3184; (i) J. P. Michael, A. S. Howard, R. B. Katz and
M. I. Zwane, Tetrahedron Lett., 1992, 33, 6023; (j) R. M. Burk
and L. E. Overman, Heterocycles, 1993, 35, 205; (k) W. H. Pearson
and F. E. Lovering, J. Org. Chem., 1998, 63, 3607; (l ) A. Padwa,
M. A. Brodney, M. Dimitroff, B. Liu and T. Wu, J. Org. Chem.,
2001, 66, 3119.
7 See, for example (a) M. Banwell, A. Edwards, J. Harvey, D. Hockless
and A. Willis, J. Chem. Soc., Perkin Trans. 1, 2000, 2175; (b) M. G.
Banwell, J. E. Harvey, D. C. R. Hockless and A. W. Wu, J. Org.
Chem., 2000, 65, 4241.
8 V. Pabuccuoglu, P. Richomme, T. Gozler, B. Kivcak, A. J. Freyer and
M. Shamma, J. Nat. Prod., 1989, 52, 785.
9 The crinine alkaloids 8-O-demethylmaritidine (M. Kihara, T. Koike,
Y. Imakura, K. Kida, T. Shingu and S. Kobayasi, Chem. Pharm.
Bull., 1987, 35, 1070), siculine,8 narcidine (E. Tojo, J. Nat. Prod.,
1991, 54, 1387), 8-hydroxy-9-methoxycrinine (B. Sener, S. Könükol,
C. Kruk and U. K. Pandit, Nat. Prod. Lett., 1993, 1, 287) and
macowine (J. J. Nair, A. K. Machocho, W. E. Campbell, R. Brun,
F. Viladomat, C. Codina and J. Bastida, Phytochemistry, 2000, 54,
Notes and references
† All new and stable compounds had spectroscopic data [IR, NMR,
mass spectrum] consistent with the assigned structure. Satisfactory
combustion and/or high-resolution mass spectral analytical data were
obtained for new compounds and/or suitable derivatives.
‡ The major and chromatographically more mobile epimer 13a is
tentatively assigned as possessing an anti-relationship between the
cyclopropyl and aryl rings. This epimer leads, via hydrogenation and
carbamate formation, to compound 3a.
1
§ Selected spectral data for compound 1: H NMR (500 MHz, CDCl3)
δ 6.72 (s, 1H), 6.57 (s, 1H), 4.47 (d, J 16.5 Hz, 1H), 4.28 (m, 1H), 3.88
(s, 3H), 3.87 (d, J 16.5 Hz, 1H), 3.53 (m, 1H), 3.47 (dd, J 12.5 and
5.5 Hz, 1H), 2.94 (ddd, J 12.5, 9.0 and 7.0 Hz, 1H), 2.28 (m, 1H), 2.25–
2.10 (complex m, 3H), 1.92–1.73 (complex m, 3H), 1.35 (ddd, J 12.5,
12.0 and 2.5 Hz, 1H), signals due to hydroxy group protons not
observed; 13C NMR (125 MHz, CD3OD) δ 147.1 (C), 145.3 (C), 138.1
(C), 121.8 (C), 112.8 (CH), 106.3 (CH), 65.2 (CH), 63.8 (CH), 60.0
(CH2), 55.4 (CH3), 51.5 (CH2), 42.6 (C), 36.2 (CH2), 32.1 (CH2), 27.1
(CH2), 22.0 (CH2); IR (neat, NaCl plates) 3369, 2917, 1558, 1507, 1443,
1277, 1131, 1013 cmϪ1; MS (EI) m/z 275.1520 (C16H21NO3 requires
275.1521, Mϩ , 100%), 258 (26), 247 (15), 246 (18), 228 (14), 204 (16),
ؒ
203 (41), 202 (17), 187 (19).
¶ Selected spectral data for compound 2: H NMR (500 MHz, CDCl3)
δ 6.68 (s, 1H), 6.58 (s, 1H), 4.42 (d, J 16.6 Hz, 1H), 3.88 (s, 3H), 3.82
1
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945) each possess
a
C8-hydroxy and
a
C9-methoxy group.
14 M. G. Banwell and M. E. Reum, in Advances in Strain in Organic
9-O-Demethyl-1,2-dihydromaritidine (J. Bastida, J. M. Llabrés,
F. Viladomat, C. Codina, M. Rubiralta and M. Feliz, Planta Med.,
1988, 54, 524) and cantabricine (L.-Z. Lin, S.-F. Hu, H.-B. Chai,
T. Pengsuparp, J. M. Pezzuto, G. A. Cordell and N. Ruangrungsi,
Phytochemistry, 1995, 40, 1549) each possess a C9-hydroxy and a
C8-methoxy group.
Chemistry, ed. B. Halton, JAI Press, Greenwich, Connecticut, 1991,
vol. 1, pp. 19–64; and references cited therein.
15 M. D. Rozwadowska, Heterocycles, 1994, 39, 903.
16 M. G. Banwell, B. L. Flynn and S. G. Stewart, J. Org. Chem., 1998,
63, 9139.
17 J. J. Nair, A. K. Machocho, W. E. Campbell, R. Brun,
F. Viladomat, C. Codina and J. Bastida, Phytochemistry, 2000, 54,
945.
18 For a commentary on the generation of quaternary stereocentres
using the enantioselective 1,2-reduction of an enone followed by
chirality transfer via an Ireland–Claisen rearrangement see E. J.
Corey, A. Guzman-Perez and S. E. Lazerwith, J. Am. Chem. Soc.,
1997, 119, 11769.
10 B. B. Kikani, J. R. McKee and M. Zanger, Synthesis, 1991, 176.
11 M. F. Comber and M. V. Sargent, J. Chem. Soc., Perkin Trans. 1,
1991, 2783.
12 A. L. Gemal and J.-L. Luche, J. Am. Chem. Soc., 1981, 103, 5454.
13 For a useful review of the Ireland–Claisen rearrangement see:
P. Wipf in Comprehensive Organic Synthesis, vol. 5, ed. B. M. Trost
and I. Fleming, Pergamon Press, Oxford, 1991, pp. 840–847.
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