Synthesis and stereochemical determination of batzelladine C methyl ester

Article abstract of DOI:10.1039/b914744f

Batzelladine C (3) is a tricyclic guanidine alkaloid of unknown stereochemistry at one centre as well as unknown absolute stereochemistry. The two possible diastereoisomers of the methyl ester corresponding to this compound have been synthesised, permitti

Full text of DOI:10.1039/b914744f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and stereochemical determination of batzelladine C methyl ester†
Michael Butters,c Christopher D. Davies,b Mark C. Elliott,*a Joseph Hill-Cousins,a Benson M. Kariuki,a
Li-ling Ooi,a John L. Wooda and Stuart V. Wordinghama
Received 22nd July 2009, Accepted 13th August 2009
First published as an Advance Article on the web 13th October 2009
DOI: 10.1039/b914744f
Batzelladine C (3) is a tricyclic guanidine alkaloid of unknown stereochemistry at one centre as well as
unknown absolute stereochemistry. The two possible diastereoisomers of the methyl ester
corresponding to this compound have been synthesised, permitting the relative and absolute
stereochemistry of this compound to be assigned.
Introduction
The batzelladine alkaloids are a structurally fascinating group
of marine natural products containing acyclic, bicyclic and
tricyclic guanidines, in some cases all within the same compound.
Batzelladines A–E were isolated in 1995,1 with a further ten
compounds isolated later by a number of groups.2 The structures
shown in Fig. 1 are representative of these natural products. These
compounds have attracted a great deal of synthetic interest,3
particularly from the groups of Overman,4 Nagasawa,5 Gin,6
Snider7 and Murphy8 and Evans,9 leading to total syntheses of
batzelladines A,10 D11 and F,12 and dehydrobatzelladine C.13 Our
own work in this area focused on the application of a three-
component coupling reaction, originally developed by Kishi,14 to
the bicyclic portion of batzelladine A (1).15,16
Discussion
Batzelladine C (3) is a tricyclic guanidine with unknown stereo-
chemistry at C-4,17 as well as unknown absolute stereochemistry.
Batzelladines J, M (5) and N share this stereochemical ambiguity.
In fact, the original report on the isolation of batzelladine C
states the stereochemistry of the right-hand ring as shown, but
does not discuss the basis of this assignment. However, the
reports of dehydrobatzelladine C and batzelladines J, M and N all
confirm this assignment. Furthermore, g-NOESY NMR spectra
of natural batzelladine C obtained in our laboratory show a clear
cross-peak between H-7 and H-8a, so we are confident that this
stereochemistry is secure.18
Our approach to this class of compound (Scheme 1) installs
this centre in a diastereoselective three-component coupling of an
alkylidenepyrrolidine 6 with an aldehyde and an isothiocyanate.
The remaining ring will be formed by iodocyclisation of a bicyclic
aCardiff School of Chemistry, Cardiff University, Main Building, Park
Place, Cardiff, CF10 3AT, UK. E-mail: elliottmc@cardiff.ac.uk; Fax: +44
(0)29 20874030; Tel: +44 (0)29 20874686
bAstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
cAstraZeneca Process R&D Avlon/Charnwood, Avlon Works, Severn Road,
Hallen, Bristol, BS10 7ZE, UK
† Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra for compounds 16–31, 1H–1H COSY and g-NOESY
NMR spectra for compound 30 and 1H NMR spectra for batzelladine C
(3). CCDC reference number 739833. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b914744f
Fig. 1 Selected batzelladine alkaloids.
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Scheme 3
Scheme 1
for X-ray analysis (Fig. 2), so that we were now confident of our
previous and subsequent (vide infra) stereochemical assignments.
guanidine 8,19 a reaction that has been used by Gin in the
total synthesis of batzelladine D.11c This route has a distinct
advantage over some previous studies towards the batzelladine
alkaloids, since only a single stereogenic centre is required to
produce all of the natural product stereochemistry. We now report
the successful realisation of this strategy, in which the methyl
esters corresponding to both diastereoisomers of batzelladine C
have been synthesised.
We have previously reported the three-component coupling
of compound 10 to give a 2 : 1 mixture of compounds 11 and
12 (Scheme 2).15 The stereochemical assignments were tentative,
based on a small nOe in the minor isomer. Clearly, before ad-
dressing the stereochemical assignment of batzelladine C, we first
needed to confirm the stereochemical outcome of this reaction,
and ideally on a substrate more closely related to that which we
intended to use in our total synthesis.
Fig. 2 Structure of compound 16 from X-ray data.
With this stereochemical assignment secured, batzelladine C
was approached as follows. Compound 17 was prepared from
succinic anhydride and (R)-(+)-a-methylbenzylamine21 according
to a known procedure (Scheme 4).22 Reduction and allylation of
this compound, as previously reported for the (S)-enantiomer,23
gave compound 19 as a 4.4 : 1 mixture of diastereoisomers in good
overall yield. The terminal double-bond was then cleaved, and the
resulting aldehyde 20 subjected to a cis-selective Wittig reaction
to give alkene 21, by which time the diastereoselectivity had been
enhanced to 6.6 : 1. Deprotection and thionation was followed by
Eschenmoser sulfide contraction to give compound 25. This was
carried out in two steps as shown, since in our hands the sulfide
contraction is more reliable (particularly on quantities > 200
mg) using the ketoester rather than methyl 2-bromoacetate. From
this point, three-component coupling gave a separable mixture of
compounds 26 and 27, which in turn gave bicyclic guanidines 28
and 29.
With the two key compounds in hand, iodocyclisation reac-
tions were attempted next. Compound 28 underwent smooth
iodocyclisation using iodine/potassium carbonate in acetonitrile
(Scheme 5). Immediate hydrogenolysis provided compound 30.
Iodocyclisation of diastereoisomer 29 was more troublesome, but
was eventually achieved using iodine monochloride–potassium
carbonate in dichloromethane. Hydrogenolysis of the interme-
diate compound then gave compound 31. The reason for the
more challenging iodocyclisation of compound 29 is unclear.
Scheme 2
To this effect, compound 15 was prepared from known lac-
tam 13 using a two-step protocol that we reported in 2006.20
Three-component coupling of this compound with hexanal and
trimethylsilyl isothiocyanate gave a 1.8 : 1 mixture favouring com-
pound 16 (Scheme 3). This compound provided crystals suitable
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Scheme 4
Calculations show that there is a significant conformational
difference between the bicyclic portions of compound 28 and
29.24 However, this does not appear to result in the side-chain
double-bond in the latter compound being further from the
guanidine nitrogen. When a mixture of these two compounds
is subjected to standard iodocyclisation conditions with iodine,
only compound 28 undergoes cyclisation. We have observed an
identical result with the diastereomeric mixture of guanidines 16
derived from compound 15.25
Not surprisingly, the NMR data for compounds 30 and 31 are
extremely similar. However, compound 30 differs in two key area—
the 1H chemical shift for H-8a is 4.11 ppm, compared to compound
31 (3.93 ppm), batzelladine C (3.86 ppm) and batzelladine C
methyl ester (3.86 ppm).1 The 13C chemical shift for C-7 is 51.8 ppm
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Scheme 5
in compound 30 compared to 53.7 ppm for compound 31 and
53.5 ppm for batzelladine C. The 13C NMR data for batzelladine
C methyl ester derived from the natural product were not reported.
In other areas of the spectra, both epimers are similar to the natural
product. However, particularly in the 1H NMR spectra, compound
31 matches the natural product data whereas compound 30 shows
a number of small but significant differences in chemical shift and
coupling constants (and peak shapes where coupling constants
could not be reliably obtained—see copies of spectra in the
ESI†).26 The optical rotation of compound 31 was -2.4 (c. 0.5,
MeOH)compared to -4.2(c. 0.93, MeOH)for the same compound
formed by methanolysis of batzelladine C. Evans has previously
noted discrepancies between reported optical rotation data for
batzelladine alkaloids,9 which can most likely be attributed to the
presence of impurities. We therefore assign structure 31 as the
relative and absolute stereochemistry of batzelladine C methyl
ester, from which the stereochemistry of batzelladine C can be
readily deduced. A number of attempts were made to transesterify
compound 31 with 4-azidobutanol in the presence of Otera’s
catalyst. Although this protocol was used by Evans in the total
synthesis of batzelladine D,9 it was unsuccessful with compound
31. Hydrolysis of compound 31 to the corresponding acid gave
a very low yield of the corresponding acid. The small amounts
of compound 31 available, as a result of it being derived from
the minor diastereoisomer from the three-component coupling,
precluded evaluation of a broader range of methods.
Fig. 3 Stereochemistry of natural batzelladine C.
on a Perkin Elmer 1600 FTIR spectrophotometer. Mass spectra
were recorded on a Fisons VG Platform II spectrometer and
on a Micromass Q-TOF Micro spectrometer. NMR spectra
were recorded on a Bruker DPX 400 spectrometer operating at
400 MHz for 1H and at 100 MHz for 13C at 25 ◦C, or on a
Bruker Avance 500 spectrometer operating at 500 MHz for 1H
◦
and 125 MHz for 13C at 25 C. All chemical shifts are reported
in ppm downfield from TMS. Coupling constants (J) are reported
in Hz. Multiplicity in 1H NMR spectroscopy is reported as singlet
(s), doublet (d), double doublet (dd), double triplet (dt), double
quartet (dq), triplet (t), and multiplet (m). Multiplicity in 13C NMR
spectroscopy was obtained using the DEPT pulse sequence. Flash
chromatography was performed using Matrex silica 60 35–70
micron. Where mixtures of diastereoisomers were not separated,
NMR data reported are for the major diastereoisomer. Copies of
NMR spectra are provided in the ESI.†
(3RS,7SR)-Methyl-7-allyl-1,2,3,5,6-hexahydro-3-pentyl-1-
thioxopyrrolo[1,2-c]pyrimidine-4-carboxylate (16)
Conclusions
Trimethylsilyl isothiocyanate (0.22 mL, 1.58 mmol) was added
to a solution of hexanal (0.19 mL, 1.58 mmol) in dry CH2Cl2
(15 mL) under N2, and the resulting yellow solution stirred for
30 min at 20 ◦C. A solution of (2Z)-methyl-2-((allylpyrrolidin-
2-ylidene)acetate (15)27 (287 mg, 1.58 mmol) in CH2Cl2 (3 mL)
was then added, and the mixture stirred for a further 2 h at
18 ◦C. The reaction was then quenched with ~0.1 M aqueous
NaOH solution (40 mL), the layers separated and the aqueous
layer extracted with CH2Cl2 (3 ¥ 35 mL). The combined organic
washings were then dried over Na2SO4, and the solvent removed
in vacuo to afford the title compound (399 mg, 78%, 29% d.e.)
as a yellow gum. The pure major diastereoisomer 11 was isolated
by column chromatography (eluting with EtOAc-Hexane, 1 : 6), to
The two possible diastereoisomers of batzelladine C methyl ester
30 and 31 have been synthesised, each in 12 steps from compound
17, and with 4.3% and 1.6% overall yields respectively. Based
on comparison of their spectroscopic data with those of natural
material, the stereochemistry of batzelladine C can be assigned as
shown in structure 32 (Fig. 3).
Experimental
General experimental points
Melting points were determined on a Gallenkamp melting point
apparatus and are uncorrected. Infrared spectra were recorded
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give the title compound (276 mg, 54%) as a yellow solid, m.p. 120–
124 ◦C. Recrystallisation from aqueous ethanol produced crystals
suitable for single-crystal X-ray diffraction analysis (found: MH+,
323.1792. C17H27N2O2S requires M, 323.1793); nmax. 3265, 3212,
2834, 1690, 1647, 1527, 1354 and 1221 cm-1; dH (400 MHz; CDCl3)
compound (9.7 g, 80%) as a colourless solid (approx. 2 : 1 mixture
of diastereoisomers), m.p. 82–84 ◦C, [a]D +60 (c 0.5, CH2Cl2)
(found: MH+, 206.1177. C12H16NO2 requires M, 206.1181); nmax.
(nujol) 3226, 2922, 2853, 1644, 1426, 1329, 1284, 1248, 1211, 1178,
1059, 1025, 989, 914, 790, 700 and 671 cm-1; dH (400 MHz; CDCl3)
7.37–7.26 (5 H, m, aromatic CH), 5.41–5.34 (1 H, m, CH–Me),
=
6.94 (1 H, broad s, NH), 5.73–5.67 (1 H, m, CH CH2), 5.09–5.03
=
=
(2 H, m, CH CH2), 4.56–4.52 (1 H, CH–allyl), 4.23–4.21 (1 H,
4.93 (1 H, t, J 6.0, CHOH), 2.69–2.58 (1 H, m, one of CH2C O),
=
m, CH–pentyl), 3.65 (3 H, s, CO2CH3), 3.32–3.26 (1 H, m, one
2.34–2.27 (1 H, m, one of CH2C O), 2.24–2.07 (1 H, m, one of
=
of pyrrolidine CH2C C), 3.04 (1 H, app, dd, J 13.3, 4.5, one of
pyrrolidine CH2), 1.90–1.79 (1 H, m, one of pyrrolidine CH2) and
1.67 (3 H, d, J 7.2, Me); dC (100 MHz; CDCl3) 174.8 (C), 140.0
(C), 128.9 (2 ¥ CH), 127.9 (CH), 127.8 (2 ¥ CH), 82.4 (CH), 50.4
(CH), 29.2 (CH2), 29.1 (CH2) and 19.0 (CH3); m/z (TOF ES+) 247
(MH+ + MeCN, 100%), 206 (MH, 85), 205 (31), 188 (14), 164 (13)
and 155 (2).
=
=
pyrrolidine CH2C C), 2.90–2.80 (1 H, m, one of CH2CH CH2),
=
2.15 (1 H, app. dt, J 13.5, 9.0, one of CH2CH CH2), 1.94–1.83 (2
H, m, pyrrolidine CH2CH–N), 1.61–1.44 (2 H, m, CH2CH–NH),
1.48–1.12 (6 H, m, 3 ¥ CH2) and 0.81 (3 H, t, J 6.8, CH3CH2); dC
(125 MHz; CDCl3) 175.2 (C=S), 166.1 (C=O), 149.8 (C), 134.1
(CH), 118.1 (CH2), 99.8 (C), 62.5(CH), 52.1(CH3), 51.3 (CH), 37.7
(CH2), 35.4 (CH2), 31.4 (CH2), 30.4 (CH2), 25.7 (CH2), 23.5 (CH2),
22.5 (CH2) and 14.0 (CH3); m/z (ES+) 323 (MH, 100%). Selected
crystallographic data:† C17H26N2O2S, FW = 322.46, T = 150 K,
(R)-5-Allyl-1-((R)-1-phenylethyl)pyrrolidin2-one (19)
Boron trifluoride diethyl etherate (5.79 ml, 47.0 mmol) was added
dropwise to a solution of hydroxy lactam 18 (6.43 g, 31.4 mmol)
in CH2Cl2 at -78 ◦C. Allyltrimethylsilane (15.0 ml, 94.1 mmol)
was then added dropwise and the reaction mixture allowed to
warm to room temperature over 16 h. The reaction was quenched
with saturated aqueous NaHCO3 solution and the aqueous layer
extracted with CH2Cl2. The combined organic fractions were dried
over Na2SO4 before the solvent was removed in vacuo affording
the title compound (6.88 g, 96%) as a pale oil (4.4 : 1 mixture of
diastereoisomers), [a]D +147 (c 1, MeOH) (found: MH+, 230.1547.
C15H20NO requires M, 230.1545); nmax. (neat) 3063, 2976, 2936,
1681, 1368, 1286, 1215, 1183, 1055, 1028, 998, 917 and 788 cm-1;
¯
˚
˚
˚
l = 0.71073 A, triclinic, P1, a = 8.89400(10) A, b = 15.5730(2) A,
◦
◦
˚
c = 26.7230(4) A, a = 106.7770(10) , b = 95.5040(10) , g =
◦
3
-3
˚
92.3280(10) , V = 3518.35(8) A , Z = 8, rc = 1.218 Mg m ,
crystal size = 0.25 ¥ 0.10 ¥ 0.10 mm, m = 0.193 mm-1, reflections
collected = 57716, independent reflections =16123, Rint = 0.102,
parameters = 905, final R1 = 0.0805, wR2 = 0.164 for I > 2s(I)
and R1 = 0.137, wR2 = 0.187 for all data.
(R)-1-(1-Phenylethyl)pyrrolidin-2,5-dione (17)
(R)-(+)-a-Methylbenzylamine (13.8 ml, 107 mmol) was added to
a suspension of succinic anhydride (10.7 g, 107 mmol) in toluene
(250 ml) and the mixture was heated under reflux for 18 h. The sol-
vent was removed in vacuo and the residue re-dissolved in acetic an-
hydride (100 ml). The resulting solution was heated under reflux for
2 h before being poured onto crushed ice with stirring. The mixture
was extracted with CH2Cl2, the combined extracts being washed
thoroughly with saturated aqueous NaHCO3 solution and dried
over Na2SO4. The solvent was removed in vacuo affording the title
compound (21.7 g, 100%) as a pure colourless oil. [a]D +91 (c 1,
CH2Cl2) Lit.22 [a]D +91.9 (c 4, CH2Cl2) (found: MH+, 204.1018.
C12H14NO2 requires M, 204.1025); nmax. (neat) 2979, 2941, 1679,
1393, 1219, 1188, 1101, 1066, 1023, 953, 821 and 786 cm-1; dH
(400 MHz; CDCl3) 7.39 (2 H, d, J 8.0, aromatic CH), 7.28–7.19
(3 H, m, aromatic CH), 5.36 (1 H, q, J 7.3, CH–Me), 2.57 (4 H, s,
2 ¥ CH2) and 1.76 (3 H, d, J 7.3, Me); dC (100 MHz; CDCl3) 177.1
d
H (400 MHz; CDCl3) 7.39 (2H, d, J 7.5, aromatic CH), 7.33–7.29
(2 H, m, aromatic CH), 7.26–7.24 (1 H, m, aromatic CH), 5.51–
5.39 (2 H, m, alkene CH and CH–Ph), 4.98–4.95 (1 H, m, one of
alkene CH2), 4.88 (1 H, app. dq, J 17.1, 1.4, one of alkene CH2),
3.76 (1 H, app. ddd, J 11.9, 8.4, 3.5, CH-allyl), 2.53–2.44 (1 H,
=
m, one of CH2C O), 2.32 (1 H, app. ddd, J 17.0, 9.9, 4.7, one
=
of CH2C O), 2.06 (1 H, ddt, J 12.9, 9.8, 8.2, one of pyrrolidine
=
CH2), 1.92–1.86 (1 H, m, one of CH2C C), 1.78–1.67 (2 H, m,
one of pyrrolidine CH2 and one of CH2C C) and 1.65 (3 H, d,
J 7.3, Me); dC (100 MHz; CDCl3) 175.6 (C O), 142.0 (C), 133.5
(CH), 128.6 (2 ¥ CH), 127.6 (CH), 127.4 (2 ¥ CH), 118.4 (CH2),
56.5 (CH), 49.7 (CH), 39.0 (CH2), 30.5 (CH2), 24.2 (CH2) and 16.5
(CH3); m/z (TOF ES+) 230 (MH, 100%).
=
=
2-(R)-5-Oxo-1-((R)-1-phenylethyl)pyrrolidin-2-yl)acetaldehyde
(20)
=
(2 ¥ C O), 139.7 (C), 128.5 (2 ¥ CH), 127.9 (CH), 127.7 (2 ¥ CH),
50.4 (CH), 28.2 (2 ¥ CH2) and 16.6 (CH3); m/z (TOF AP+) 204
(MH, 100%), 141 (33) and 105 (6).
Potassium osmate dihydrate (cat.), sodium periodate (24.1 g,
113 mmol) and 2,6-lutidine (6.56 ml, 56.3 mmol) were added
to a solution of allyl lactam 19 (6.45 g, 28.2 mmol) in dioxane-
H2O (3 : 1, 520 ml) and the resulting suspension was allowed to
stir at room temperature for 18 h. The reaction was quenched
with water and the mixture extracted with CH2Cl2. The combined
extracts were dried over Na2SO4 before the solvent was removed
in vacuo. Flash chromatography on silica gel (EtOAc–acetone
1 : 2) afforded the title compound (4.87 g, 75%) as a colourless
oil (6.4 : 1 mixture of diastereoisomers), [a]D +124 (c 1, MeOH)
(found: MH+, 232.1330. C14H18NO2 requires M, 232.1338); nmax.
(neat) 3061, 2975, 1720, 1670, 1417, 1373, 1286, 1215, 1182, 1026,
788 and 758 cm-1; dH (400 MHz; CDCl3) 9.33 (1 H, s, aldehyde),
5-Hydroxy-1-((R)-1-phenylethyl)pyrrolidin-2-one (18)
LiEt3BH (82.8 ml of 1.0 M solution in THF, 82.8 mmol) was
added dropwise to a solution of imide 17 (12.0 g, 59.1 mmol)
in THF (150 ml) at -78 ◦C. The mixture was allowed to stir
for 40 min before the THF was removed in vacuo. The residue
was cooled to 0 ◦C and the reaction quenched by dropwise
addition of saturated aqueous NaHCO3 solution. The mixture
was extracted with CH2Cl2, the combined extracts being treated
with 30% H2O2 solution (10 ml), washed with brine and dried
over Na2SO4. The solvent was removed in vacuo affording the title
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=
7.34–7.24 (5 H, m, aromatic CH), 5.52 (1 H, q, J 7.2, CH–Me),
4.20 (1 H, app. ddd, J 11.8, 7.9, 3.5, CHN), 2.54–2.45 (1 H, m,
CH2), 2.03 (2 H, app. q, J 7.1, CH2C C), 1.80–1.71 (1 H, m, one
of pyrrolidine CH2), 1.35–1.22 (8 H, broad m, 4 ¥ CH2) and 0.88
=
=
one of pyrrolidine CH2C O), 2.36 (1 H, ddd, J 16.7, 9.7, 4.2,
(3 H, t, J 6.8, CH3); dC (100 MHz; CDCl3) 178.2 (C O), 134.1
=
one of pyrrolidine CH2C O), 2.26 (1 H, ddd, J 18.0, 12.7, 8.5,
(CH), 124.1 (CH), 54.6 (CH), 34.5 (CH2), 31.9 (CH2), 30.4 (CH2),
29.7 (CH2), 29.2 (CH2), 27.7 (CH2), 27.0 (CH2), 22.8 (CH2) and
14.3 (CH3); m/z (TOF AP+) 251 (MH + MeCN, 100%), 210 (MH,
43), 124 (4) and 83 (3).
one of pyrrolidine CH2), 2.15 (1 H, app. dd, J 18.0, 8.9, one of
CH2CHO), 2.06 (1 H, dd, J 18.1, 3.5, one of CH2CHO), 1.65–1.61
(1 H, m, one of pyrrolidine CH2) and 1.58 (3 H, d, J 7.3, Me);
=
dC (100 MHz; CDCl3) 199.8 (aldehyde CH), 175.2 (lactam C O),
(R)-5-((Z)-Non-2-enyl)pyrrolidine-2-thione (23)
141.3 (C), 128.8 (2 ¥ CH), 127.9 (CH), 127.4 (2 ¥ CH), 50.8 (CH),
48.9 (CH), 48.6 (CH2), 30.0 (CH2), 25.9 (CH2) and 16.0 (CH3);
m/z (TOF ES+) 232 (MH, 100%).
Lawesson’s reagent (1.91 g, 4.71 mmol) was added to a solution
of lactam 22 (1.79 g, 8.56 mmol) in THF (80 ml). The resulting
solution was allowed to stir at room temperature for 2 h before
the solvent was removed in vacuo. Chromatography on silica gel
(EtOAc–petroleum ether 1 : 9) afforded the title compound (1.62 g,
84%) as a yellow oil, [a]D +37 (c 1, MeOH) (found: MH+, 226.1621.
C13H24NS requires M, 226.1629); nmax. (neat) 3162, 2925, 2854,
1530, 1456, 1377, 1294, 1119, 1068 and 726 cm-1; dH (400 MHz;
CDCl3) 7.87–7.63 (1 H, broad s, NH), 5.60 (1 H, dt, J 11.4, 7.5,
alkene CH), 5.35–5.27 (1 H, m, alkene CH), 3.94 (1 H, app. quintet,
(R)-5-((Z)-Non-2-enyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one (21)
n-Butyllithium (15.3 ml of a 2.5 M solution in hexanes, 38.3 mmol)
was added drop-wise to a solution of heptyltriphenylphosphonium
iodide (18.7 g, 38.3 mmol) in THF (150 ml) at 0 ◦C. The solution
◦
was allowed to stir at 0 C for 2 h before a solution of aldehyde
20 (4.42 g, 19.1 mmol) in THF (15 ml) was added at -78 ◦C. The
resulting solution was allowed to warm to room temperature and
stirred for 16 h. The reaction was quenched with saturated aqueous
NaHCO3 solution and the aqueous layer extracted with CH2Cl2.
The combined organic fractions were dried over Na2SO4 before
the solvent was removed in vacuo. Chromatography on silica gel
(EtOAc–hexane 1 : 2) afforded the title compound (3.45 g, 58%)
as a yellow oil (6.6 : 1 mixture of diastereoisomers), [a]D +110 (c 1,
MeOH) (found: MH+, 314.2499. C21H32NO requires M, 314.2484);
nmax. (neat) 2928, 2855, 1686, 1416, 1365, 1265, 1216, 1182, 1118
and 787 cm-1; dH (400 MHz; CDCl3) 7.39 (2 H, d, J 7.4, aromatic
CH), 7.31 (2 H, app. t, J 7.4, aromatic CH), 7.25 (1 H, d, J 7.0,
aromatic CH), 5.49–5.36 (2 H, m, CHMe and alkene CH), 5.09–
5.02 (1 H, m, alkene CH), 3.76–3.65 (1H, m, CHN), 2.51 (1 H,
=
J 7.0, CHNH), 2.98 (1 H, ddd, J 18.2, 9.4, 5.2, one of CH2C S),
=
=
2.93–2.84 (1 H, m, one of CH2C S), 2.39–2.24 (3 H, m, CH2C C
=
and one of pyrrolidine CH2), 2.06–2.00 (2 H, m, CH2C C), 1.90–
1.81 (1 H, m, one of pyrrolidine CH2), 1.39–1.27 (8 H, broad m,
4 ¥ CH2) and 0.88 (3 H, t, J 6.8, CH3); dC (100 MHz; CDCl3)
=
205.6 (C S), 134.7 (CH), 123.4 (CH), 62.5 (CH), 43.2 (CH2), 33.3
(CH2), 31.9 (CH2), 29.7 (CH2), 29.2 (2 ¥ CH2), 27.7 (CH2), 22.8
(CH2) and 14.3 (CH3); m/z (TOF ES+) 226 (MH, 100%).
(E)-Methyl 2-((R)-5-((Z)-non-2-enyl)pyrrolidin-2-ylidene)-3-
oxobutanoate (24)
Sodium hydrogencarbonate (2.26 g, 26.8 mmol) and methyl 2-
bromoacetoacetate15 (2.62 g, 13.4 mmol) were added to a solution
of thiolactam 23 (1.51 g, 6.71 mmol) in CH2Cl2 (50 ml), and the
mixture was heated under reflux for 16 h. The reaction mixture was
then cooled before being filtered through silica and concentrated
in vacuo. Chromatography on silica gel (Et2O–petroleum ether
1 : 9) afforded the title compound (1.74 g, 84%) as an orange
oil, [a]D +73 (c 1, MeOH) (found: MH+, 308.2221. C18H30NO3
requires M, 308.2226); nmax. (neat) 3203, 2928, 2855, 1694, 1600,
1538, 1434, 1359, 1315, 1242, 1189, 1069, 1013, 914 and 784 cm-1;
dH (400 MHz; CDCl3) 5.61–5.54 (1 H, m, alkene CH), 5.36–5.29
(1 H, m, alkene CH), 3.93 (1 H, app. quintet, J 6.6, CHNH), 3.73
(3 H, s, OCH3), 3.22 (1 H, ddd, J 18.6, 9.5, 5.4, one of pyrrolidine
=
app. dt, J 17.1, 8.8, one of CH2C O), 2.35 (1 H, ddd, J 17.1, 9.8,
4.9, one of CH2C O), 2.10–2.00 (2 H, m, CH2C C), 1.94–1.88 (1
=
=
=
H, m, one of pyrrolidine CH2), 1.81 (2 H, app. q, J 6.5, CH2C C),
1.73–1.67 (1 H, m, one of pyrrolidine CH2), 1.65 (3 H, d, J 7.2,
Me), 1.30–1.22 (8 H, broad m, 4 ¥ CH2) and 0.88 (3 H, t, J 7.0,
=
CH3CH2); dC (100 MHz; CDCl3) 175.6 (C O), 142.1 (C), 133.4
(CH), 128.5 (2 ¥ CH), 127.5 (CH), 127.3 (2 ¥ CH), 124.0 (CH),
57.1 (CH), 49.7 (CH), 32.2 (CH2), 31.9 (CH2), 30.5 (CH2), 29.6
(CH2), 29.1 (CH2), 27.6 (CH2), 24.4 (CH2), 22.8 (CH2), 16.5 (CH3)
and 14.3 (CH3); m/z (TOF ES+) 314 (MH, 100%).
(R)-5-((Z)-Non-2-enyl)pyrrolidine-2-one (22)
=
CH2C C), 3.07 (1 H, app. ddd, J 18.6, 9.4, 7.3, one of pyrrolidine
Sodium metal (1.19 g, 51.6 mmol) was added in portions to a
solution of alkenyl lactam 21 (3.23 g, 10.3 mmol) in liquid NH3–
THF–EtOH (8 : 1 : 1, 240 ml) at -78 ◦C until the blue colour
persisted for longer than 3 min. After the solution had turned
colourless, solid NH4Cl was added and the ammonia allowed to
evaporate. The reaction mixture was then washed with water and
extracted with EtOAc. The combined extracts were dried over
Na2SO4 before the solvent was removed in vacuo affording the
title compound (1.93 g, 89%) as a pure yellow oil, [a]D +15
(c 1, MeOH); (found: MH+, 210.1848. C13H24NO requires M,
210.1858); nmax. (neat) 3225, 2920, 2860, 1694, 1462, 1379, 1346,
1292, 1262, 1204, 1083 and 734 cm-1; dH (400 MHz; CDCl3) 6.00–
5.73 (1 H, broad s, NH), 5.59–5.52 (1 H, m, alkene CH), 5.34–5.27
(1 H, m, alkene CH), 3.71–3.64 (1 H, m, CHNH), 2.38–2.32 (2 H,
=
=
CH2C C), 2.40 (3 H, s, CH3), 2.38–2.22 (2 H, m, CH2C C),
2.18–2.09 (1 H, m, one of pyrrolidine CH2), 2.01 (2 H, app. q,
J 6.8, CH2C C), 1.70–1.61 (1 H, m, one of pyrrolidine CH2),
1.37–1.21 (8 H, broad m, 4 ¥ CH2) and 0.87 (3 H, t, J 6.9, CH3);
dC (100 MHz; CDCl3) 197.9 (C O), 173.8 (C), 169.4 (C), 134.3
(CH), 123.7 (CH), 98.6 (C), 60.9 (CH), 50.7 (CH3), 35.1 (CH2),
33.7 (CH2), 31.9 (CH2), 31.0 (CH3), 29.7 (CH2), 29.1 (CH2), 27.6
(CH2), 26.9 (CH2), 22.8 (CH2) and 14.3 (CH3); m/z (TOF AP+)
308 (MH, 100%) and 276 (22).
=
=
(Z)-Methyl 2-(R)-5-((Z)-non-2-enyl)pyrrolidin-2-ylidene)acetate
(25)
Sodium metal (128 mg, 5.57 mmol) was dissolved in dry MeOH
(15 ml) under nitrogen and allowed to stir for 30 min. A solution
=
=
m, CH2C O), 2.30–2.17 (3 H, m, CH2C C and one of pyrrolidine
5006 | Org. Biomol. Chem., 2009, 7, 5001–5009
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of b-keto-ester 24 (1.71 g, 5.57 mmol) in dry MeOH (5 ml)
was then added and the mixture heated at reflux for 2 h. The
solvent was removed in vacuo and the resulting residue dissolved
in chloroform, washed with saturated aqueous sodium carbonate
solution and dried over sodium sulfate. The solvent was removed in
vacuo. Chromatography on silica gel (Et2O–petroleum ether 1 : 9)
afforded the title compound (1.24 g, 84%) as a yellow oil, [a]D
+149 (c 1, MeOH) (found: MH+, 266.2108. C16H28NO2 requires M,
266.2120); nmax. (neat) 3362, 2925, 2855, 1667, 1606, 1469, 1430,
1294, 1237, 1147 and 1041 cm-1; dH (400 MHz; CDCl3) 8.08–7.87
(1 H, broad s, NH), 5.57–5.50 (1 H, m, alkene CH), 5.38–5.30 (1 H,
Data for compound 27. [a]D +99 (c 1, MeOH); found: MH+,
407.2734. C23H39N2O2S requires M, 407.2732; nmax. (neat) 3198,
2980, 1693, 1644, 1427, 1381, 1223, 1155, 1105, 976, 933, 889 and
778 cm-1; dH (400 MHz; CDCl3) 6.98 (1 H, app. broad d, J 3.4,
NH), 5.54 (1 H, dt, J 10.8, 7.3, alkene CH), 5.35–5.28 (1 H, m,
=
alkene CH), 4.91 (1 H, tt, J 8.6, 2.9, CHNC S), 4.28 (1 H, app.
dt, J 7.5, 3.8, CH-pentyl), 3.73 (3 H, s, OCH3), 3.29 (1 H, ddd,
=
J 18.9, 9.9, 2.9, one of pyrrolidine CH2C C), 3.01 (1 H, app. dt,
=
J 18.9, 9.4, one of pyrrolidine CH2C C), 2.69–2.63 (1 H, m, one
=
=
of CH2C C), 2.39 (1 H, app. dt, J 14.0, 8.3, one of CH2C C),
2.13–1.95 (3 H, broad m, CH2C C and one of pyrrolidine CH2),
1.86–1.79 (1 H, m, one of pyrrolidine CH2), 1.57–1.42 (2 H, broad
=
=
m, alkene CH), 4.48 (1 H, s, CHC O), 3.79 (1 H, app. quintet, J
6.5, CHNH), 3.63 (3 H, s, OCH3), 2.68–2.53 (2 H, m, pyrrolidine
m, CH2), 1.39–1.20 (14 H, broad m, 7 ¥ CH2) and 0.89–0.85 (6 H,
=
=
=
=
CH2C C), 2.30 (1 H, app. dt, J 14.3, 7.2, one of CH2C C),
m, 2 ¥ CH3); dC (100 MHz; CDCl3) 176.0 (C S), 166.2 (C O),
150.7 (C), 134.2 (CH), 123.8 (CH), 100.5 (C), 63.1 (CH), 52.0
(CH), 51.6 (CH3), 37.0 (CH2), 32.0 (CH2), 31.6 (CH2), 31.2 (CH2),
30.6 (CH2), 29.8 (CH2), 29.2 (CH2), 27.8 (CH2), 24.9 (CH2), 23.9
(CH2), 22.8 (2 ¥ CH2), 14.3 (CH3) and 14.2 (CH3); m/z (TOF ES+)
407 (MH, 100%).
=
2.24–2.17 (1 H, m, one of CH2C C), 2.13–2.06 (1 H, m, one of
=
pyrrolidine CH2), 2.02 (2 H, app. q, J 6.8, CH2C C), 1.65–1.56
(1 H, m, one of pyrrolidine CH2), 1.35–1.20 (8 H, broad m, 4 ¥
CH2) and 0.87 (3 H, t, J 6.9, CH3); dC (100 MHz; CDCl3) 171.1
(C), 166.0 (C), 133.7 (CH), 124.5 (CH), 76.3 (CH), 59.8 (CH),
50.3 (CH3), 34.1 (CH2), 32.1 (CH2), 32.0 (CH2), 29.7 (CH2), 29.2
(CH2), 28.0 (CH2), 27.7 (CH2), 22.8 (CH2) and 14.3 (CH3); m/z
(TOF ES+) 266 (MH, 100%).
(3S,7R)-7-((Z)-Non-2-enyl)-4-(methoxycarbonyl)-3-pentyl-2,3,6,
7-tetrahydropyrrolo[1,2-c]pyrimidine-1(5H)-iminium formate (28)
(3S,7R)-Methyl 1,2,3,5,6,7-hexahydro-7-((Z)-non-2-enyl)-3-
pentyl-1-thioxopyrrolo[1,2-c]pyrimidine-4-carboxylate (26) and
(3R,7R)-methyl 1,2,3,5,6,7-hexahydro-7-((Z)-non-2-enyl)-3-
pentyl-1-thioxopyrrolo[1,2-c]pyrimidine-4-carboxylate (27)
Iodomethane (0.02 ml, 0.291 mmol) was added to a solution of
bicyclic thiourea 26 (118 mg, 0.291 mmol) in dry MeOH (3 ml)
and the mixture was heated at reflux for 1 h. The volatiles were
removed in vacuo and the resulting residue re-dissolved in dry
MeOH (3 ml). The solution was transferred to a mixture of
NH4OAc (112 mg, 1.45 mmol) in dry MeOH (2 ml) and liquid
ammonia bubbled through the reaction for 10 min. The resulting
suspension was heated in a sealed tube at 80 ◦C for 48 h. The
solvent was removed in vacuo before chromatography on silica
gel (CH2Cl2–MeOH–HCO2H–H2O 84 : 14 : 0.5 : 0.5) gave the title
compound (121 mg, 96%) as an orange oil, [a]D +7 (c 1, MeOH)
(found: MH+, 390.3134. C23H40N3O2 requires M, 390.3121); nmax.
(CH2Cl2) 3229, 3155, 2927, 2856, 1699, 1649, 1599, 1548, 1438,
1379, 1346, 1212, 1177, 1104, 912 and 646 cm-1; dH (400 MHz;
CDCl3) 8.18 (1 H, s, NH), 8.08–7.77 (2 H, broad s, NH2), 5.57
(1 H, dt, J 11.0, 7.2, alkene CH), 5.52–5.43 (1 H, m, alkene CH),
Hexanal (1.10 ml, 8.98 mmol) was added to a solution of
trimethylsilyl isothiocyanate (1.27 ml, 8.98 mmol) in CH2Cl2
(40 ml) and the solution was stirred at room temperature for
30 min. A solution of alkylidenepyrrolidine 25 (1.19 g, 4.49 mmol)
in CH2Cl2 (10 ml) was then added and the resulting solution
allowed to stir for 45 min. The reaction was quenched with ~0.1 M
NaOH solution and the aqueous layer extracted with CH2Cl2.
The combined extracts were dried over sodium sulfate before
the solvent was removed in vacuo. Chromatography on silica gel
(Et2O–petroleum ether 1 : 9) gave, in order of elution, compound
26 (833 mg, 46%) and compound 27 (425 mg, 23%), both as yellow
oils.
=
4.73–4.69 (1 H, m, CHNC N), 4.46–4.42 (1 H, m, CH-pentyl),
Data for compound 26. [a]D -36 (c 1, MeOH); found: MH+,
407.2728. C23H39N2O2S requires M, 407.2732; nmax. (neat) 3198,
2914, 2860, 1699, 1660, 1432, 1386, 1222, 1162, 1098, 971, 933,
893, 827 and 776 cm-1; dH (400 MHz; CDCl3) 6.72 (1 H, broad s,
NH), 5.53 (1 H, dt, J 10.8, 7.4, alkene CH), 5.34–5.27 (1 H, m,
3.74 (3 H, s, OCH3), 3.32 (1 H, dd, J 18.7, 7.9, one of pyrrolidine
=
=
CH2C C), 2.93–2.83 (1 H, m, one of pyrrolidine CH2C C), 2.49–
=
2.45 (1 H, m, one of CH2C C), 2.34 (1 H, dt, J 14.3, 9.1, one of
=
=
CH2C C), 2.11–1.95 (4 H, broad m, CH2C C and pyrrolidine
CH2), 1.71–1.50 (3 H, broad m, methylene protons), 1.43–1.24 (13
H, broad m, methylene protons) and 0.89–0.85 (6 H, m, 2 ¥ CH3);
=
alkene CH), 4.56 (1 H, app. ddt, J 8.5, 6.4, 3.2, CHNC S), 4.28–
=
=
4.26 (1 H, m, CH–pentyl), 3.72 (3 H, s, OCH3), 3.39–3.32 (1 H,
dC (100 MHz; CDCl3) 165.1 (C O), 150.9 (C N), 149.7 (C), 134.7
(CH), 123.0 (CH), 102.0 (C), 60.3 (CH), 51.9 (CH3), 50.9 (CH),
37.5 (CH2), 31.9 (CH2), 31.4 (CH2), 29.6 (CH2), 29.5 (CH2), 29.2
(CH2), 28.9 (CH2), 27.7 (CH2), 26.6 (CH2), 24.1 (CH2), 22.8 (CH2),
22.6 (CH2) and 14.3 (2 ¥ CH3); m/z (TOF AP+) 390 (MH, 100%).
=
ddd, J 18.2, 5.4, 3.7, one of pyrrolidine CH2C C), 3.06 (1 H, app.
=
broad dd, J 13.4, 6.2, one of side-chain CH2C C), 2.92 (1 H,
=
app. dt, J 18.2, 10.4 one of pyrrolidine CH2C C), 2.21 (1 H, dt,
=
J 13.7, 9.3, one of side-chain CH2C C), 2.08 (2 H, app. broad q,
=
J 7.3, CH2C C), 1.95–1.90 (2 H, m, pyrrolidine CH2), 1.63–1.50
(2 H, broad m, CH2), 1.43–1.21 (14 H, broad m, 7 ¥ CH2) and
0.89–0.86 (6 H, m, 2 ¥ CH3); dC (100 MHz; CDCl3) 175.5 (C S),
166.3 (C O), 150.0 (C), 134.0 (CH), 124.4 (CH), 99.9 (C), 63.4
(CH), 52.3 (CH), 51.5 (CH3), 38.0 (CH2), 32.0 (CH2), 31.6 (CH2),
30.7 (CH2), 29.9 (CH2), 29.2 (CH2), 28.8 (CH2), 27.9 (CH2), 26.0
(CH2), 23.7 (CH2), 22.9 (CH2), 22.8 (CH2) and 14.3 (2 ¥ CH3);
m/z (TOF ES+) 407 (MH, 100%).
(3R,7R)-7-((Z)-Non-2-enyl)-4-(methoxycarbonyl)-3-pentyl-2,3,6,
7-tetrahydropyrrolo[1,2-c]pyrimidine-1(5H)-iminium formate (29)
=
=
Iodomethane (0.04 ml, 0.0.621 mmol) was added to a solution of
bicyclic thiourea 27 (252 mg, 0.621 mmol) in dry MeOH (5 ml)
and the mixture was heated at reflux for 1 h. The volatiles were
removed in vacuo and the resulting residue re-dissolved in dry
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Org. Biomol. Chem., 2009, 7, 5001–5009 | 5007
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MeOH (5 ml). The solution was transferred to a mixture of
NH4OAc (239 mg, 3.10 mmol) in dry MeOH (3 ml) and liquid
ammonia bubbled through the reaction for 10 min. The resulting
suspension was heated in a sealed tube at 80 ◦C for 48 h. The
solvent was removed in vacuo before chromatography on silica
gel (CH2Cl2–MeOH–HCO2H–H2O 84 : 14 : 0.5 : 0.5) gave the title
compound (233 mg, 86%) as an orange oil, [a]D +19 (c 1, MeOH)
(found: MH+, 390.3113. C23H40N3O2 requires M, 390.3121); nmax.
(CH2Cl2) 3241, 3148, 2957, 2927, 2856, 1696, 1681, 1655, 1548,
1436, 1385, 1349, 1184 and 1106 cm-1; dH (400 MHz; CDCl3) 8.99–
8.65 (1 H, broad s, NH), 8.16–7.60 (2 H, broad s, NH2), 5.58 (1 H,
dt, J 10.6, 7.4, alkene CH), 5.39–5.32 (1 H, m, alkene), 4.96–4.88 (1
(CH2), 24.3 (CH2), 22.8 (CH2), 22.6 (CH2) and 14.3 (2 ¥ CH3);
m/z (TOF ES+) 390 (MH, 100%), 146(2) and 130 (4).
(4R,7S,8aR)-Methyl 7-heptyl-4-pentyl-1,2,4,5,7,8-hexahydro-
11aH-2a1,5,6-triaza-acenaphthylene-3-carboxylate (batzelladine
C methyl ester) (31)
Potassium carbonate (51 mg, 0.366 mmol) was added to a solution
of bicyclic guanidine 29 (53 mg, 0.122 mmol) in dry CH2Cl2 (2 ml)
at 0 ◦C. Iodine monochloride (0.18 ml of a 1 M solution in CH2Cl2,
0.183 mmol) was added dropwise and the resulting suspension
was allowed to warm to room temperature and stirred for ~3 h
(TLC). The solvent was removed in vacuo before chromatography
on silica gel (EtOAc–CH2Cl2 1 : 2) afforded the iodinated tricyclic
guanidine (51 mg, 81%) as a brown oil. The tricyclic guanidine
(41 mg, 0.0796 mmol) was immediately re-dissolved in EtOAc
(3 ml), and triethylamine (0.05 ml, 0.398 mmol) and 10% Pd/C
(cat.) added. The black suspension was de-gassed and stirred
under an atmosphere of H2 for 16 h. The reaction mixture was
filtered before chromatography on silica gel (MeOH–EtOAc 1 : 19)
afforded the title compound (17 mg, 55%) as a colourless oil, [a]D
-2.4 (c 0.5, MeOH); lit. [a]D -4.2 (c 0.93, MeOH)1 (found: MH+,
390.3113. C23H40N3O2 requires M, 390.3121); nmax. (CH2Cl2) 3177,
2926, 2856, 1682, 1644, 1574, 1435, 1372, 1336, 1199, 1097 and
736 cm-1; dH (400 MHz; MeOD); 4.46–4.44 (1 H, m, H-4), 3.93 (1
H, tdd, J 11.4, 5.4, 2.7, H-8a), 3.70 (3 H, s, OCH3), 3.60 (1 H, app.
td, J 11.1, 6.4, H-7), 3.32 (1 H, dd, J 18.2, 7.8, H-2b), 2.79 (1 H,
dddd, J 18.2, 12.0, 7.5, 1.4, H-2a), 2.38 (1 H, ddd, J 13.1, 3.9, 2.9,
H-8b), 2.33–2.27 (1 H, m, H-1b), 1.72–1.52 (5 H, m, H-1a, H-10
and H-15), 1.35–1.24 (17 H, m, H-8a and 8 ¥ CH2) and 0.88–0.85
(6 H, m, 2 ¥ CH3); dC (125 MHz; MeOD) 58.9 (CH), 53.8 (CH),
52.5 (CH), 52.2 (CH3), 38.2 (CH2), 36.0 (CH2), 33.3 (CH2), 33.1
(CH2), 32.7 (CH2), 31.1 (CH2), 30.6 (CH2), 30.5 (CH2), 30.4 (CH2),
26.1 (CH2), 24.5 (CH2), 23.8 (CH2), 23.7 (CH2), 14.5 (CH3) and
14.4 (CH3); m/z (TOF ES+) 390 (MH, 100%), 361 (8) and 342 (1).
=
H, m, CHNC N), 4.43 (1 H, app. dd, J 7.0, 3.8, CH–pentyl), 3.74
(3 H, s, OCH3), 3.20 (1 H, ddd, J 19.0, 10.0, 3.8, one of pyrrolidine
=
=
CH2C C), 3.07–2.98 (1 H, m, one of pyrrolidine CH2C C), 2.52–
=
2.36 (2 H, m, CH2C C), 2.21 (1 H, app. dq, J 12.7, 9.1, one of
=
pyrrolidine CH2), 2.00 (2 H, app. q, 6.6, CH2C C), 1.93–1.86
(1 H, m, one of pyrrolidine CH2), 1.58–1.40 (3 H, m, methylene
protons), 1.36–1.24 (13 H, broad m, methylene protons) and 0.87
=
(6 H, app. t, J 6.4, 2 ¥ CH3); dC (100 MHz; CDCl3) 165.2 (C O),
151.4 (C N), 150.6 (C), 135.1 (CH), 122.2 (CH), 102.8 (C), 60.1
=
(CH), 51.9 (CH3), 50.3 (CH), 36.7 (CH2), 31.9 (CH2), 31.5 (CH2),
30.9 (CH3), 29.7 (CH2), 29.2 (2 ¥ CH2), 27.8 (CH2), 26.4 (CH2),
24.1 (CH2), 22.8 (CH2), 22.7 (CH2), 14.3 (CH3) and 14.2 (CH3);
m/z (TOF AP+) 390 (MH, 100%) and 376 (1).
(4S,7S,8aR)-Methyl 7-heptyl-4-pentyl-1,2,4,5,7,8-hexahydro-
11aH-2a1,5,6-triaza-acenaphthylene-3-carboxylate (30)
Iodine (350 mg, 1.38 mmol) and potassium carbonate (95 mg,
0.690 mmol) were added to a solution of bicyclic guanidine 28
(100 mg, 0.230 mmol) in MeCN (3 ml), and the resulting mixture
was allowed to stir at room temperature for 3 h. The reaction
mixture was filtered through silica and concentrated in vacuo. The
crude iodinated tricyclic guanidine was immediately re-dissolved
in EtOAc (6 ml), and triethylamine (0.16 ml, 1.15 mmol) and
10% Pd/C (cat.) added. The black suspension was degassed
and stirred under an atmosphere of H2 for 16 h. The reaction
mixture was then filtered through celite and the solvent removed
in vacuo. Chromatography on silica gel (EtOAc–CH2Cl2 1 : 2)
afforded the title compound (49 mg, 55%) as a yellow oil, [a]D -13
(c 0.5, MeOH) (found: MH+, 390.3111. C23H40N3O2 requires M,
390.3121); nmax. (CH2Cl2) 3180, 2931, 2856, 1704, 1679, 1644, 1573,
1493, 1437, 1373, 1335, 1227, 1195, 1115, 1080, 917 and 702 cm-1;
Acknowledgements
We are grateful to the EPSRC and AstraZeneca for financial
support, and to Professors Andrew Evans (Liverpool University)
and David Gin (Memorial Sloan-Kettering Cancer Center, New
York) for helpful discussions. We would like to thank Professor
Mark Hamann (University of Mississippi) for providing a sample
of natural batzelladine C, and Dr Robert Jenkins and Mr Robin
Hicks (Cardiff University) for technical assistance.
d
H (400 MHz; MeOD) 4.40 (1 H, app. dd, J 7.4, 4.2, H-4), 4.11 (1
H, app. tdd, J 10.3, 6.5, 3.8, H-8a), 3.74 (3 H, s, OCH3), 3.67–3.60
(1 H, m, H-7), 3.41 (1 H, app. dd, J 18.7, 9.0, H-2b), 2.89 (1 H,
ddd, J 18.7, 11.4, 8.9, H-2a), 2.46–2.39 (2 H, m, H-1b and H-8b),
1.77–1.62 (2 H, m, H-1a and H-8a), 1.60–1.48 (3 H, m, three of
H-10/H-15), 1.41–1.27 (17 H, m, one of H-10/H15 and 8 ¥ CH2)
and 0.90–0.87 (6 H, m, 2 ¥ CH3); dC (100 MHz; CDCl3) 165.0
(C), 149.1 (C), 148.5 (C), 103.3 (C), 57.4 (CH), 52.0 (CH3), 51.3
(CH), 50.9 (CH), 37.1 (CH2), 34.7 (CH2), 33.9 (CH2), 31.9 (CH2),
31.4 (CH2), 30.0 (CH2), 29.6 (CH2), 29.4 (CH2), 29.2 (CH2), 25.5
Notes and references
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18 Sample of batzelladine C kindly provided by Professor Mark Hamann
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simplified compounds 33 and 34, with identical results obtained at
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25 S. V. Wordingham, PhD Thesis, Cardiff University, 2006.
26 In the reported data for batzelladine C, the 1H chemical shifts for H-1b
and H-8b appear to have been transposed. This has been confirmed
by examination of the 1H-1H COSY NMR spectra in reference 1. Our
own data for compound 31 are identical in this region to those of the
natural product.
27 J. L. Wood, PhD Thesis, Cardiff University, 2008.
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