Investigations of cascade cyclizations of terpenoid polyalkenes via radical cations. A biomimetic-type synthesis of (±)-3-hydroxy-spongian-16-one

Article abstract of DOI:10.1055/s-2001-15074

A short and efficient synthesis of the tetracyclic oxygenated diterpene analog of 8, i.e., of 3-hydroxy-spongian-16-one (7), has been achieved in only five steps via a cascade cyclization of the functionalized terpenoid polyalkene 4. Photoinduced electron transfer serves as the pivotal step for selectively creating a radical cation intermediate. Such polycyclizations are radical-driven upon regio- and stereoselective trapping of the radical cation by a nucleophile, such as water in the present case. The overall reaction sequence mimics the non-oxidative biosynthesis of terpenes.

Full text of DOI:10.1055/s-2001-15074

1114
SHORT PAPER
Investigations of Cascade Cyclizations of Terpenoid Polyalkenes via Radical
Cations. A Biomimetic-type Synthesis of ( )-3-Hydroxy-spongian-16-one
A
B
iomimetic
r
-type Syn
a
thesis of
(
n
)-3-Hydrox
k
Max-Planck-Institut für Strahlenchemie, P.O. Box 101365, 45413 Mülheim an der Ruhr, Germany
Fax +49(208)3063951; E-mail: demuthm@mpi-muelheim.mpg.de
Received 21 March 2001
3). We report herein a short biomimetic-type synthesis of
Abstract: A short and efficient synthesis of the tetracyclic oxygen-
ated diterpene analog of 8, i.e., of 3-hydroxy-spongian-16-one (7),
has been achieved in only five steps via a cascade cyclization of the
functionalized terpenoid polyalkene 4. Photoinduced electron trans-
the 3-hydroxyl analog of 8, i.e., of ( )-3-hydroxy-spon-
gian-16-one (7), which can be considered as a straight
synthetic precusor of 8 if access to the latter compound
fer serves as the pivotal step for selectively creating a radical cation would specifically be required. Photoinduced electron
intermediate. Such polycyclizations are radical-driven upon regio-
transfer (PET) served in the pivotal step to initiate the
and stereoselective trapping of the radical cation by a nucleophile,
highly stereo- and regioselective cyclization and function-
such as water in the present case. The overall reaction sequence
alization of the acyclic polyalkene terpenoid 4.
mimics the non-oxidative biosynthesis of terpenes.
Isoprenoid polyalkene radicals, formed by anti-Mar-
Key words: photoinduced electron transfer, radical cation, biomi-
kovnikov addition of water to their parent radical cations,
which are readily accessible via PET, undergo cascade cy-
clizations.4 More recent investigations along these lines
revealed straightforward synthetic applications, i.e.,
ready access to a steroidal product in high enantiomeric
purity5 and to the naturally abundant stypoldione in race-
mic form.6 In the present case, PET-triggered cyclization
of 4 yields 7 as the major photoproduct in which 7 stereo-
genic centers are created in a single photochemical step
Scheme). This result is highly remarkable in view of the
256 theoretically possible stereoisomers, which could
form in such a process. Spontaneous folding of the poly-
alkene chain in all-pre-chair conformation, as depicted (4
5) en route to 7, is in analogy to earlier observations5
our preferred notion concerning the initial mechanistic
metic synthesis, photochemistry, 3-hydroxy-spongian-16-one, rad-
ical cyclization, natural products
Oxygenated tetracyclic diterpenes from marine sponges,
such as spongian-16-one (8) from the sponge Dictyoden-
drilla cavernosa,1 found in waters of the Eastern sea-
boards of Australia and New Zealand, represent an
important class of natural products due to their antimicro-
bial properties against leukaemia cells and herpes simplex
virus type 1.2 A synthesis of ( )-8 has been reported by
Pattenden and co-workers,3 who used a radical-driven
polycyclization step to build up the basic tetracyclic
framework of the target compound (for earlier synthetic
activities related to this field, see citations 6 and 7 in ref.
Scheme
Synthesis 2001, No. 8, 18 06 2001. Article Identifier:
1437-210X,E;2001,0,08,1114,1116,ftx,en;C03101SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

SHORT PAPER
A Biomimetic-type Synthesis of ( )-3-Hydroxy-spongian-16-one
1115
steps. Interestingly, strong evidence for an analogous bio- oxidation of the terminal C=C bond of 4 giving rise to the
mimetic process, albeit carbocationically driven, is found formation of the intermediate radical cation 5. The two
for the stepwise cyclization of 2,3-oxidosqualene to pro- ‘inner’ C=C bonds are seemingly efficiently shielded
tosterol.7 The regio- and stereoselective addition of water from the radical acceptor, i.e., from the oxidized biphenyl
including the cyclization and termination events are (= biphenyl+·; for a discussion of the radical acceptor
mechanistically presumed for PET-initiated polycycliza- mechanism of the 1,4-dicyanotetramethylbenzene/biphe-
tions, again in analogy to our earlier findings,8–10 to occur nyl couple, see ref. 16). Further, the 2(5H)-furanone moi-
in the following order: a) water addition to the radical cat- ety can by no means be oxidized by biphenyl+· because of
ion site of 5, b) radical cyclization to 6 and c) termination its high lying oxidation potential.
of the cyclization cascade by either hydrogen atom trans-
In summary, this synthesis of ( )-3-hydroxy-spongian-
fer to the C(13) radical in 6 or its reduction to the parent
16-one (7) in only five steps demonstrates the effective-
anion followed by protonation ( 7). The latter termina-
ness of PET-induced cascade polyene cyclizations as the
tion mechanism seems, however, to be favorable under
pivotal step for the synthesis of polycyclic (natural) prod-
the applied reaction conditions when considering the rel-
ucts bearing an oxygen function at C(3). In such a cycliza-
atively low reduction potential of an -carboxylate radical
tion event, 7 asymmetric centers emerge with well-
defined and predictable stereochemistry in a single photo-
such as the C(13) radical in 6.
The synthesis starts with the conjugate addition of (E,E)- chemical step. In contrast to the usually lengthy prepara-
farnesyltri-n-butylstannane (1) to -methylen- -butyro- tion of the starting materials for pure radical-driven
lactone (2) upon treatment of 1 with n-BuLi, CuI, LiBr polycyclizations, as e.g., the example in ref. 3, the precur-
and TMSCl in THF by adopting a procedure for Michael sors for radical cation-initiated cyclization cascades, be-
additions of allylic ligands to a variety of , -unsaturated ing terpenoid polyenes, are more readily available.
ketones with allylic copper reagents.11 The coupling prod-
uct 3 was isolated in 92% yield after chromatography.
All reactions were carried out under Ar atm, the purification of re-
(E,E)-Farnesyltri-n-butylstannane (1) was readily pre-
pared in 90% yield by treatment of (E,E)-farnesylbromide
with tri-n-butylstannyl chloride and magnesium turnings
in THF adopting a procedure reported for a related exam-
ple.12 Lactone 3 can then be converted to the terpenoid
photoeduct 4 in good yields by following known proce-
dures for analogous functional group transformations [ref.
13 for (a) and ref. 14 for (b) in the Scheme]. (E,E)-Farne-
sylmethyl-4,5-dihydro-2(3H)-furanone (3) was first treat-
ed with lithium hexamethyldisilazide and phenylselene-
nyl bromide to introduce a phenylseleno group in -posi-
tion of the lactone carbonyl in 68% yield. Subsequent ox-
idation and in situ elimination of the seleno moiety with a
mixture of m-chloroperbenzoic acid and pyridine afforded
the (E,E)-farnesylmethyl-2(5H)-furanone (4) in 52%
yield. With compound 4 in hand, the pivotal photochemi-
cal step was achieved upon irradiation of 4 ( max = 300
nm, Rayonet reactor) in MeCN–H2O (10:1) at –25°C to-
gether with the electron acceptor couple 1,4-dicyanotet-
ramethylbenzene/biphenyl in catalytic amount (2 mol%)
to afford 7 as the major photoproduct in 23% yield after
purification. MeCN–H2O is routinely employed as a polar
solvent mixture for such PET transformations in order to
facilitate the electron transfer; at the same time the co-sol-
vent water acts as the nucleophile to trap the intermediate
radical cation in 5 ( 6). The radical saturation step 6
7 is, as mentioned earlier, the result of a reduction/proto-
nation sequence as a consequence of the estimated rela-
tively low reduction potential of the C(13) radical in 6.
Notably, protonation occurs in the present example exclu-
sively from the less hindered exo face affording 7 with cis
junction of the CD rings. The structure of 7 was unambig-
uously determined by NOE and X-ray analyses.15 The fact
action products was carried out by flash column chromatography
using Sepakron-FPGC glass columns from Kronlab with different
I.D. and length, dry packed with silica gel (0.063–0.200 mm). IR
spectra were recorded on a FT-IR-spectrometer Perkin–Elmer 1600
Series. Mass spectra were recorded on a Finnigan MAT 311A or
8230. 1H and 13C NMR spectra were recorded using Bruker AC-250
or AM-400 instruments. NOE: abbreviations: s (strong), m (medi-
um) and w (weak).
(E,E)-Farnesyltri-n-butylstannane (1)
To a stirred suspension of magnesium turnings (1.06 g, 44 mmol) in
THF (12 mL), a solution containing (E,E)-farnesylbromide (11.5 g,
0.04 mol) and tri-n-butylstannyl chloride (6.5 g, 0.02 mol) in THF
(20 mL) was added dropwise at 0°C. The reaction was heated to re-
flux for 2 h, cooled to 0°C in an ice-bath, and quenched with sat.
NH4Cl (10 mL). After filtration and removal of most the THF in
vacuo, Et2O (40 mL) was added to the residue and the organic phase
was separated, washed with H2O (2 30 mL), once with brine (30
mL), dried (Na2SO4), and evaporated under reduced pressure. Upon
chromatography (column: I.D. 52 mm, length 1121 mm; CH2Cl2–
pentane, 40:1) of the residue, 1 was obtained as a colorless oil (9.2
g, 18.4 mmol, 90%).
1H NMR (250 MHz, CDCl3): = 5.35 (t, 1H, J = 8.9 Hz), 5.11–5.05
(m, 2H), 2.05–1.97 (m, 8H), 1.67 (s, 3H), 1.67–1.63 (m, 2H), 1.59
(s, 6H), 1.56 (s, 3H), 1.50–1.21 (m, 12H), 0.91–0.88 (m, 6H), 0.86–
0.84 (m, 9H).
13C NMR (62.9 MHz, CDCl3): = 134.72 (Cq), 131.17 (Cq), 129.23
(Cq), 124.57 (CH), 124.45 (CH), 122.83 (CH), 39.91 (CH2), 39.80
(CH2), 29.24 (CH2), 27.40 (CH2), 26.77 (CH2), 26.34 (CH2), 25.67
(CH3), 17.65 (CH3), 15.95 (CH3), 13.70 (CH2), 10.65 (CH2), 9.39
(CH3).
MS: m/z (%) = 496 (7, M+, C27H52Sn), 439 (6), 325 (2), 291 (100),
235 (73), 179 (64), 121 (20), 81 (13), 69 (56), 41 (30).
HRMS: m/z calcd for C27H52Sn: 496.3090. Found: 496.3089.
(E,E)-Farnesylmethyl-4,5-dihydro-2(3H)-furanone (3)
that no mono- and bicyclic products have been found after A solution of CuI (7.5 g, 37.5 mmol) and anhyd LiBr (3.4 g, 37.5
mmol) in THF (50 mL) was stirred for 5 min and then cooled to
–78°C. Concurrently, n-BuLi (15%, 25 mL, 37.5 mmol) was added
photochemical transformation of 4 points to an exclusive
Synthesis 2001, No. 8, 1114–1116 ISSN 0039-7881 © Thieme Stuttgart · New York

1116
F. Goeller et al.
SHORT PAPER
dropwise to a solution of 1 (18.75 g, 37.5 mmol) in THF (50 mL)
and stirred for 15 min at –78°C. This solution was then transferred
to the CuI/LiBr solution (–78°C) to yield a tan solution. TMSCl
(4.01 mL, 31.6 mmol) was added followed by the addition of -me-
thylen- -butyrolactone (2, 2.80 mL, 31.6 mmol). The mixture was
stirred for 30 min, and the reaction was quenched with sat. NH4Cl
(80 mL). After extraction with Et2O (3 100 mL), the combined or-
ganic layers were dried (Na2SO4). The solvent was removed in vac-
uo and the residue was chromatographed (column: I.D. 52 mm,
length 1121 mm; Et2O–pentane, 15:1) to give lactone 3 (8.6 g, 28.5
mmol, 92%) as a colorless oil.
transferred into a cylindrical Pyrex irradiation vessel equipped with
a cooling finger. The solution was stirred and degassed (Ar) for 30
min. The irradiation was conducted in a Rayonet reactor ( max = 300
nm) for 22 h at –25°C. Thereafter, the reaction mixture was concen-
trated in vacuo and chromatographed (column: I.D. 18.5 mm, length
298 mm; Et2O–pentane, 2:1) to give the tetracyclic product 7, the
major component (0.24 g, 7.55 mmol, 23%), as colorless crystals
(mp 214°C).
IR (KBr): = 3609, 1771 cm–1.
1H NMR (250 MHz, CDCl3): = 4.20 (d, 1H, J = 9.7 Hz), 4.10 (dd,
1H, J = 9.7, 5.3 Hz), 3.20 (dd, 1H, J = 11.4, 4.9 Hz), 2.54 (dd, 1H,
J = 7.8, 7.7 Hz), 2.31–2.24 (m, 2H), 2.07 (dd, 1H, J = 7.8, 5.3 Hz),
1.85–1.10 (m, 10H), 0.95 (s, 3H), 0.82 (s, 3H), 0.79 (s, 3H), 0.78–
0.70 (m, 2H), 0.74 (s, 3H).
13C NMR (62.9 MHz, CDCl3): = 178.76 (Cq), 78.62 (CH), 67.46
(CH2), 56.14 (CH), 55.45 (CH), 50.30 (CH), 42.06 (CH2), 38.79
(Cq), 38.32 (CH2), 37.33 (CH), 36.93 (Cq), 35.43 (Cq), 27.88 (CH3),
27.10 (CH2), 22.19 (CH2), 17.53 (CH2), 17.30 (CH2), 16.25 (CH3),
15.29 (CH3), 15.26 (CH3).
IR (film): = 1781 cm–1.
1H NMR (250 MHz, CDCl3): = 5.10–5.05 (m, 3H), 4.34–4.09 (m,
2H), 2.52–2.32 (m, 2H), 2.09–1.88 (m, 12H), 1.66 (s, 1H), 1.64 (s,
3H), 1.58 (s, 9H).
13C NMR (62.9 MHz, CDCl3): = 179.50 (Cq), 136.70 (Cq), 135.26
(Cq), 131.23 (Cq), 124.26 (CH), 123.98 (CH), 122.74 (CH), 66.35
(CH2), 39.65 (CH2), 39.61 (CH2), 38.57 (CH), 30.39 (CH2), 28.70
(CH2), 26.69 (CH2), 26.64 (CH2), 25.61 (CH3), 25.50 (CH2), 17.60
(CH3), 15.99 (CH3), 15.94 (CH3).
NOE (400 MHz, CDCl3, saturation
enhancement): 3.17 (HC-3)
MS: m/z (%) = 304 (15, M+, C20H32O2), 289 (1), 261 (10), 235 (8),
0.95 (s, H3C-20) and 0.76 (m, H3C-19) and 0.74 (s, HC-5); 2.51
180 (11), 136 (24), 95 (22), 81 (57), 69 (100), 55 (24), 41 (64).
(HC-13)
4.09 (w, HHC-15) and 2.04 (s, HC-14) and 1.57 (m,
H2C-11); 2.04 (HC-14) 4.19 (w, HHC-15) and 4.09 (s, HHC-15)
and 2.52 (s, HC-13) and 1.03 (s, H2C-7) and 0.71 (m, HC-9); 0.813
(H3C-17) 4.19 (m, HHC-15).
HRMS: m/z calcd for C20H32O2: 304.2395. Found: 304.2394.
(E,E)-Farnesylmethyl-2(5H)-furanone (4)
Lactone 3 (7.5 g, 24.6 mmol) in THF (37 mL) was added to a THF
solution (200 mL) containing lithium hexamethyldisilazide [pre-
pared from bis(trimethylsilylamine) (7.15 g, 44.3 mmol) and n-
BuLi (15%, 32.4 mL, 49 mmol) at –78°C]. After 25 min, phenylse-
lenyl bromide (11.56 g, 49 mmol) in THF (50 mL) was added to this
solution and immediately thereafter the mixture was quenched with
H2O (200 mL). The reaction mixture was poured into Et2O (500
mL) and the organic phase was separated, washed sequentially with
H2O (3 80 mL), Na2CO3 (80 mL) and brine (80 mL), then dried
(Na2SO4), and concentrated in vacuo. The residue was chromato-
graphed (column: I.D. 37 mm, length 539 mm; Et2O–pentane, 15:1)
to afford the -phenylseleno lactone derivative of 3 (7.6 g, 16.5
mmol, 68%) as a colorless oil.
MS: m/z (%) = 320 (36, M+, C20H32O3), 302 (60), 287 (76), 259 (18),
207 (100), 189 (87), 135 (61), 121 (70), 107 (65), 95 (64), 81 (67),
67 (58), 55 (70), 41 (92).
HRMS: m/z calcd for C20H32O3: 320.2351. Found: 320.2353.
References
(1) Kernan, M. R.; Cambie, R. C.; Bergquist, P. R. J. Nat. Prod.
1990, 53, 724.
(2) Miles, D. H.; Nguyen, C. L.; Miles, D. H. Curr. Med. Chem.
1998, 5, 421.
(3) Pattenden, G.; Roberts, L.; Blake, A. J. J. Chem. Soc., Perkin
Trans. 1 1998, 863.
(4) Heinemann, C.; Xing, X.; Warzecha, K.-D.; Ritterskamp, P.;
Görner, H.; Demuth, M. Pure Appl. Chem. 1998, 70, 2167.
(5) Heinemann, C.; Demuth, M. J. Am. Chem. Soc. 1999, 121,
4894.
The -phenylseleno lactone derivative of 3 (7.6 g, 16.5 mmol) was
dissolved in EtOAc (400 mL) prior to its treatment with pyridine
(5.7 mL, 0.07 mmol) and m-CPBA (8.6 g, 0.05 mol). The mixture
was stirred for 20 min at r.t., washed with H2O (3 100 mL), dried
(Na2SO4), concentrated in vacuo, and chromatographed (column:
I.D. 37 mm, length 539 mm; Et2O–pentane, 10:1) to give 4 (2.5 g,
8.5 mmol, 52%) as a colorless oil.
(6) Xing, X.; Demuth, M. Eur. J. Org. Chem. 2001, 537.
(7) Corey, E. J.; Virgil, S. C.; Cheng, H.; Baker, C. H.; Matsuda,
S. P. T.; Singh, V.; Sarshar, S. J. Am. Chem. Soc. 1995, 117,
11819.
IR (film): = 1755 cm–1.
(8) Xing, X.; Demuth, M. J. Am. Chem. Soc., accepted.
(9) Xing, X. Ph.D. Thesis; Max-Planck-Institut für
Strahlenchemie/University of Essen: Germany, 1997.
(10) Xing, X.; Demuth, M. EPA Newsletter 1998, 64, 101.
(11) Lipshutz, B. H.; Ellsworth, E. L.; Dimrock, S. H.; Smith, R.
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Tetrahedron Lett. 1985, 26, 4079.
(13) Hannesian, S.; Murray, P. J. Tetrahedron Lett. 1987, 28,
5055.
1H NMR (400 MHz, CDCl3): = 7.07 (t, 1H, J = 1.6 Hz), 5.08–5.05
(m, 3H), 4.72 (d, 2H, J = 1.6 Hz), 2.30–2.25 (m, 4H), 2.04–1.93 (m,
8H), 1.66 (s, 3H), 1.64 (s, 3H), 1.56 (s, 6H).
13C NMR (100 MHz, CDCl3): = 174.32 (Cq), 144.26 (CH), 136.75
(Cq), 135.30 (Cq), 133.92 (Cq), 131.23 (Cq), 124.25 (CH), 123.97
(CH), 122.59 (CH), 70.04 (CH2), 39.66 (CH2), 39.57 (CH2), 26.69
(CH2), 26.51 (CH2), 25.67 (CH3), 25.61 (CH2), 25.40 (CH2), 17.60
(CH3), 16.03 (CH3), 15.94 (CH3).
MS: m/z (%) = 302 (13, M+, C20H30O2), 279 (5), 259 (12), 233 (10),
(14) Reich, H. J. In Organic Reactions, Vol. 44; Wiley: New
York, 1994.
(15) Goeller, F. Ph.D. Thesis; Max-Planck-Institut für
Strahlenchemie/University of Essen: Germany, in progress.
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1997, 69, 109.
149 (26), 136 (25), 98 (30), 81 (42), 69 (100), 55 (17), 41 (55).
HRMS: m/z calcd for C20H30O2: 302.2245. Found: 302.2245.
3-Hydroxy-spongian-16-one (7)
(E,E)-farnesylmethyl-2(5H)-furanone (4, 1 g, 3.3 mmol), biphenyl
(0.45 g, 2.96 mmol) and 1,4-dicyanotetramethylbenzene (0.16 g,
0.86 mmol) were dissolved in MeCN–H2O (400 mL, 10:1) and
Synthesis 2001, No. 8, 1114–1116 ISSN 0039-7881 © Thieme Stuttgart · New York