Formal Alder-ene reaction of a bicyclo[1.1.0]butane in the synthesis of the tricyclic quaternary ammonium core of daphniglaucins

Article abstract of DOI:10.1016/j.tetlet.2008.07.179

A tricyclic substructure of the tetracyclic nitrogen core of the daphniglaucins was formed by an oxidative activation of the allyl side chain of a bicyclo[1.1.0]butylmethylamine, a spontaneous intramolecular formal Alder-ene reaction, and a selective cycl

Full text of DOI:10.1016/j.tetlet.2008.07.179

Tetrahedron Letters 49 (2008) 5986–5989
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Formal Alder-ene reaction of a bicyclo[1.1.0]butane in the synthesis
of the tricyclic quaternary ammonium core of daphniglaucins
*
Masafumi Ueda , Maciej A. A. Walczak, Peter Wipf
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A tricyclic substructure of the tetracyclic nitrogen core of the daphniglaucins was formed by an oxidative
activation of the allyl side chain of a bicyclo[1.1.0]butylmethylamine, a spontaneous intramolecular
formal Alder-ene reaction, and a selective cyclization of a triol intermediate.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 4 July 2008
Accepted 29 July 2008
Available online 5 August 2008
P(O)Ph2
Br
Ar
HN
Among complex alkaloids, quaternary ammonium salts occupy
a unique position because of their frequently intricate architecture.
Some of these compounds are used medicinally as anticancer and
antimicrobial agents,1 and they have also found utility as chiral
phase transfer catalysts.2 These polycyclic alkaloids constitute
challenging targets for natural product total synthesis (Fig. 1).3
For example, the daphniglaucins are cytotoxic quaternary Daphni-
phyllum alkaloids isolated in 2003 by Kobayashi et al. from the
leaves of Daphniphyllum glaucescens and have an unusual frame-
work consisting of a novel fused-polycyclic skeleton assembled
around a 1-azoniatetracyclo[5.2.2.0.1,60.4,9]undecane ring system.3c–e
Despite these attractive structural features, a total synthesis or a
partial synthetic approach has not yet been reported.
In this Letter, we describe our studies on the use of a bicy-
clo[1.1.0]butane building block in the synthesis of the cyclic qua-
ternary ammonium scaffold of daphniglaucins. To the best of our
knowledge, this sequence represents the first use of this highly
strained hydrocarbon in alkaloid synthesis.4 We have previously
reported on the preparations and ring transformations of bicyclob-
utylmethylamines.5,6 An intramolecular ene reaction of N-allylated
derivatives of 1 provides a stereoselective access to spirocyclic pyr-
N
Ph
Bu4NHSO4, NaOH (50% aq.)
PhMe, RT, 36 h
P(O)Ph2
Ph
Ar
1
2
Scheme 1. Cascade N-allylation/formal Alder-ene sequence.
rolidines 2 under remarkably mild phase transfer conditions
(Scheme 1).
In the continuation of our explorations of the novel intra-
molecular cycloaddition chemistry of bicyclo[1.1.0]-butanes,5,6
we intended to demonstrate their utility for the synthesis of bio-
logically interesting cyclic quaternary ammonium salts. We envi-
sioned that a tricyclic substructure of the core heterocycle of
daphniglaucin A, that is, the 1-azoniatricyclo[5.2.2.05]undecane 3,
could be derived from a triol 4, which could be obtained from spi-
rocycle 5 via oxidative cleavage and reduction (Scheme 2). An
intramolecular formal Alder-ene reaction of bicyclobutylmethyl-
amine 6 would produce 5. The aldehyde group in the nitrogen side
CO2Me
OH
CO2Me
H
OH
OH
R
N
N
NH
OH
R1O
R1O
R
N
N
OH
N
HO
H
OH
4
3
OH
N
HO
subincanadine A
daphniglaucin A: R=H
daphniglaucin B: R=OMe
OR1
lycovatine A
H
NP(O)Ph2
O
Figure 1. Representative polycyclic quaternary alkaloids.
OR2
N
P(O)Ph2
6
5
R2O
* Corresponding author. Tel.: +1 412 624 8606; fax: +1 412 624 0787.
E-mail address: pwipf@pitt.edu (P. Wipf).
Present address: Kobe Pharmaceutical University, Motoyamakita, Higashinada,
Kobe 658-8558, Japan.
Scheme 2. Retrosynthetic strategy toward cyclic quaternary ammonium salts from
bicyclobutanes. The corresponding core structure of daphniglaucins is highlighted.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.179

M. Ueda et al. / Tetrahedron Letters 49 (2008) 5986–5989
5987
Ph2(O)P
Ph
rt to
150 ºC
Br
Br
N
Ph
9
(1)
NR
NHP(O)Ph2
SO2Tol
Cl
i-iii
Br
iv
HO
OH
H
TrO
7
8
Ph2(O)P
rt to
150 ºC
N
(2)
(3)
NR
Ph
11
Ph2(O)PN
Ph2(O)PN
OTBS
v
TBSO
TrO
TrO
10
12
MeO2C
Ts
NH
MeO2C
Br
Ph
N
NaH, DMF
50 ºC
Ts
51%
Ph2(O)PN
14
Ph2(O)PN
13
Ph
vii
vi
O
HO
TrO
TrO
CHO
DMP,
Ph2(O)P
Ph
N
2,6-lutidine
OH
(4)
O2N
N
CH2Cl2, rt
P(O)Ph2
59%
H
Ph
N
CHO
Ph2(O)PN
N
viii
NO2
TrO
Ph2(O)PN
Scheme 3. Formal Alder-ene reactions of terminally unsubstituted bicyclobutyl-
methylamines require electron-deficient enophiles.
16
15
TrO
Scheme 4. Reagents and conditions: (i) TrCl, Et3N, DMAP, CH2Cl2, rt, 71%; (ii)
(COCl)2, DMSO, Et3N, CH2Cl2, À78 °C, 92%; (iii) H2NP(O)Ph2, p-TolSO2H, Et2O, rt,
94%; (iv) MeLi, t-BuLi, Et2O, THF, À78 °C; 8; (v) Bu4NHSO4, 50% aq NaOH, toluene, rt,
58% (2 steps); (vi) TBAF, THF, rt, 85%; (vii) TPAP, NMO, CH2Cl2, benzene, rt to reflux,
67% (6:1 dr); (viii) 2,4-dinitrophenylhydrazine, MeOH, rt, 86%.
Table 1
Frontier molecular orbital calculations of the HOMO–LUMO gapa as a function of R1
and R2 substituents on ene and enophile
R1
Me
R2
Me
R2
R2
R1
Me
DE (LUMO–
Entry R1
HOMO of
LUMO of
bicylobutane (eV)
alkene (eV)
HOMO) (eV)
BnO
Ph2(O)PN
BocN
OBn
1
2
3
4
Ph
H
À7.95
À9.37
H
H
H
5.25
5.25
5.25
13.20
14.62
14.98
12.32
iii-iv
i-ii
15
TrO
HO
CHO À9.73
17
18
H
À9.37
CHO 2.95
a
Calculated with a HF/6-31G* basis set using MACSPARTAN 06.
OBn
OBn
OH
N
N
viii-ix
v-vii
19
20
OH
chain in 6 was found to be essential for the thermal ene reaction of
bicyclo[1.1.0]-butanes lacking conjugated aromatic substituents.
The need for an electron-poor enophile in this process was sup-
ported by preliminary experimental as well as theoretical studies
(Scheme 3 and Table 1).
X
x
N
BnO
(X = Cl/OMs)
Even upon heating unactivated allylic and propargylic bicyclo-
butylmethylamines to 150 °C, only starting material was isolated
(Scheme 3, Eqs. 1 and 2). More vigorous conditions led to decom-
position, but ene-products could not be identified. In contrast, an
electron-deficient ester function provided the cycloaddition prod-
uct in 51% yield at 50 °C (Scheme 3, Eq. 3). In situ oxidation of a
propargyl alcohol to the ynal with Dess-Martin periodinane
(DMP) led to the analogous cycloaddition product at room temper-
ature and in good yield (Scheme 3, Eq. 4).
21
OH
Scheme 5. Reagents and conditions: (i) NaBH4, MeOH, rt, 79%; (ii) BnBr, KOH, 18-
crown-6, THF, H2O, rt, 86%; (iii) concd HCl, THF, rt; (iv) (Boc)2O, NaHCO3, MeCN,
H2O, rt, 69% (2 steps); (v) MsCl, Et3N, CH2Cl2, rt; (vi) TFA, CH2Cl2, rt; (vii) Et3N,
MeCN, rt, 75% (3 steps); (viii) OsO4, NaIO4, 2,6-lutidine, t-BuOH, H2O, rt; (ix) NaBH4,
MeOH, rt, 45% (2 steps); (x) MsCl, NaHCO3, CH2Cl2, H2O, rt, 61%.
drawing aldehyde or ester function on the allylic amide side
chain failed under the classical thermal conditions.
Table 1 provides an overview of HOMO–LUMO energies calcu-
*
lated at the HF/6-31G level for substituted enophiles and bicyc-
The synthesis of an appropriately substituted 1-azoniatricy-
clo[5.2.2.01,6]undecane segment of daphniglaucin is outlined in
Schemes 4 and 5. 1,5-Pentanediol (7) was selectively O-tritylated,
oxidized to the aldehyde and then condensed with N,N-di-
phenylphosphinamide in the presence of p-toluenesulfinic acid to
afford the imine precursor 8.7,8 Treatment of 1,1-dibromo-2-chlo-
romethylcyclopropane (9) with MeLi followed by t-BuLi generated
bicyclo[1.1.0]butan-1-yllithium in situ,9 which, upon addition of 8,
eliminated the sulfinylate and added to the resulting imine to give
amide 10. This labile 1,2-adduct was immediately subjected to N-
alkylation with allylbromide 1110 under phase-transfer conditions
to give bicyclobutane 12 in 58% overall yield from 8. Desilylation of
lobutanes. In order to minimize the HOMO–LUMO gap, the ene
reaction is expected to proceed via the interaction of the HOMO
of the bicyclobutane with the LUMO of the alkene. A large frontier
orbital energy difference was observed between electron-rich
alkenes and terminal bicyclobutanes or electron deficient bicyclo-
butanes bearing a formyl group (entries 2 and 3). In contrast, a
phenyl substituent on the bicyclobutane or a carbonyl substituent
at the alkene considerably enhances the reactivity by diminishing
the HOMO–LUMO gap by ca. 1.4 and 2.3 eV, respectively (entries
1 and 4). In practice, all intramolecular ene reactions that we at-
tempted with analogs of 6 that did not contain an electron-with-

5988
M. Ueda et al. / Tetrahedron Letters 49 (2008) 5986–5989
Figure 2. Stereoview of the X-ray crystal structure of hydrazone 16.
787; (c) Bai, L.-P.; Zhao, Z.-Z.; Cai, Z.; Jiang, Z.-H. Bioorg. Med. Chem. 2006, 14,
5439; (d) Jayasuriya, H.; Herath, K. B.; Ondeyka, J. G.; Polishook, J. D.; Bills, G. F.;
Dombrowski, A. W.; Springer, M. S.; Siciliano, S.; Malkowitz, L.; Sanchez, M.;
Guan, Z.; Tiwari, S.; Stevenson, D. W.; Borris, R. P.; Singh, S. B. J. Nat. Prod. 2004,
67, 1036.
12 with TBAF afforded the allylic alcohol 13. Several oxidants, sol-
vents, and reaction temperature conditions were examined in our
attempts to optimize the conversion of 13 to 14. The best result
was obtained when TPAP in DCM was used as the oxidant at room
temperature for 1 h; aldehyde 14 was not isolated from the reac-
tion mixture but was immediately heated after the addition of ben-
zene as a cosolvent, thus affording the formal ene product 15 in
67% yield as a 6:1 mixture of diastereomers.11–13 The major isomer
was isolated by chromatography on SiO2, and its relative configu-
ration was secured by an X-ray structure analysis of the hydrazone
derivative 16 (Fig. 2).5b
2. For reviews, see: (a) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656; (b)
Maruoka, K.; Ooi, T.; Kano, T. Chem. Commun. 2007, 1487; (c) O’Donnell, M. Acc.
Chem. Res. 2004, 37, 506.
3. (a) Kubota, T.; Sunaura, T.; Morita, H.; Mikami, Y.; Hoshino, T.; Obara, Y.;
Nakahata, N.; Kobayashi, J. Heterocycles 2006, 69, 469; (b) Ishiyama, H.;
Matsumoto, M.; Sekiguchi, M.; Shigemori, H.; Ohsaki, A.; Kobayashi, J.
Heterocycles 2005, 66, 651; (c) Kobayashi, J.; Takatsu, H.; Shen, Y.-C.; Morita,
H. Org. Lett. 2003, 5, 1733; (d) Takatsu, H.; Morita, H.; Shen, Y.-C.; Kobayashi, J.
Tetrahedron 2004, 60, 6279; (e) Morita, H.; Takatsu, H.; Shen, Y.-C.; Kobayashi, J.
Tetrahedron Lett. 2004, 45, 901; (f) Kobayashi, J.; Sekiguchi, M.; Shimamoto, S.;
Shigemori, H.; Ishiyama, H.; Ohsaki, A. J. Org. Chem. 2002, 67, 6449; (g) Penelle,
J.; Tits, M.; Christen, P.; Molgo, J.; Brandt, V.; Frédérich, M.; Angenot, L.
Phytochemistry 2000, 53, 1057; (h) Penelle, J.; Tits, M.; Christen, P.; Brandt, V.;
Frédérich, M.; Angenot, L. J. Nat. Prod. 1999, 62, 898.
4. For the use of an 1-(arylsulfonyl)bicyclobutane in the synthesis of two
isoprenoids, see: Gaoni, Y.; Tomazic, A. J. Org. Chem. 1985, 50, 2948.
5. (a) Wipf, P.; Stephenson, C. R. J.; Okumura, K. J. Am. Chem. Soc. 2003, 125,
14694; (b) Wipf, P.; Walczak, M. A. A. Angew. Chem., Int. Ed. 2006, 45,
4172.
The major diastereomer 15 was used in the subsequent trans-
formation to the quaternary ammonium salt 21 (Scheme 5). Reduc-
tion of the aldehyde with NaBH4 and protection of the resulting
alcohol with BnBr provided benzyl ether 17. We determined
empirically that the best strategy for formation of the tricyclic
ammonium ion was to close the fused six-membered ring before
installing the second, bridged six-membered ring. Accordingly, 17
was converted to the primary alcohol 18 by concurrent solvolysis
of N,N-diphenylphosphinoyl and trityl groups, followed by N-Boc
protection. Mesylation of the primary hydroxyl group of 18, cleav-
age of the Boc group with TFA, and cyclization in the presence of
triethylamine furnished indolizidine 19. Oxidative ring opening
of the cyclobutene was readily accomplished by a Johnson–Lemi-
eux oxidation in the presence of 2,6-lutidine, and the resulting
dialdehyde was reduced to diol 20 with NaBH4.14 Finally, double
mesylation of diol 20 with excess MsCl in NaHCO3/H2O/DCM
resulted in spontaneous cyclization followed by in situ hydrolysis
of the unreacted neopentyl mesylate to give the tricyclic quater-
nary ammonium salt 21.15,16 Target compound 21 was isolated
as an approximately 4:1 mixture of chloride and mesylate salts
based on 1H NMR integration of the mesylate methyl group.
In conclusion, we have successfully extended the utility of the
bicyclobutane strained ring system to alkaloid synthesis. The key
reaction for the construction of the tricyclic quaternary ammonium
core of daphniglaucin was based on the thermal intramolecular
formal Alder-ene reaction of the N-allylated bicyclo[1.1.0]butyl-
methylamine 14. Further studies toward the total synthesis of
daphniglaucins and other applications of bicyclobutanes in target-
directed synthesis are currently in progress in our laboratories.
6. Walczak, M. A. A.; Wipf, P. J. Am. Chem. Soc. 2008, 130, 6924, and references
cited therein.
7. Angehrn, P.; Buchmann, S.; Funk, C.; Goetschi, E.; Gmuender, H.; Hebeisen, P.;
Kostrewa, D.; Link, H.; Luebbers, T.; Masciadri, R.; Nielsen, J.; Reindl, P.; Ricklin,
F.; Schmitt-Hoffmann, A.; Theil, F. J. Med. Chem. 2004, 47, 1487.
8. Côté, A.; Boezio, A. A.; Charette, A. B. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5405.
9. Weber, J.; Haslinger, U.; Brinker, U. H. J. Org. Chem. 1999, 64, 6085.
10. DeBoef, B.; Counts, W. R.; Gilbertson, S. R. J. Org. Chem. 2007, 72, 799.
11. Experimental protocol for the formation of 15 from 13: TPAP (96 mg, 0.27 mmol)
was added to a stirred solution of alcohol 13 (1.8 g, 2.7 mmol), powdered 4 Å
sieves (2 g) and 4-methylmorpholine N-oxide (651 mg, 5.39 mmol) in CH2Cl2
(30 mL) at rt. The reaction mixture was stirred for 1 h at rt, diluted with
benzene (200 mL), heated at reflux for 4 h and filtered through a thin pad of
Celite. The filtrate was concentrated and purified by chromatography on SiO2
(AcOEt) to afford a diastereomeric mixture (6:1) of spirocycles (1.21 g, 67%) as
a colorless foam, which was carefully re-purified by chromatography on SiO2
(AcOEt) to give the major isomer 15 (942 mg, 52%).
12. Spectral data of 15: IR (neat) 3413, 3057, 2937, 2869, 1723, 1489, 1439, 1190,
1121, 1073, 1047, 909, 729 cmÀ1 1H NMR (300 MHz, CDCl3) d 9.74 (s, 1H),
;
7.95–7.88 (m, 2H), 7.78–7.71 (m, 2H), 7.54–7.20 (m, 21H), 6.47 (d, J = 3.0 Hz,
1H), 6.11 (d, J = 3.0 Hz, 1H), 3.52–3.37 (m, 2 H), 3.30–2.78 (m, 4H), 2.58 (dd,
J = 18.0, 3.0 Hz, 1H), 2.45 (d, J = 13.5 Hz, 1H), 2.44–2.38 (m, 1H), 2.22 (d,
J = 13.5 Hz, 1H), 1.93–1.76 (m, 1H), 1.55–1.18 (m, 4H), 1.02–0.88 (m, 1H); 13C
NMR (75 Hz, CDCl3) d 201.4, 144.3, 141.2, 134.5, 133.0, 132.8 (d, J = 9.0 Hz),
132.2 (d, J = 9.8 Hz), 131.7 (d, J = 2.3 Hz), 131.4 (d, J = 3.0 Hz), 131.3, 131.1,
128.6, 128.4, 128.2, 128.1, 127.7, 126.7, 86.2, 64.2, 63.1, 59.7 (d, J = 1.5 Hz),
50.3, 44.5, 33.7 (d, J = 4.5 Hz), 34.7, 33.8 (d, J = 5.3 Hz), 29.9, 23.8; MS (ESI) m/z
(rel intensity) 688 ([M+Na]+, 90), 527 (25), 443 (37), 243 (100); HRMS (ESI)
calcd for C44H44NO3PNa (M+Na) 688.2957, found 688.2964.
Acknowledgments
13. For reactions of bicyclo[1.1.0]butanes with benzyne that afforded a mixture of
ene and other cycloaddition products, see: (a) Pomerantz, M.; Gruber, G. W.;
Wilke, R. N. J. Am. Chem. Soc. 1968, 90, 5040; (b) Pomerantz, M.; Wilke, R. N.;
Gruber, G. W.; Roy, U. J. Am. Chem. Soc. 1972, 94, 2752; (c) Gassman, P. G.;
Richmond, G. D. J. Am. Chem. Soc. 1968, 90, 5637; (d) Gassman, P. G.; Richmond,
G. D. J. Am. Chem. Soc. 1970, 92, 2090.
This work was supported in part by NIH Grant P50-GM067082
and Merck Research Laboratories. We thank Dr. Steve Geib for an
X-ray crystallographic analysis. M.U. is grateful for the support
from Hyogo Science and Technology Association.
14. Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217.
15. Experimental protocol for the formation of 21 from 20: To a solution of diol 20
(18 mg, 0.054 mmol) in CH2Cl2 (3 mL) were added NaHCO3 (10 mg,
0.12 mmol), H2O (0.12 mL) and MsCl (0.009 mL, 0.12 mmol) at 0 °C. The
reaction mixture was stirred for 5 h at rt and concentrated in vacuo. The
residue was dissolved in CH2Cl2 and an insoluble solid was removed by
filtration. After the solvent was evaporated under reduced pressure, the
residue was dissolved in water. The solution was filtered through a small pad
References and notes
1. For recent examples, see: (a) Hung, T. M.; Ngoc, T. M.; Youn, U. J.; Min, B. S.; Na,
M. K.; Thuong, P. T.; Bae, K. H. Biol. Pharm. Bull. 2008, 31, 159; (b) Wu, Y.-R.; Ma,
Y.-B.; Zhao, Y.-X.; Yao, S.-Y.; Zhou, J.; Zhou, Y.; Chen, J.-J. Planta. Med. 2007, 73,

M. Ueda et al. / Tetrahedron Letters 49 (2008) 5986–5989
5989
of Celite and the filtrate was concentrated in vacuo to form white solid, which
was recrystallized in CH2Cl2 and hexane to afford the ammonium salt 21
(12 mg, 61%) as a 4:1 mixture of ClÀ and MsOÀ counterions.
J = 11.5 Hz, 1H), 3.45–3.23 (m, 5H), 3.19–3.12 (m, 1H), 2.34 (s, 0.6H, CH3SO À)),
2.18–2.11 (m, 1H), 2.08 (td, J = 12.0, 5.5 Hz, 1H), 1.98–1.91 (m, 1H), 1.84–31.66
(m, 5H), 1.63–1.55 (m, 1H), 1.51 (q, J = 11.5 Hz, 1H), 1.41–1.29 (m, 1H); 13C
NMR (75 Hz, CD3OD) d 139.8, 129.6, 129.1, 128.9, 74.4, 74.0, 71.2, 69.5, 60.8,
55.4 (2C), 54.2, 41.6, 32.1, 31.7, 22.3, 21.8, 20.7; MS (ESI) m/z (rel. intensity)
316 ([MÀCl]+ or [MÀOMs]+, 100), 224 (30); HRMS (ESI) calcd for C20H30NO2
(MÀCl or MÀOMs) 316.2277, found 316.2265.
16. Spectral data of 21: White solid; IR (neat) 3224, 2932, 2844, 1452, 1360, 1195,
1171, 1098, 1072, 740 cmÀ1 1H NMR (500 MHz, DMSO-d6) d 7.37–7.29 (m,
;
5H), 5.60–5.10 (br, 1H), 4.47, 4.44 (AB, J = 12.0 Hz, 2H), 3.84 (t, J = 11.5 Hz, 1H),
3.75 (t, J = 8.5 Hz, 1H), 3.62 (d, J = 11.5 Hz, 1H), 3.53 (d, J = 11.5 Hz, 1H), 3.52 (t,