Total synthesis of flustramine C via dimethylallyl rearrangement

Article abstract of DOI:10.1021/ol0627348

(Chemical Equation Presented) The marine natural product flustramine C from the bryozoan Flustra foliacea was synthesized in five steps and 38% yield starting from N_b-methyltryptamine. The key step is the biomimetic oxidation of the natural pro

Full text of DOI:10.1021/ol0627348

ORGANIC
LETTERS
2007
Vol. 9, No. 2
283-286
Total Synthesis of Flustramine C via
Dimethylallyl Rearrangement
Thomas Lindel,* Laura Bra1uchle, Gregor Golz, and Petra Bo1hrer
Ludwig Maximilian UniVersity, Department of Chemistry and Biochemistry,
Butenandtstrasse 5-13, D-81377 Munich, Germany
thomas.lindel@cup.uni-muenchen.de
Received November 8, 2006
ABSTRACT
The marine natural product flustramine C from the bryozoan Flustra foliacea was synthesized in five steps and 38% yield starting from
Nb-methyltryptamine. The key step is the biomimetic oxidation of the natural product deformylflustrabromine causing selective 1,2-rearrangement
of the inverse prenyl group. By 1H,15N HMBC experiments, it is unambiguously shown that the reaction with t-BuOCl commences with chlorination
of the side chain nitrogen. Deformylflustrabromine itself was synthesized via Danishefsky inverse prenylation.
The bryozoan Flustra foliacea has been a rich source of
brominated indole alkaloids bearing isoprenyl substituents
at various positions.1 The discovery of deformylflustrabro-
mine (1, Figure 1) as a major metabolite of F. foliacea
Flustramine C (2) is functionalized by a 1,1-dimethylallyl
(“inverse prenyl”) group at the bridgehead C3a and co-
occurred with hydroxylated flustraminol A (3) in the same
specimen of F. foliacea.4 The biosynthesis of 2 and 3 could
involve oxidation of deformylflustrabromine (1). Whereas
flustraminol A (3) appears to be formed via epoxidation of
the indole C2-C3 double bond of 1, the biogenesis of
flustramine C (2) requires oxidation and rearrangement of
the prenyl group. It is unclear whether the prenyl shift is
enzyme assisted. Christophersen et al. did not report optical
activity for flustramine C (2) or flustraminol A (3),4 and
Ko¨nig et al. isolated (-)-2.3a The optical purity of (-)-2
22
([R]D ) -10.1) has not been determined.
(1) (a) Carle´, J. S.; Christophersen, C. J. Am. Chem. Soc. 1979, 101,
4012-4013. (b) Carle´, J. S.; Christophersen, C. J. Org. Chem. 1980, 45,
1586-1589. (c) Wright, J. L. C. J. Nat. Prod. 1984, 47, 893-895. (d)
Laycock, M. V.; Wright, J. L. C.; Findlay, J. A.; Patil, A. D. Can. J. Chem.
1985, 64, 1312-1316. (e) Keil, P.; Nielsen, E. G.; Anthoni, U.; Christo-
phersen, C. Acta Chem. Scand. B 1986, 40, 555-558. (f) Holst, P. B.;
Anthoni, U.; Christophersen, C.; Nielsen, P. H. J. Nat. Prod. 1994, 57,
997-1000.
Figure 1. Inversely prenylated bromoindole alkaloids from the
bryozoan Flustra foliacea.
(2) Lysek, N.; Rachor, E.; Lindel, T. Z. Naturforsch. C: Biosci. 2002,
57c, 1056-1061.
collected near the North Sea island of Helgoland2,3 prompted
us to investigate the chemical link between 1 and the pyrrolo-
[2,3-b]indole flustramine C (2).
(3) (a) Peters, L.; Ko¨nig, G. M.; Terlau, H.; Wright, A. D. J. Nat. Prod.
2002, 65, 1633-1637. (b) Peters, L.; Wright, A. D.; Krick, A.; Ko¨nig, G.
M. J. Chem. Ecol. 2004, 30, 1165-1181.
(4) Carle´, J. S.; Christophersen, C. J. Org. Chem. 1981, 46, 3440-3443.
10.1021/ol0627348 CCC: $37.00
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Published on Web 12/22/2006

Deformylflustrabromine (1) affects the nicotinic acetyl-
choline receptor (nAChR).5 Flustramine C (2) shows elevated
concentrations in exposed parts of F. foliacea, and it is
secreted into the surrounding water and could play an
important role in ecological interactions.3 It has also been
suggested that the Flustra alkaloids are important for the
bryozoan by controlling bacterial growth on its surface.6
There are two total syntheses of flustramine C by the
Sakamoto7 and Funk8 groups, both utilizing intermediates
oxygenated at the indole 2-position. Our approach presented
here employs deformylflustrabromine (1) as an immediate
precursor. For the synthesis of deformylflustrabromine, Nb-
methyltryptamine (4) was converted to Nb-formyl-Nb-meth-
yltryptamine9 which cleanly underwent Danishefsky inverse
prenylation10-12 upon treatment with t-BuOCl and freshly
prepared prenyl-9-BBN,13 affording 1,1-dimethylallyl indole
5 in 80% yield (Scheme 1). It proved to be beneficial if 1,1-
(3:1) affording the natural product flustrabromine (6, X-ray
analysis)15 in 61% yield.16 As a side product, minor amounts
(15%) of the 4-brominated analogue were obtained.17 Alka-
line hydrolysis of flustrabromine (6) afforded deformylflus-
trabromine (1).
With gram quantities of deformylflustrabromine (1) in
hand, we were now able to investigate our key question. For
oxidative conversion of 1 to 2, we first investigated t-BuOCl.
On treatment of deformylflustrabromine (1) with 1 equiv of
t-BuOCl in the presence of NEt3 in THF at -78 °C, an
isolable, yet unstable, intermediate was formed (Scheme 2).
Scheme 2. Conversion of Deformylflustrabromine (1) to
Flustramine C (2)a
Scheme 1. Synthesis of Deformylflustrabromine (1)
a Compounds were characterized by 1H,15N HMBC experiments.
The ESI(-)FTMS spectrum indicated replacement of a
hydrogen by a chlorine atom. In the NMR spectrum,
chemical shifts of the side chain had shifted downfield and
the signals of the indole moiety remained almost unchanged.
We concluded that the side chain nitrogen had been
(10) (a) Schkeryantz, J. M.; Woo, J. C. G.; Danishefsky, S. J. J. Am.
Chem. Soc. 1995, 117, 7025-7026. (b) Schkeryantz, J. M.; Woo, J. C. G.;
Siliphaivanh, P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1999,
121, 11964-11975.
dimethylallene14 and 9-BBN-H were allowed to react for
18 h at room temperature before use.
Monobromination of 5 proceeded on treatment with 1
equiv of N-bromosuccinimide (NBS) in HOAc/HCO2H
(11) Liu, K.; Wood, H. B.; Jones, A. B. Tetrahedron Lett. 1999, 40,
5119-5122.
(12) (a) Roe, J. M.; Webster, R. A. B.; Ganesan, A. Org. Lett. 2003, 5,
2825-2827. (b) Hewitt, P. R.; Cleator, E.; Ley, S. V. Org. Biomol. Chem.
2004, 2, 2415-2417.
(13) Kramer, G. W.; Brown, H. C. J. Organomet. Chem. 1977, 132,
9-27.
(5) Sala, F.; Mulet, J.; Reddy, K. P.; Bernal, J. A.; Wikman, P.; Valor,
L. M.; Peters, L.; Ko¨nig, G. M.; Criado, M.; Sala, S. Neurosci. Lett. 2005,
373, 144-149.
(6) Peters, L.; Ko¨nig, G. M.; Wright, A. D.; Pukall, R.; Stackebrandt,
E.; Eberl, L.; Riedel, K. Appl. EnViron. Microbiol. 2003, 69, 3469-3475.
(7) Kawasaki, T.; Terashima, R.; Sakaguchi, K.; Sekiguchi, H.; Sakamoto,
M. Tetrahedron Lett. 1996, 37, 7525-7528.
(8) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677-680.
(9) (a) Nakagawa, M.; Yoshikawa, K.; Hino, T. J. Am. Chem. Soc. 1975,
97, 6496-6501. (b) Bosch, J.; Roca, T.; Armengol, M.; Ferna´ndez-Forner,
D. Tetrahedron 2001, 57, 1041-1048.
(14) (a) Mayr, H.; Halberstadt-Kausch, I. K. Chem. Ber. 1982, 115,
3479-3515. (b) Crandall, J. K.; Keyton, D. J.; Kohne, J. J. Org. Chem.
1968, 33, 3655-3657.
(15) (a) Wulff, P.; Carle´, J. S.; Christophersen, C. Comp. Biochem.
Physiol. 1982, 71b, 523-524. (b) For a recent synthesis of debrominated
flustrabromine, see: Zhun, I. V.; Ignatenko, A. V. Russ. Chem. Bull. 2004,
53, 2221-2223.
(16) The solvent mixture had been used for the dibromination of
tryptamine affording a mixture of three regioisomers: Miyake, F. Y.;
Yakushijin, K.; Horne, D. A. Org. Lett. 2004, 6, 711-713.
284
Org. Lett., Vol. 9, No. 2, 2007

chlorinated, as shown in structure 7. This was supported by
downfield shift (δ 322 ppm compared to δ 127 ppm). This
is due to the formation of a 3-chloroindolenine partial struc-
ture with an imine nitrogen.
1
a H,15N HMBC experiment revealing δN 105 ppm for the
side chain and 127 ppm for the indole nitrogen (CDCl3,
referenced to δ(NH3) 0 ppm). In comparison to compound
1, the signal of the indole nitrogen had shifted by only 0.1
ppm, and the chlorinated side chain nitrogen exhibited a
downfield shift of about 75 ppm.
On standing in CDCl3, we observed cyclization and
rearrangement of 7 to protonated compound 10 which was
also characterized by 2D NMR. Deprotonation of 10 on
treatment with 2 N NaOH afforded flustramine C (2) in 60%
overall yield. Mechanistically, the reaction of 7 could
commence with intra- or intermolecular chlorination of the
indole 3-position affording chloroindolenine 8 which loses
chloride-forming cation 9.1,5 Sigmatropic rearrangement
would then yield protonated flustramine C (2).
Over days in CDCl3 at room temperature, chloroindolenine
11 reacted to give a mixture of compounds among which
the protonated forms of 5-chloroflustramine C (12) and
flustramine C were the major components. After treatment
with 2 N NaOH, 5-chloroflustramine C (13, 30%) and
flustramine C (2, 25%) were isolated. As an intermediate,
N-chlorotrialkylammonium cation 14 is possible. It is known
that N-chlorotrialkylammonium salts are selective agents for
the chlorination of aromates.18
The synthesis of flustramine C was substantially improved
by replacing t-BuOCl with 1 equiv of NBS, providing 2 in
an isolated yield of 90% (Scheme 4). No brominated side
N-Chlorinated intermediate 7 was always accompanied by
a minor side product (1:4) which was formed exclusively
when 2 equiv of t-BuOCl was employed. On the basis of
ESI(+)HRMS and NMR spectra, we found that dichlorinated
compound 11 (Scheme 3) was generated. Whereas the 15N
Scheme 4. Most Efficient Conversion of
Deformylflustrabromine (1) to Flustramine C (2)
Scheme 3. Conversion of Deformylflustrabromine (1) to
5-Chloroflustramine C (13) by Treatment with 2 equiv of
a
t-BuOCl/NEt3
product was formed. In this case, we were not able to isolate
any intermediate of the reaction pathway. Thus, initial
formation of a 3-bromoindolenine without side chain bro-
mination may also be possible.
The biosynthesis of flustramine C and dihydroflustramine
C (17) in Flustra foliacea has never been investigated.
However, biosynthesis of prenylated indole alkaloids in
general has been the subject of intense investigation.19 It is
discussed (a) where and how inverse or direct prenyl groups
are initially introduced and (b) if and how migrations of
inverse or direct prenyl groups may proceed. In this paper,
we give an example of possible biomimetic chemistry
regarding the latter part.
Starting from the natural product 15,15a Scheme 5 outlines
three possible pathways. Following a classical proposal, aza-
Claisen rearrangement of an N-prenylated precursor (16, path
A) could occur. Alternatively, direct introduction of an
inverse prenyl group by SN2′ reaction at C3 may occur (path
B), without the involvement of inverse prenylation at C2,
as proposed by Harrison for the biosynthesis of roquefort-
ine.20 Inverse prenyl groups at C3 may also arise via a 1,2-
shift from C2 (path C), as proposed by Barrow21 and by
1
a Intermediate 11 was characterized by H,15N HMBC.
NMR chemical shift of the side chain nitrogen is close to
the case of N-chlorinated compound 7 (δ 101 ppm compared
to δ 105 ppm), the indole nitrogen experienced a pronounced
(18) (a) Smith, J. R. L.; McKeer, L. C.; Taylor, J. M. J. Chem. Soc.,
Perkin Trans. 2 1987, 1533-1537. (b) Smith, J. R. L.; McKeer, L. C.;
Taylor, J. M. J. Chem. Soc., Perkin Trans. 2 1988, 385-391.
(19) For a review on the biosynthesis of tryptophan-derived prenylated
alkaloids, see: Williams, R. M.; Sanz-Cervera, J. F.; Stocking, E. In Top.
Curr. Chem.; Leeper, F., Vederas, J.C., Eds.; Springer-Verlag: Berlin, 2000;
Vol. 209, pp 97-173.
(20) (a) Bhat, B.; Harrison, D. M.; Lamont, H. M. J. Chem. Soc., Chem.
Commun. 1990, 1518-1519. (b) Bhat, B.; Harrison, D. M.; Lamont, H. M.
Tetrahedron 1993, 49, 10663-10668.
(17) In the crystal, the E-rotamer of 6 occurs, and in solution, both
rotamers are present in almost equal percentages. CCDC-270034 (6) contains
the supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam. ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB21EZ, UK; fax (+44) 1223-336-033 or deposit@
ccdc.cam.ac.uk).
Org. Lett., Vol. 9, No. 2, 2007
285

shift of a nonfunctionalized inverse prenyl group from the
indole 2-position to the 3-position. Surprisingly, few 1,2-
prenyl shifts have been exploited for the total syntheses of
indole alkaloids. Successful reactions include acid-induced
rearrangements of N-prenylated indoles to varying mixtures
of 2-inversely and 2-directly prenylated indoles,25 of a
3-prenylated pyrrolo[2,3-b]indole to a 2-prenylated indole
under ring opening,26 and of a 3-prenylated indole to a 1:9
mixture of inversely and directly 2-prenylated indoles.27 In
the absence of the C2-C3 double bond, acid-catalyzed aza-
Claisen rearrangement of inversely N-prenylated indoles
resulted in 7-prenylation.28
Scheme 5. Possible Biogenetic Pathways toward
Dihydroflustramine C (17) and Flustramine C (2), Starting from
the Natural Product 15
Our novel approach to flustramine C (2) is quite efficient
(five steps, 38% yield starting from Nb-methyltryptamine (4)).
Acknowledgment. This work was funded in part by the
BMBF (Bonn, Germany, grant 03F0254A) and the BASF
AG (Ludwigshafen).
Supporting Information Available: Detailed experi-
mental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0627348
(22) Gorst-Allman, C. P.; Steyn, P. S.; Vleggaar, R. J. Chem. Soc., Chem.
Commun. 1982, 652-653.
(23) (a) Stocking, E. M.; Sanz-Cervera, J. F.; Williams, R. M. Angew.
Chem., Int. Ed. 1999, 38, 786-789. (b) Stocking, E. M.; Williams, R. M.;
Sanz-Cervera, J. F. J. Am. Chem. Soc. 2000, 122, 9089-9098.
(24) For examples, see: (a) Williams, R. M.; Cao, J.; Tsujushima, H.;
Cox, R. J. J. Am. Chem. Soc. 2003, 125, 12172-12178. (b) Cushing, T.
D.; Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 1996, 118,
557-579. (c) Stoermer, D.; Heathcock, C. H. J. Org. Chem. 1993, 58, 564-
568.
Gorst-Allman22 for the biosynthesis of roquefortine and by
Williams for paraherquamide A.23
Our investigation shows that, from a chemical perspective,
the biogenesis of flustramine C (2) may indeed proceed via
inverse prenylation of the indole 2-position (path C) in an
oxidative process.
Beyond ring contractions of carbazole derivatives,24 the
conversion of 1 to 2 is the first chemically achieved 1,2-
(25) (a) Casnati, G.; Marchelli, R.; Pochini, A. J. Chem. Soc., Perkin
Trans. 1 1970, 754-757. (b) Cardoso, A. S.; Lobo, A. M.; Prabhakar, S.
Tetrahedron Lett. 2000, 41, 3611-3613.
(26) Muthusubramanian, P.; Carle´, J. S.; Christophersen, C. Acta Chem.
Scand. B 1983, 37, 803-807.
(27) Plate, R.; Ottenheijm, H. C. J. Tetrahedron Lett. 1986, 27, 3755-
3758.
(21) Barrow, K. D.; Colley, P. W.; Tribe, D. E. J. Chem. Soc., Chem.
Commun. 1979, 225-226.
(28) Roe, J. M.; Webster, R. A. B.; Ganesan, A. Org. Lett. 2003, 5,
2825-2827.
286
Org. Lett., Vol. 9, No. 2, 2007