The asymmetric synthesis and stereochemical assignment of chelonin B

Article abstract of DOI:10.1016/S0040-4039(01)01555-6

The first total synthesis of the marine natural product (S)-(+)-chelonin B is described. The key reactions employed include Sharpless asymmetric dihydroxylation of a styrene derivative, catalytic ring-opening of an epoxide and sequential deprotection-rearrangement of a phthalimido indole acetate.

Full text of DOI:10.1016/S0040-4039(01)01555-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7671–7674
The asymmetric synthesis and stereochemical assignment of
chelonin B
Nicholas J. Lawrence* and Simon M. Bushell
Department of Chemistry, University of Manchester Institute of Science and Technology, PO Box 88,
Manchester M60 1QD, UK
Received 12 July 2001; revised 7 August 2001; accepted 23 August 2001
Abstract—The first total synthesis of the marine natural product (S)-(+)-chelonin B is described. The key reactions employed
include Sharpless asymmetric dihydroxylation of a styrene derivative, catalytic ring-opening of an epoxide and sequential
deprotection–rearrangement of a phthalimido indole acetate. © 2001 Elsevier Science Ltd. All rights reserved.
The aromatic alkaloid chelonin B (1a) was isolated by
Faulkner and Bobzin from the purple dendritic sponge
Chelonaplysilla sp., collected from a marine lake on
Kaibaku Island, Palau.1 The structure of chelonin B
(Fig. 1) was revealed by both high resolution mass
(both by Somei and co-workers) but each in racemic
form.
A useful strategy for the synthesis of 1,2-amino alco-
hols emerged from our study6 of pyridine bis(oxazoline)
catalyzed asymmetric reduction of ketones.7 Our
approach to chelonin B incorporating this strategy
involves the formation of bond a via epoxide ring-open-
ing and bond b by intramolecular O“N acyl transfer.
1
measurement and H and 13C NMR techniques.2 The
specific rotation for chelonin B was never recorded and
the stereochemistry of chelonin B depicted in the origi-
nal paper was arbitrary.3 Chelonin B possesses anti-
microbial activity.
Sharpless dihydroxylation of the substituted styrene 3
(prepared by Wittig methylenation of the commercially
available benzaldehyde 2) using the (DHQ)2PHAL lig-
and gave the diol 4 (Scheme 1). The conditions used
can be reasonably and reliably expected to produce the
S enantiomer, as shown.8
Chelonin B has not yet been prepared by asymmetric
synthesis. A total synthesis would serve two purposes.
Firstly, greater quantities of chelonin B and related
derivatives would become available for further biologi-
cal evaluation and secondly the stereochemistry of the
natural product would be assigned.
Despite much effort we were unable to develop a
convenient analytical HPLC method for separation of
the enantiomers of the diol 4. Nevertheless we were
The chelonin indole alkaloids have received surprisingly
very little attention. Only the natural products bromo-
chelonin B (1b)4 and chelonin A5 have been prepared
HO
H
N
H
N
b
a
H
N
OMe
O
MeO
Br
N
H
OMe
R
OMe
Chelonin B 1a R = H
Bromochelonin B 1b R = Br
Chelonin A
Figure 1. Chelonin alkaloids from Chelonaplysilla sp.
Keywords: asymmetric dihydroxylation; oxiranes; phthalimide; natural products.
* Corresponding author. Present address: Department of Chemistry, Cardiff University, PO Box 912, Cardiff, CF10 3TB, UK. Tel.:+44 (0)29 2087
4000, ext. 7109; fax: +44 (0)29 2087 4030; e-mail: lawrencenj1@cardiff.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01555-6

7672
N. J. Lawrence, S. M. Bushell / Tetrahedron Letters 42 (2001) 7671–7674
OH
O
O
H
O
HO
g
e, f
a
b,c,d
H
N
OH
(70%)
MeO
(88%)
(96%)
(90%)
MeO
MeO
MeO
MeO
O
Br
Br
4 (96% e.e.)
Br
5 (96% e.e.)
Br
2
Br
6 (99% e.e.)
3
Scheme 1. Reagents and conditions: (a) Ph3PMeBr (1.1 equiv.), n-BuLi (1.1 equiv.), THF, 0°C to rt, 1 h; (b) K3Fe(CN)6 (3 equiv.),
K2OsO4·2H2O (0.2 mol%), (DHQ)2PHAL (1 mol%), H2O/tert-BuOH (1:1, v/v), 0°C, 4 h; (c) rt, 0.5 h; (d) Na2SO3 (excess), 0°C,
1 h; (e) TMSCl (1.3 equiv.), MeC(OMe)3, CH2Cl2, 40°C to rt, 1 h; (f) K2CO3 (1.5 equiv.), MeOH, rt, 2 h; (g) phthalimide (1.1
equiv.), potassium phthalimide (5 mol%), DMF, 90°C, 18 h.
confident that the enantiomeric excess was high and
could be determined later in the synthetic sequence.
Transformation of the (S)-diol 4 into the corresponding
enantiomerically enriched (S)-isomer of oxirane 5 was
achieved in 90% chemical yield, according to the
method of Sharpless and co-workers.9 Fortunately, we
were able to determine accurately the enantiopurity of
the oxirane 5 (e.e. 96% by HPLC), so we can be certain
that the enantiomeric excess of the diol 4 was at least
96%.10
The indole acetyl group was then introduced via reac-
tion of the C-1 hydroxyl group with inexpensive indole-
3-acetic acid (Scheme 3). This was achieved efficiently
by treatment of a 1:1 mixture of the alcohol 6 and
indole-3-acetic acid with 1 equiv. of DCCI, in the
presence of DMAP (5 mol%).14 Treatment of the ester
7 with hydrazine monohydrate,15 in refluxing iso-
propanol for 12 h, furnished the optically active amide
(S)-8 in 74% yield. It was clear that under these reac-
tion conditions the desired O“N acyl transfer had also
1
taken place. The NH and OH signals in the H NMR
Introduction of the nitrogen atom at C-2 was achieved
by reaction of the oxirane 5 with phthalimide. The use
of potassium phthalimide alone was very inefficient and
resulted in very poor yields of 6. Presumably the alkox-
ide 7, generated from the ring-opening process, is suffi-
ciently nucleophilic to also react with the oxirane itself.
We were keen to avoid the use of Lewis acids to
catalyse the reaction, as the benzylic position of 6 is
somewhat sensitive to racemization. We soon found
that the ideal conditions for the transformation 5“6
involved the use of catalytic potassium phthalimide (5
mol%) in hot DMF. The alkoxide 7, generated upon
oxirane ring-opening in the presence of phthalimide,
simply regenerates the potassium phthalimide, as illus-
trated in Scheme 2.11 The acidity of these species, of
course, supports this cycle (pKa phthalimide 13.4;12
pKa secondary alcohol13 (propan-2-ol) 30 (measured in
DMSO)).
spectrum of 8 appeared as a triplet (l 7.80 ppm, J 6.0
Hz, 1H) and singlet (l 3.32 ppm, 1H), respectively. The
signal for the benzylic proton (t, J 5.7 Hz, 1H) at C-1
was observed at l 4.52 ppm, significantly upfield of the
benzylic signal of the starting material (l 6.06 ppm).
Unequivocal proof that the O“N acyl transfer had
taken place was provided by the X-ray crystal structure
of 8 (Fig. 2). This also established, without doubt, that
the absolute configuration of the C-1 chiral centre of 8
was indeed S, as expected from the initial Sharpless
dihydroxylation reaction.
Finally, the chemoselective BH3·SMe2 reduction of 8,
using a protocol developed by Bussolari and co-work-
ers,16 in refluxing THF, furnished the target natural
product 1a in 62% yield. HPLC analysis revealed that
the enantiomeric excess of the sample was 97%, thus
allaying our fears concerning the possible loss of stereo-
H
O
O
N
5
MeO
Br
O
MeO
7
N
+
O
O
+
K
K
O
Br
(5 mol%)
O
H N
O
O
HO
(110 mol%)
N
O
6
MeO
Br
Scheme 2. Phthalimide oxirane ring-opening with catalytic potassium phthalimide.

N. J. Lawrence, S. M. Bushell / Tetrahedron Letters 42 (2001) 7671–7674
7673
O
O
h
HN
HO
O
O
N
(92%)
N
O
MeO
O
MeO
7 (98% e.e.)
6
Br
Br
(74%)
i
HO
H
N
H
N
OH
j,k,l
(62%)
NH
NH
O
MeO
MeO
Br
Br
(S)-(+)-Chelonin B 1a (97% e.e.)
8 (98% e.e.)
Scheme 3. Reagents and conditions: (h) indole-3-acetic acid (1 equiv.), DCCI (1 equiv.), 4-DMAP (5 mol%), CH2Cl2/THF (1:1,
i
v/v), rt, 16 h; (i) H2NNH2 (1.5 equiv.), PrOH, reflux, 12 h; (j) BH3·SMe2 (2 equiv.), THF, reflux, 20 min; (k) MeOH, rt, 2 min;
(l) HCl (aq.), 0°C, 30 min.
References
1. Bobzin, S. C.; Faulkner, D. J. J. Nat. Prod. 1991, 54,
225–232.
2. Bobzin, S. C.; Faulkner, D. J. J. Org. Chem. 1991, 56,
4403–4407.
3. D.J. Faulkner, personal communication.
4. Hasegawa, M.; Yamada, K.; Nagahama, Y.; Somei, M.
Heterocycles 1999, 51, 2815–2821.
5. Somei, M.; Aoki, K.; Nagahama, Y.; Nakagawa, K.
Figure 2. ORTEP representation of the X-ray crystal struc-
Heterocycles 1995, 41, 5–8.
ture of amide 8.
6. Bushell, S. M. Ph.D. Dissertation, UMIST, Manchester,
UK, 2000.
chemical integrity over the final three transformations.
The H NMR spectrum of the sample was identical to
that of the natural product. HPLC analysis of a sample
of the authentic natural product and the synthetic
material showed that they were of the same stereochem-
ical configuration. Indeed no (R)-chelonin B could be
detected in the sample of the natural product.
1
7. Lawrence, N. J.; Bushell, S. M. Tetrahedron Lett. 2000,
41, 4507–4512.
8. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-
L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L.
J. Org. Chem. 1992, 57, 2768–2771.
9. Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48,
10515–10530.
In conclusion, we have developed a concise synthesis of
chelonin B and assigned its absolute stereochemistry.
We believe that the approach will be applicable to
many other important classes of 1,2-amino alcohol
derivatives.
10. Enantiomeric excesses throughout were determined by
HPLC: Conditions and retention times: 5: Chiralpak
AS column, 95:5 hexane:2-propanol, 0.5 cm3 min−1
;
13.53 (R) and 14.31 (S); 6: Chiralcel OD column, 9:1
hexane:2-propanol, 1.0 cm3 min−1; 26.58 (S) and 14.31
(R); 1a: Chiralcel OJ column, 65:35 hexane:2-propanol,
1.0 cm3 min−1; 26.32 (R) and 38.40 (S).
Acknowledgements
11. (a) The use of catalytic amount of potassium phthal-
imide in this manner is rare, but has been used by
Mosher and co-workers to ring-open without comment,
see: Williams, T. M.; Crumbie, R.; Mosher, H. S. J.
Org. Chem. 1985, 50, 91–97; (b) The catalytic cycle is
similar in concept to that involved in the base-catalysed
addition of alkynes to carbonyl compounds recently
described by Babler and co-workers; see: Babler, J. H.;
Liptak, V. P.; Phan, N. J. Org. Chem. 1996, 61, 416–
417.
We thank Professor John Faulkner (Scripps Inst.) for
kindly providing a sample of natural chelonin B. We
also thank the EPSRC for a studentship (Catalysis and
Catalytic Processes Programme; GR/L57906 to SMB)
and Research Grants (GR/L52246: NMR spectrometer;
GR/L84391: chromatographic equipment) and the
Chemical Database Service at Daresbury. We thank
Dr. Robin Pritchard and Mr. John Warren of the
X-ray crystal structure laboratory at UMIST, for
obtaining the X-ray structure of the amide 8.

7674
N. J. Lawrence, S. M. Bushell / Tetrahedron Letters 42 (2001) 7671–7674
12. Koppel, I.; Koppel, J.; Degerbeck, L. G.; Ragnarson, U.
J. Org. Chem. 1991, 56, 7172–7174.
1978, 17, 522–524.
15. Tsuge, O.; Tanaka, J.; Kanemasa, S. Bull. Chem. Soc.
13. Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org.
Jpn. 1985, 58, 1991–1999.
Chem. 1980, 45, 3295–3299.
14. Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl.
16. Bussolari, J. C.; Rehborn, D. C.; Combs, D. W. Tetra-
hedron Lett. 1999, 40, 1241–1244.