Diastereoselective cationic tandem cyclizations to N-heterocyclic scaffolds: Total synthesis of (-)-dysibetaine PP

Article abstract of DOI:10.1021/ol052598r

Herein, we report a short and diastereoselective synthesis of the natural product (-)-dysibetaine PP. The key step in the synthetic sequence is a novel highly diastereoselective tandem-cyclization reaction of an enantiomerically pure dipeptide. This cyclization methodology is applied in the synthesis of a broader range of N-heterocyclic scaffolds.

Full text of DOI:10.1021/ol052598r

ORGANIC
LETTERS
2006
Vol. 8, No. 2
239-242
Diastereoselective Cationic Tandem
Cyclizations to N-Heterocyclic
Scaffolds: Total Synthesis of
(−)-Dysibetaine PP
Denis R. IJzendoorn, Peter N. M. Botman, and Richard H. Blaauw*
Chiralix B.V., P.O. Box 31070, 6503 CB Nijmegen, The Netherlands
richard.blaauw@chiralix.com
Received October 26, 2005
ABSTRACT
Herein, we report a short and diastereoselective synthesis of the natural product (−)-dysibetaine PP. The key step in the synthetic sequence
is a novel highly diastereoselective tandem-cyclization reaction of an enantiomerically pure dipeptide. This cyclization methodology is applied
in the synthesis of a broader range of N-heterocyclic scaffolds.
(-)-Dysibetaine PP is a natural product that has been recently
isolated from the Micronesian sponge Dysidea herbacea.1
Its tricyclic dipeptidyl betaine structure contains an unusual
quaternized N,N-acetal motif, making it an interesting target
for total synthesis.2 To approach this particular structural
arrangement, we chose L-allysine ethylene acetal (1) as a
starting material. This unnatural amino acid has already
proven to be a versatile chiral building block for the
preparation of various pipecolic acid derivatives and natural
products.3 We envisaged that a tandem-cyclization strategy
as outlined in Scheme 1, could provide an entry to the
required N,N-acetal moiety.4,5 Treatment of L-allysine eth-
ylene acetal-derived dipeptides (2) with a catalytic amount
of a protic acid, should activate the masked aldehyde and
invoke the first cyclization. Then, upon elimination of the
ethylene glycol moiety an N-acyliminium ion (3) is gener-
ated,6 which can be trapped by the second amine present in
the molecule forming the desired byclic N,N-acetals (4).
This paper details the results of our studies on the scope,
limitations and diastereoselectivity of the cationic tandem-
cyclization strategy, leading to a broad range of enantio-
merically pure N-heterocyclic scaffolds. Finally, the devel-
oped methodology is successfully applied in the first total
synthesis of the natural product (-)-dysibetaine PP.
To investigate the scope and selectivity of the tandem-
cyclization strategy, we initially focused on dipeptides
composed of L-allysine ethylene acetal and different R-amino
acids. Cyclization precursors 7a-i were synthesized by a
BOP/DIPEA-mediated coupling of methyl ester 5 with a
(1) Sakai, R.; Suzuki K.; Shimamoto, K.; Kamiya, H. J. Org. Chem.
2004, 69, 1180.
(2) Baker, D. D.; Alvi, K. A. Curr. Opin. Biotech. 2004, 15, 576.
(3) (a) Botman, P. N. M.; Dommerholt, F. J.; de Gelder, R.; Broxterman,
Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett.
2004, 6, 4941. (b) Wijdeven, M. A.; Botman, P. N. M.; Wijtmans, R.;
Schoemaker, H. E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett. 2005, 7,
4005.
(4) For previous work in this area, see: (a) Mizutani, N.; Chiou, W.-H.;
Ojima, I. Org. Lett. 2002, 4, 4575. (b) Vink, M. K. S.; Schortinghuis, C.
A.; Mackova-Zabelinskaja, A.; Fechter, M.; Pochlauer, P.; Castelijns, A.
M. C. F.; van Maarseveen, J. H.; Hiemstra, H.; Griengl, H.; Schoemaker,
H. E.; Rutjes, F. P. J. T. AdV. Synth. Catal. 2003, 345, 483. (c) Katritzky,
A. R.; He, H.-Y.; Wang, J. J. Org. Chem. 2002, 67, 4951.
(5) For approaches to N,N-acetals on solid support, see: (a) Nielsen, T.
E.; Le Quement, S.; Meldal, M. Org. Lett. 2005, 7, 3601. (b) Rinnova´, M.;
Nefzi, A.; Houghten, R. A. Tetrahedron Lett. 2002, 43, 2343.
(6) For recent reviews on N-acyliminium ion chemistry, see: (a)
Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C.
A. Chem. ReV. 2004, 104, 1431. (b) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817.
10.1021/ol052598r CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/15/2005

the smooth formation of N,N-acetal 8a in a yield of 82%
(entry 1). The cyclization product was obtained as a 5:1
mixture of diastereomers, of which the major isomer proved
to be the depicted C5-C8a trans-isomer.
Scheme 1. Tandem-Cyclization Strategy
In the cyclizations of dipeptides 7b and 7c, bearing
L-alanine and D-alanine, respectively, a pronounced influence
of the stereochemistry of the amino acid side chain was
observed (entries 2 and 3). The dipeptide containing the
natural antipode (7b) yielded bicyclic product 8b with an
excellent selectivity of 15:1, again in favor of the C5-C8a
trans-isomer. However, the D-alanine-containing dipeptide
7c cyclized to a 2:1 mixture of diastereomers, albeit still with
the trans-isomer in excess. In these two particular examples,
the diastereomers were separated by preparative HPLC in
order to unequivocally determine the relative stereochemistry
of the N,N-acetal products by 2D NMR analysis.8
The same side-chain influence was observed when the
tandem cyclizations were performed with dipeptides 7d-i
containing the two enantiomers of valine (entries 4 and 5),
phenylalanine (entries 6 and 7), and allylglycine (entries 8
and 9), respectively. The products of the L,L-dipeptides were
formed with consistently high diastereoselectivities, whereas
the reactions with the D,L-dipeptides were much less selec-
tive. Although the diastereomers of products 8d-i were not
variety of N-Cbz-protected R-amino acids (6a-i) in an
average overall yield of 70-80% (Table 1).7 Treatment of
Table 1. Tandem Cyclizations of R-Amino Acid-Based
Dipeptides
1
separated, the H NMR spectra closely resembled those of
products 8b and 8c, allowing the determination of the
stereochemistry by comparison. Especially the chemical shift
of the C5-proton, adjacent to the methyl ester, proved to be
characteristic for the two diastereomers. For the C5-C8a
trans-isomers this proton resonated at approximately 5.0
ppm, whereas in the C5-C8a cis-isomers the proton signal
was found at about 4.0 ppm. This difference in chemical
shift was observed for all products 8. Finally, the Cbz
protective groups of the cyclized products 8 could easily be
removed under acidic conditions yielding the corresponding
amines 9 as the corresponding HBr salts.
We now turned our attention to the tandem-cyclizations
of â-amino acid-containing dipeptides. To this end, methyl
ester 5 was coupled to both the enantiomers of N-Cbz-â3-
phenylalanine, using the same protocol as for the synthesis
of peptides 7a-i. In this way, cyclization precursors 10a
and 10b were obtained (Scheme 2). Activation of the acetal
yield A yield B
dr
yield
entry amino acid R1
(%)
(%)
(trans/cis)b C (%)
1
2
3
4
5
6
7
8
9
Gly (6a)
L-Ala (6b)
D-Ala (6c)
L-Val (6d)
D-Val (6e)
L-Phe (6f)
D-Phe(6g)
H
70
72
75
69
72
79
78
72
76
82
79
76
76
80
87
88
78
70
5:1
15:1c
2:1c
9:1
4:1d
13:1
1:1
99
e
e
97
84
95f
95
83
81
Me
Me
iPr
iPr
Bn
Bn
Scheme 2. Cyclizations of â-Amino Acid-Containing
Dipeptides
L-Alga(6h) allyl
15:1
1:1d
D-Alga (6i) allyl
a Alg ) allylglycine. b Determined by HPLC analysis of the crude
reaction mixtures. c Diastereomers were separated by preparative HPLC.
d Determined by 1H NMR of the crude reaction mixture. e Deprotection not
performed. f Deprotected by treatment with H2 over Pd/C.
dipeptide 7a, bearing glycine as the second amino acid, with
a catalytic amount of TsOH in refluxing toluene resulted in
with TsOH initiated the formation of N,N-acetals 11a and
11b respectively, both in 84% yield.
(7) Compound 5 was used crude after N-protection (Cbz-OSu), O-
methylation (MeI), and N-deprotection (Pd/C, H2) of L-allysine ethylene
acetal (1) according to ref 3a. The amino acids 6a-i were used crude after
N-protection (Cbz-OSu, dioxane, aqueous NaOH).
(8) For more details, see the Supporting Information.
240
Org. Lett., Vol. 8, No. 2, 2006

The selectivity of these reactions proved to be excellent.
The (S)-â3-phenylalanine-containing product 11a was iso-
lated with a diastereomeric ratio of 19:1, while the (R)-â3-
phenylalanine-containing counterpart 11b was formed as a
single diastereomer (>99:1).9 In both cases, the depicted
C5-C8a trans-isomer was formed, as determined by NMR
studies. Furthermore, the stereochemical assignment was
unequivocally proven by the crystal structure determination
of Cbz-deprotected product 12b (Figure 1).
by changing the cyclization conditions to BF3‚OEt2 (1.6
equiv) in CH2Cl2 at lower temperature, which resulted in
the efficient formation of tricyclic product 14. The N,N-acetal
was isolated as a 4:1 mixture of diastereomers, which could
be separated by preparative HPLC. Again, the major isomer
was determined to be the C5-C8a trans-isomer by NMR
studies.
To probe whether the cyclization methodology could be
extended to C-C-bond formation, precursor 17 was prepared
by coupling of 5 with indolyl derivative 1610 (Scheme 4).
Scheme 4. Intramolecular C-C Bond Formation
Figure 1. Chem3D representation of the crystal structure of 12b.
To further investigate the scope of the tandem-cyclization
strategy, precursor 13 was prepared by coupling of 5 with
anthranilic acid (Scheme 3). Cyclization of 13 under the
Scheme 3. Cyclization of an Anthranilic Acid-Based
Dipeptide
As with the anthranilic acid-based precursor, cyclization with
TsOH (10 mol %) in toluene at reflux did not lead to a
satisfactory result. However, when the reaction was per-
formed in neat TFA the desired tetracyclic product 18 was
obtained in 61% yield as an 80:1 mixture of diastereomers
(HPLC). In sharp contrast to all previous examples, in this
case, the major diastereomer was determined to be the
depicted C5-C8a cis-isomer.
With the tandem-cyclization methodology in hand, we now
turned our attention to the total synthesis of the natural
product (-)-dysibetaine PP (Scheme 5). It was envisaged
that tandem cyclization of dipeptide 20, constructed from
L-allysine ethylene acetal methyl ester 5 and (S)-N-Cbz-2-
amino-5-hexenoic acid 21,11 would provide N,N-acetal 19
efficiently and with good diastereoselectivity. This interme-
diate could then be converted to the required tricyclic
skeleton by ozonolysis and a subsequent reductive cycliza-
tion, after which the natural product should be readily
obtainable.
Consequently, dipeptide 20 was prepared using the same
protocol as for all previous cyclization precursors. Gratify-
ingly, treatment of 20 with a catalytic amount of TsOH in
standard conditions (cat. TsOH, toluene, reflux) suffered
severely from oxidation of the anticipated product, leading
to a nearly 1:1 mixture of desired product 14 and side product
15. Even when the reaction was carried out under an
atmosphere of argon, the formation of 15 could not be
suppressed. However, this problem could be circumvented
(10) Horwell, D. C.; Naylor, D.; Willems, H. M. G. Bioorg. Med. Chem.
Lett. 1997, 7, 31.
(11) (a) For the synthesis of (S)-2-amino-5-hexenoic acid, see: Wolf,
L. B.; Sonke, T.; Tjen, K. C. M. F.; Kaptein, B.; Broxterman, Q. B.;
Schoemaker, H. E.; Rutjes, F. P. J. T. AdV. Synth. Catal. 2001, 343, 662.
(b) Allevi, P.; Anastasia, M. Tetrahedron: Asymmetry 2003, 14, 2005.
(9) Only one diastereomer of 11b could be detected by HPLC.
Org. Lett., Vol. 8, No. 2, 2006
241

Scheme 5. Retrosynthetic Approach toward (-)-Dysibetaine
Scheme 6. Total Synthesis of (-)-Dysibetaine PP
PP
refluxing toluene, resulted in a very smooth cyclization to
afford bicyclic N,N-acetal 19 (Scheme 6). The product was
obtained as a 10:1 mixture of diastereomers in favor of the
desired C5-C8a trans-isomer, which was in good agreement
with the results obtained with other L,L-dipeptides (Table
1). Next, the olefinic side chain of 19 was subjected to an
ozonolysis reaction, yielding aldehyde 21 in a virtually
quantitative yield. Subsequent treatment of 21 with Pd/C
under an atmosphere of hydrogen not only effected the
removal of the Cbz protecting group but also the concomitant
intramolecular reductive amination, yielding very efficiently
the tricyclic product 22. The final steps of the synthesis
involved the stereoselective quaternization of the amine by
treatment with methyl iodide followed by the formation of
the inner salt via saponification of the methyl ester, affording
the natural product (-)-dysibetaine PP in a yield of 82%
over the last three steps.
diastereoselectivity of the tandem cyclizations are currently
in progress.
Acknowledgment. Dr. Rene´ de Gelder (Radboud Uni-
versity Nijmegen, NL) is kindly acknowledged for the
determination of the crystal structure of 12b. Dr. Bernard
Kaptein (DSM Research, Geleen, NL) is thanked for the
generous gift of (R)-â3-phenylalanine. SenterNovem (Min-
istry of Economic Affairs, The Netherlands) is gratefully
acknowledged for providing financial support.
In conclusion, we have developed a diastereoselective
cationic tandem-cyclization strategy for the preparation of a
diverse range of N-heterocyclic scaffolds. This versatile
method allows the conversion of L-allysine ethylene acetal-
containing dipeptides to densely functionalized N,N-acetals.
The tandem-cyclization reaction was successfully applied as
the key step in the first total synthesis of the natural product
(-)-dysibetaine PP. Investigations into the origin of the
Supporting Information Available: Experimental details
and spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL052598R
242
Org. Lett., Vol. 8, No. 2, 2006