Progress toward the total synthesis of callipeltin A (I): Asymmetric synthesis of (3S,4R)-3,4-dimethylglutamine

Article abstract of DOI:10.1021/ol006679t

(equation presented) During the total synthesis of the novel cyclic depsipeptide callipeltin A (1), the unit (3S,4R)-3,4-dimethylglutamine, was successfully synthesized by asymmetric Michael addition and subsequent electrophilic azidation. The key feature of this approach is the generation of three adjacent stereogenic centers using the same camphorsultam chiral auxiliary.

Full text of DOI:10.1021/ol006679t

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4157-4160
Progress toward the Total Synthesis of
Callipeltin A (I): Asymmetric Synthesis
of (3S,4R)-3,4-Dimethylglutamine
,†
Bo Liang,† Patrick J. Carroll,§ and Madeleine M. Joullie´*
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
mjoullie@sas.upenn.edu
Received October 2, 2000
ABSTRACT
During the total synthesis of the novel cyclic depsipeptide callipeltin A (1), the unit (3S,4R)-3,4-dimethylglutamine, was successfully synthesized
by asymmetric Michael addition and subsequent electrophilic azidation. The key feature of this approach is the generation of three adjacent
stereogenic centers using the same camphorsultam chiral auxiliary.
Cyclic depsipeptides have emerged as a very important class
of bioactive compounds from marine natural products.1 In
1996, Minale et al. reported the isolation of three new cyclic
depsipeptides, callipeltins A (1), B (2), and C2 (Figure 1),
from a shallow water sponge Callipeltin sp. These com-
pounds showed marked activity in cytotoxic assays against
KB and P388 cells and in anti-HIV and antifungal tests. The
structures of the callipeltins were determined by interpretation
of spectral data, chemical degradation, and evaluation of the
amino acids obtained by acid hydrolysis. In our efforts to
synthesize a series of bioactive cyclic depsipeptides, we chose
callipeltin A (1) as a target due to its interesting anti-HIV
properties and its novel amino acid residues: â-methoxy-
tyrosine (â-OMeTyr), (2R,3R,4S)-4-amino-7-guanidino-2,3-
dihydroxy heptanoic acid (AGDHE), and (3S,4R)-3,4-
dimethyl-L-glutamine. En route to a total synthesis of
callipeltin A (1), we developed a novel chiral auxiliary-
controlled asymmetric synthesis of (3S,4R)-3,4-dimethyl-
glutamine.
We envisioned that the erythro-3,4-dimethyl groups of 3,4-
dimethylglutamine would arise from an asymmetric Michael
addition,3-5,6h to give stereocontrolled substitution at C(â)
and C(γ), followed by an electrophilic azidation6a,b or
amination6c-h which would generate the R-amino group. The
retrosynthetic analysis of the protected 3,4-dimethylglutamine
(3) is shown in Figure 2.
Camphor derivatives have been shown to be very useful
auxiliaries in organic synthesis.7 According to the procedure
reported by Capet,8 the chiral auxiliary (-)-camphorsultam
(6) was synthesized in high yield (Scheme 1). Reaction with
trans-crotonyl chloride provided compound 7,9 which was
(3) (a) Yamaguchi, M.; Tsukamoto, M.; Tanaka, S.; Hirao, I. Tetrahedron
Lett. 1984, 25, 5661-5664. (b) Blarer, S. J.; Schweizer, W. B.; Seebach,
D. HelV. Chim. Acta 1982, 65, 1637-1654. (c) Kawasaki, H.; Tomioka,
K.; Koga, K. Tetrahedron Lett. 1985, 25, 3031-3034. (d) Yamaguchi, M.;
Hasebe, K.; Tanaka, S.; Minami, T. Tetrahedron Lett. 1986, 27, 959-962.
(4) (a) Heathcock, C. H.; Henderson, M. A.; Oare, D. A.; Sanner, M. A.
J. Org. Chem. 1985, 50, 3019. (b) Oare, D. A.; Henderson, M. A.; Sanner,
M. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 132-157.
(5) (a) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771-806
and references therein. (b) Oppolzer, W.; Poli, G. Tetrahedron Lett. 1986,
27, 4717-4720.
† Department of Chemistry.
§ X-ray Crystallography Facilities, Department of Chemistry.
(1) Ireland, C. M.; Molinski, T. F.; Roll, D. M.; Zabriskie, T. M.; McKee,
T. C.; Swersey, J. C.; Foster, M. P. Natural Product Peptides from Marine
Organisms. In Biorganic Marine Chemistry; Scheuer, P. J., Ed.; Springer-
Verlag: Berlin Heidelberg, 1989; pp 1-46.
(2) (a) Zampella, A.; Valeria D’Auria, M.; Gomez Paloma, L.; Casapullo,
A.; Minale, L.; Debitus, C.; Henin, Y. J. Am. Chem. Soc. 1996, 118, 6202-
6209. (b) Valeria D’Auria, M.; Zampella, A.; Gomez Paloma, L.; Minale,
L. Tetrahedron 1996, 52, 9589-9596.
10.1021/ol006679t CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/02/2000

Scheme 1
analysis (Figures 3 and 4). The ratio of the major to minor
isomer was 4:1. Unfortunately, the stereochemistry of the
major isomer did not match that of the desired compound.
Figure 1. Structures of callipeltin A (1) and B (2); callipeltin C is
an acyclic callipeltin A.
Figure 3. ORTEP drawing of compound 8.
subjected to Michael addition3d,4b with the lithium enolate
of dibenzylpropionylamide to afford two diastereomeric
isomers, 8 and 9, both with erythro-dimethyl groups. The
stereochemistries of both products were determined by X-ray
Using the same procedure,8 we synthesized the (+)-
camphorsultam (10) (Scheme 2) and treated it with trans-
Scheme 2
Figure 2. Retrosynthetic analysis of 3,4-dimethylglutamine.
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Org. Lett., Vol. 2, No. 26, 2000

Figure 4. ORTEP drawing of compound 9.
Figure 6. ORTEP drawing of compound 13.
To improve the ratio of the major to minor isomer, we
prepared N,N-diisopropylpropionyl amide (Scheme 3), which
crotonyl chloride to provide compound 11.9 By employing
the same Michael addition protocol, we obtained a 3:1 major
to minor isomer ratio for the Michael adducts. Their
stereochemistries were also determined by X-ray analysis
(Figures 5 and 6). Heathcock and co-workers have thor-
Scheme 3
was treated with LDA and reacted with compound 11 to give
a 25:1 ratio of major isomer to minor isomer.
In the transition state models shown in Figure 7, with a
large chiral auxiliary X and large R groups, transition state
A is favored over transition state B, according to the
Heathcock model.4b A bulky amide shows erythro-selectivity
as amide enolates are known to prefer the (Z)-form.10 We
only observed anti products in our reactions. We presume
that the amide enolate approaches the enone at an angle
similar to the Bu¨rgi-Dunitz trajectory.4b,11 The attack from
the Re face of the enone (shown as C) is favored over that
from the Si face (shown as D) due to the chiral auxiliary.
When R is changed from benzyl to a bulkier isopropyl group,
the Si face of the enone is more encumbered by the chiral
auxiliary, making the enolate attack occur almost exclusively
from the Re face.
Figure 5. ORTEP drawing of compound 12.
oughly investigated the stereochemistry of the Michael
addition of N,N-disubstituted amides to R,â-unsaturated
ketones,4b and the formation of anti products was expected.
(6) (a) Evans, D. A.; Britton, T. C. J. Am. Chem. Soc. 1987, 109, 6881-
6883. Evans, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1989, 111, 1063-
1072. (b) Evans, D. A.; Evrard, D. A.; Rychnovsky, S. D.; Fru¨h, T.;
Whittingham, W. G.; DeVries, K. M. Tetrahedron Lett. 1992, 33, 1189-
1192. (c) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F., Jr.
Tetrahedron 1988, 44, 5525-5540. (d) Gennari, C.; Colombo, L.; Bertolini,
G. J. Am. Chem. Soc. 1986, 108, 6394-6395. (e) Evans, D. A.; Britton, T.
C.; Dorow, R. L.; Dellaria, J. F. J. Am. Chem. Soc. 1986, 108, 6395-
6397. (f) Trimble, L. A.; Vederas, J. C. J. Am. Chem. Soc. 1986, 108, 6397-
6399. (g) Loreto, M. A.; Pellacani, L.; Tardella, P. A. Tetrahedron Lett.
1989, 30, 2975-2978. (h) Oppolzer, W.; Tamura, O. Tetrahedron Lett.
1990, 31, 991-994.
(7) (a) Oppolzer, W. Tetrahedron 1987, 43, 1969-2004 and references
therein. (b) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241-1250. (c) Kim,
B. H.; Curran, D. P. Tetrahedron 1993, 49, 293-318.
(8) Capet, M.; David, F.; Bertin, L.; Hardy, J. C. Synth. Commun. 1995,
25, 3323-3327 and references therein.
Starting with the major Michael adduct 12 (Scheme 4),
electrophilic azidation,6a,b using hexamethyldisilazide (KH-
(9) Oppolzer, W.; Chapuis, C.; Bernardinelli, G. HelV. Chim. Acta 1984,
67, 1397-1401.
(10) Morrison, J. D. Asymmetric Synthesis; Academic Press: 1984; Vol.
3.
(11) (a) Bu¨rgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973,
95, 5065-5067. (b) Bu¨rgi, H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16,
153-161.
Org. Lett., Vol. 2, No. 26, 2000
4159

Figure 8. ORTEP drawing of compound 16.
(16) with SnCl2,6b followed by Boc protection of the resulting
free amine in one pot, afforded compound 17. Hydrolysis
of the chiral auxiliary with LiOH (5 equiv) in THF:H2O (2:
1) provided the desired fragment 3, with no epimerization
of the R-amino center.13
In summary, we have developed a novel chiral auxiliary-
controlled Michael addition and a subsequent electrophilic
azidation sequence to make an unusual amino acid. It is
noteworthy that three adjacent stereogenic centers were
generated using the same chiral auxiliary.
Figure 7. Transition states of Michael addition.
MDS) and 2,4,6-triisopropylbenenesulfonyl azide (trisyl
azide),12 successfully installed the azide in the R-position
with the desired stereochemistry, which was confirmed in
its X-ray structure (Figure 8). Reduction of the resulting azide
Acknowledgment. We thank the NIH (CA-40081) and
NSF (CHE-01449) for financial support of this work.
Supporting Information Available: General experimen-
tal procedures and characterizations of all new compounds
including X-ray data. This material is available free of charge
via Internet at http://pubs.acs.org.
Scheme 4
OL006679T
(12) Harmon, R. E.; Wellman, G.; Gupta, S. K. J. Org. Chem. 1973, 38,
11-16.
(13) After conversion of the acid to the methyl ester (MeI, K2CO3, Bu4-
NI, DMF), Boc removal, and the formation of the (-) Mosher amide, no
epimerized isomer was detected by 500 MHz 1H NMR and 19F NMR
analysis.
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Org. Lett., Vol. 2, No. 26, 2000