Enantiospecific synthesis of N-Boc-Adda: a linear approach.

Article abstract of DOI:10.1021/ol006347o

[structure: see text] Synthesis of the unusual amino acid (2S,3S,8S, 9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4,6-decadienoic acid (Adda), a unit of numerous cyanobacterial toxins, is described. Construction of the target molecule was achieved in 1

Full text of DOI:10.1021/ol006347o

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2901-2903
Enantiospecific Synthesis of
N-Boc-Adda: A Linear Approach
Clay Pearson, Kenneth L. Rinehart,* Michihiro Sugano, and
Jennifer R. Costerison
Roger Adams Laboratory, UniVersity of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
krinehar@uiuc.edu
Received July 18, 2000
ABSTRACT
Synthesis of the unusual amino acid (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4,6-decadienoic acid (Adda), a unit of numerous
cyanobacterial toxins, is described. Construction of the target molecule was achieved in 13 steps with an overall yield of 40%. The work is
highlighted by a novel one-pot transformation from isoxazolidin-5-one intermediate 6 to the final product, a step that can also be used to form
â-amino acids.
Nodularin, 1, motuporin, 2, and microcystins, 3, are marine-
derived natural products (Figure 1) that contain the unusual
amino acid (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8-tri-
methyl-10-phenyl-4,6-decadienoic acid (Adda), 4. Nodularin1
and the microcystins1 have been isolated from cyanobacteria
while motuporin2 was obtained from the marine sponge
Theonella swinhoei. Nodularin and microcystins are hepa-
totoxins and tumor promoters whereas motuporin displays
in Vitro cytotoxicity against various cancer cell lines.1,3 These
compounds exhibit inhibitory activity against serine-threo-
nine protein phosphatases associated with the intracellular
signaling process.3,4 Structure-activity relationship (SAR)
studies on these compounds may shed new light on that
process, but before comprehensive SAR studies can become
a reality, a short and stereoselective route to Adda is required,
one that is capable of producing 4 on a gram scale. Toward
this goal we report here the first linear synthesis of Adda.
The unique structure of Adda has stimulated several groups
to develop routes to the unusual amino acid or its deriva-
tives.5 Our procedure described in the present report provides
N-Boc-Adda (5) in the fewest steps (13), from commercially
available material, with a much higher overall yield (40%)
than previously reported.5 Our synthesis employs the Evans
aldol reaction to lay the stereochemical framework for all
stereogenic centers found in Adda.6 The final step in the
synthesis introduces a new “one-pot” procedure to stereo-
selectively synthesize allylic amines via an isoxazolidin-5-
one intermediate (6).7
The stereochemistry at C-8 and C-9 of Adda was
established using an Evans aldol reaction between acylated
oxazolidinone 7 and phenylacetaldehyde (Scheme 1). Re-
placement of the chiral auxiliary with a Weinreb amide
allowed for epimerization-free methylation of alcohol 8.5e
DIBAL-H reduction of Weinreb amide 9 followed by a
(5) (a) Namikoshi, M.; Rinehart, K. L.; Dahlem, A. M.; Beasley, V. R.;
Carmichael, W. W. Tetrahedron Lett. 1989, 30, 4349-4352. (b) Chakraborty,
T. K.; Joshi, S. P. Tetrahedron Lett. 1990, 30, 2043-2046. (c) Beatty, M.
F.; Jennings-White, C.; Avery, M. A. J. Chem. Soc., Perkin Trans. 1 1992,
1637-1641. (d) Schreiber, S. L.; Valentekovich, R. J. J. Am. Chem. Soc.
1995, 117, 9069-9070. (e) Humphrey, J. M.; Aggen, J. B.; Chamberlin A.
R. J. Am. Chem. Soc. 1996, 118, 11759-11770. (f) Sin, N.; Kallmerten, J.
Tetrahedron Lett. 1996, 37, 5645-5648. (g) D’Aniello, F.; Mann, A. J.
Org. Chem. 1996, 61, 4870-4871. (h) Kim, H. Y.; Toogood, P. L.
Tetrahedron Lett. 1996, 37, 2349-2352. (i) Panek, J. S.; Hu, T. J. Org.
Chem. 1997, 62, 4914-4915. (j) Cundy, D. L.; Donohue, A. C.; McCarthy,
T. D. J. Chem. Soc., Perkin Trans. 1 1999, 559-567.
(1) Rinehart, K. L.; Harada, K.; Namikoshi, M.; Chen, C.; Harvis, C.
A.; Munro, M. H. G.; Blunt, J. W.; Mulligan, P. E.; Beasley, V. R.; Dahlem,
A. M.; Carmichael, W. W. J. Am. Chem. Soc. 1988, 110, 8557-8558.
(2) Silva, D.; Williams, D. E.; Andersen, R. J.; Klix, H.; Holmes, C. F.
B.; Allen, T. M. Tetrahedron Lett. 1992, 33, 1561-1564.
(3) Rinehart, K. L.; Namikoshi, M.; Choi, B. W. J. Appl. Phycol. 1994,
6, 159-176.
(6) Evans, D. A. Aldrichimica Acta. 1982, 15, 23-32.
(7) Baldwin, J. E.; Adlington, R. M.; Mellor, L. C. Tetrahedron 1994,
50, 5049-5066.
(4) Mehrotra, A. P.; Gani, D. Tetrahedron Lett. 1996, 37, 6915-6918
and references therein.
10.1021/ol006347o CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/10/2000

Scheme 1
with a two unit “linker” (-X-N-R) that could undergo an
intramolecular Mitsunobu reaction to give a five-membered
ring product (conjugate addition would result in a seven-
membered ring) followed by cleavage of the linker between
the N-X bond to give the amine target.
To accomplish this goal, alcohol 15 was added to a mixture
of NaH and tert-butyl-N-hydroxycarbamate to give 16
(Scheme 2). Intramolecular Mitsunobu reaction of 16 pro-
vided isoxazolidin-5-one, 6, which was isolated in low yield
due to decomposition on silica gel. Various reagents were
investigated that are capable of cleaving N-O bonds under
Mitsunobu conditions, thereby eliminating the need to isolate
the labile isoxazolidin-5-one. SmI2 has been reported to effect
N-O bond cleavage and served as a valuable reagent for
our purposes.9 N-Boc-Adda (5) was synthesized in 64% yield
from 16 by a Mitsunobu cyclization followed by SmI2
reduction in a “one pot” process. SmI2 cleaves N-O bonds
in high yield; however, the reagent is expensive and the
Figure 1. Structures of nodularin, motuporin, microcystin LR,
Adda, and N-Box-Adda.
Wittig reaction with (carbethoxyethylidene)triphenylphos-
phorane provided olefin 10 in 81% yield from 7.5e DIBAL-H
reduction of 10 followed by allylic alcohol oxidation (MnO2)
provided aldehyde 11 in 97% yield. A second Wittig reaction,
between 11 and (carbethoxymethylene)triphenylphosphorane,
provided ester 12 in 96% yield, completing the diene system
of Adda. A second DIBAL-H reduction and MnO2 oxidation
gave aldehyde 13. An Evans aldol reaction between 13 and
acylated oxazolidinone 14 (the enantiomer of 7) yielded
alcohol 15 in 91% yield, completing the stereochemical
framework of Adda.
(8) A Mitsunobu reaction between 15 and HN3 gave good yields of the
azide but with complete loss of stereocontrol (possibly due to [3,3]
sigmatropic rearrangement). Mitsunobu reactions were also tested with
phthalimide and N-(tert-butoxycarbonyl)-p-toluenesulfonamide, but the
yields were low and stereocontrol was poor.
(9) (a) Keck, G. E.; McHardy, S. F.; Wager, T. T. Tetrahedron Lett.
1995, 36, 7419-7422. (b) Guagnano, V. M.S. Thesis, University of Illinois
at Urbana-Champaign, January 1997.
The next step involved replacing the alcohol at C-3 of 15
with an amine, resulting in inversion of configuration.8 To
avoid conjugate addition and potential [3,3] sigmatropic
rearrangements, we proposed replacing the chiral auxiliary
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Org. Lett., Vol. 2, No. 18, 2000

excellent levels of stereocontrol (less than 1% of a diastereo-
mer detected at -78 °C).
Scheme 2
This approach provided N-Boc-Adda (5) in 40% yield
from 13 steps using commercially available starting material.
Our earlier synthesis of N-Boc-Adda was accomplished by
a convergent procedure that required 16 steps with an overall
yield of 29%.10 Other representative sequences gave 12%
in 23 steps,5d 5% in 21 steps,5e or 5% in 19 steps.5h We have
also used the present methodology to synthesize D-erythro-
â-methylaspartic acid, a component of nodularin, the mi-
crocystins, and motuporin, from trans-cinnamaldehyde. This
approach has the advantages of brevity and stereocontrol and
the possibility of utilizing the olefin portion as a synthon
for other functional groups, including the enantiospecific
synthesis of allylic and nonallylic amines.
reaction is sluggish at low temperatures. Sodium naphthalide
is an inexpensive alternative that effects N-O bond cleavage
at -78 °C. “One-pot” sodium naphthalide reduction of 16
provided N-Boc-Adda (5) in equivalent yields but with
greater diastereomeric purity at a much lower cost than SmI2.
The “one-pot” Mitsunobu reaction and sodium naphthalide
(or SmI2) reduction provide an efficient route to allylic
amines that can be carried out at low temperatures with
Acknowledgment. The research described was supported
by a grant from the National Institute of General Medical
Sciences (GM54063, to K.L.R.) and a fellowship from
Sankyo Co., Ltd., to M.S.
Supporting Information Available: Complete experi-
mental procedures and characterization for compounds 5-16.
This material is available free of charge via the Internet at
http:/pubs.acs.org.
(10) Pearson, J. C.; Rinehart, K. L.; Sugano, M. Tetrahedron Lett. 1999,
40, 411-414.
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