Scheme 1. Retrosynthetic Analysis of Azimine and Carpaine
Scheme 2 a
the first total syntheses of 1 and a new approach to the total
synthesis of 2 based on a route shown in Scheme 1 by using
a macrocyclic dilactonization of azimic acid (3) and carpamic
acid (4) (actually, their N-derivatives were to be used) and
the intramolecular hetero-Diels-Alder reaction of the N-
acylnitroso compound 9 as a key step.
Our synthesis began with (S)-1,2,4-butanetriol (10) as a
single source of chirality (Scheme 2). Accordingly, 10 was
converted to (S)-2,4-dihydroxybutanal which was protected
as the benzylidene acetal 1112 to prevent possible racemiza-
tion in the basic medium in the sequential Wittig reaction
by keeping the equatorial arrangement of the 2-phenyl and
4-formyl groups intact.13 Thus, the Wittig reaction of the
a Reagents and conditions: (a) PhCHO, TsOH, then Swern
oxidation (ref 12a,b); (b) Br-Ph3P+CH2CHdCHCH2CH2CH2OH,
LiHMDS, THF-HMPA (2:1), rt, 66%; (c) MOMCl, i-Pr2NEt,
CH2Cl2, 60 °C, 93%; (d) DIBAL-H, CH2Cl2, 0 °C, 84%; (e) TsCl,
Et3N, DMAP, CH2Cl2, rt, 91%; (f) hν, I2, benzene, 94%; (g) NaCN,
DMSO, 50 °C, 95%; (h) NaOH, MeOH-H2O, reflux; (i) CH2N2,
Et2O, 0 °C, 94% over two steps; (j) NH2OH‚HCl, KOH, MeOH, 0
°C, 88%; (k) NaIO4, H2O-DMF (50:1), 0 °C, 69%.
aldehyde 11 with [(2E)-6-hydroxy-2-hexenyl](triphenyl)phos-
phonium bromide, using LiHMDS, produced the (4S)-dienol
12 (66% yield) with no epimerization as a 6:1 unseparable
mixture of 6-Z/E geometrical isomers based on integration
of NMR signals. After protection of the hydroxyl group as
the MOM ether followed by DIBAL-H reduction, the result-
ing alcohol 13 (4-Z/E ) 6:1) was converted to the tosylate
and photoisomerized to give the pure (E,E)-isomer 14 by
irradiation (I2, benzene) with a 100 W high-pressure mercury
lamp. Conversion to the hydroxamic acid 15 was then ac-
complished by a sequence of reactions involving nucleophilic
displacement of the tosylate by cyanide ion, alkaline hy-
drolysis, esterification with diazomethane, and treatment with
hydroxylamine. Upon oxidation of 15 with NaIO4 in aqueous
medium14 at 0 °C, the in situ generated acylnitroso compound
16 underwent intramolecular Diels-Alder reaction to afford
a 6.4:1 mixture of the trans and cis adducts (with respect to
H4a and H5) 17 and 18 in 69% total yield. The trans
(8) For the synthesis of racemic carpamic acid, see: (a) Brown. E.;
Bourgouin, A. Chem. Lett. 1974, 109-112. (b) Brown, E.; Bourgouin, A.
Tetrahedron 1975, 31, 1047-1051. (c) Holmes, A. B.; Swithenbank, C.;
Williams, S. F. J. Chem. Soc., Chem. Commun. 1986, 265-266. See also
ref 7c,d. For the synthesis of (+)-carpamic acid, see: (d) Singh, R.; Ghosh,
S. K. Tetrahedron Lett. 2002, 43, 7711-7715. See also ref 7e.
(9) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614-
5616.
(10) Corey, E. J.; Nicolaou, K. C.; Lawrence, S.; Melvin, S., Jr. J. Am.
Chem. Soc. 1975, 97, 654-655.
(11) For a review, see: (a) Kibayashi, C,; Aoyagi, S. Synlett 1995, 873-
879 and references therein. See also: (b) Aoyagi, S.; Tanaka, R.; Naruse,
M.; Kibayashi, C. J. Org. Chem. 1998, 63, 8397-8406. (c) Abe, H.; Aoyagi,
S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122, 4583-4592. (d) Ozawa,
T.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 2001, 66, 3338-3347.
(12) For the preparation of 11 from 10, see: (a) Pawlak, J.; Nakanishi,
K.; Iwashita, T.; Borowski, E. J. Org. Chem. 1987, 52, 2896-2901. (b)
Thiam, M.; Slassi, A.; Chastrette, F.; Amouroux, R. Synth. Commun. 1992,
22, 83-95. See also the preparation of the antipode of 11 from (R)-10: (c)
Isobe, M.; Ichikawa, Y.; Bai, D.-l.; Goto, T. Tetrahedron Lett. 1985, 26,
5203-5206. (d) Herradon, B. Tetrahedron: Asymmetry 1991, 2, 191-194.
(13) Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1994, 59,
1358-1364.
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