C O M M U N I C A T I O N S
transannular bond formation. The stereochemistry of this reaction
may be rationalized by the sequence: (1) homolytic dissociation
of one C-N bond in the photoexcited state of the azo compound
to give an N/C diradical, (2) cyclohexyl ring flip of this intermedi-
ate, and (3) transannular bond formation by a radical displacement
of molecular nitrogen with inversion. This point must remain a
speculation even though there have been several theoretical and
mechanistic studies on the photochemical decomposition of such
cyclic azo compounds (especially bicyclo[2.2.2]-diazooctane).10
Unfortunately, this large body of work afforded no useful guidance
as to the improvement of the yield of 6 in the N2 extrusion step. It
is likely that transannular bond formation in this photochemical
reaction is disfavored by the high angle strain in the product 6.14
The ring contraction of the R-diazoketone 7 proceeded cleanly,
despite the greater ring strain in the product to form, after trapping
of the intermediate ketene with methanol, the endo-methyl ester,
as expected for steric reasons.
Figure 2. ORTEP representation of compound 5.
ketone 6 by protection as the dimethoxy ketal in 91% yield,
ultraviolet irradiation in CH3CN solution at 50 °C under N2, to
effect loss of nitrogen, and deketalization by exposure to HOAc-
H2O at 23 °C to give, after chromatographic purification, the
required pentacycle in 6% yield. The anti relationship of the fused
cyclobutanes in 6 was unambiguously established by nOe (NOESY1D
experiments on a 600 MHz NMR spectrometer). The problem of
improving the yield in the photochemical N2 extrusion step has
not yet been solved, and it remains an unmet challenge to minimize
the formation of unsaturated products from fragmentation and
various unidentified and apparently oligomeric (polar) materials.
This has been a recurring issue with the N2 extrusion reaction of
other bridged azo compounds.10 R-Hydroxymethylenation of ketone
6 (HCOOEt, NaOMe, C6H6 at 23 °C) followed by treatment with
tosyl azide-Et3N in CH2Cl2 at 23 °C provided the R-diazo ketone
7 (80% yield from 6).11 Photo-Wolff rearrangement of 7 by
ultraviolet irradiation at 23 °C in methanol solution in the presence
of triethylamine gave a 3:1 mixture of endo- and exo-methyl esters
(72%), which was transformed into the aldehyde 8 without
purification of intermediates by the sequence: (1) reduction
COOMe f CH2OH using i-Bu2AlH in C7H8 at -78 °C (>95%
yield), (2) Swern oxidation CH2OH f CHO (95% yield), and (3)
epimerization of the endo/exo diastereomers (at CR of formyl) in
Et3N solution under N2 at 23 °C for 6 days to give 8 and the endo
diastereomer in a ratio of 7:1 (>95%). The methyl ester of (()-
pentacycloanammoxic acid (1) was synthesized from 8 by the
sequence: (1) Wittig coupling with the ylide from 7-triphenylphos-
phonioheptanoate12 in THF to form selectively the Z olefinic
product, (2) double bond reduction by diimide13 (generated from
H2NNH2, O2, and CuSO4 as catalyst) in EtOH-H2O at 23 °C, and
The above discussion underscores the extraordinary nature of
the biosynthesis of 1 by anammoxic microbes(s), especially if it
occurs from a C20-fatty acid derivative via a thermally activated
(i.e., nonphotochemical) process.
Supporting Information Available: Experimental procedures and
characterization data for the process shown in Scheme 1 (PDF). X-ray
crystallographic data for 3 and 5 (CIF). This material is available free
References
(1) Damste´, J. S. S.; Strous, M.; Rijpstra, W. I. C.; Hopmans, E. C.;
Greenevasen, J. A. J.; van Duin, A. C. T.; van Niftrik, L. A.; Jetten, M.
S. M. Nature 2002, 419, 708-712.
(2) DeLong, E. F. Nature 2002, 419, 676-677.
(3) (a) Fang, W.; Rogers, D. W. J. Org. Chem. 1992, 57, 2294-2297. (b)
Santos, J. C.; Fuentealba, P. Chem. Phys. Lett. 2003, 377, 449-454.
(4) For a recent review, see: Hopf, H. Angew. Chem., Int. Ed. 2003, 42,
2822-2825.
(5) (a) Mehta, G.; Viswanath, M. B.; Sastry, G. N.; Jemmis, E. D.; Reddy,
D. S. K.; Kunwar, A. C. Angew. Chem., Int. Ed. Engl. 1992, 31, 1488-
1490. (b) Mehta, G.; Viswanath, M. B.; Kunwar, A. C. J. Org. Chem.
1994, 59, 6131-6132. (c) Li, W.; Fox, M. A. J. Am. Chem. Soc. 1996,
118, 11752-11758.
(6) (a) Greiving, H.; Hopf, H.; Jones, P. G.; Bubenitschek, P.; Desvergne,
J.-P.; Bouas-Laurent, H. J. Chem. Soc., Chem. Commun. 1994, 1075-
1076. (b) Hopf, H.; Greiving, H.; Jones, P. G.; Bubenitshek, P. Angew.
Chem., Int. Ed. 1995, 34, 685-687. (c) Gao, X.; Friscic, T.; MacGillivray,
L. R. Angew. Chem., Int. Ed. 2004, 43, 232-236. See also (d) Zitt, H.;
Dix, I.; Hopf, H.; Jones, P. G. Eur. J. Org. Chem. 2002, 2298-2307.
(7) (a) Cope, A. C.; Burg, M. J. Am. Chem. Soc. 1952, 74, 168-172. See
also (b) Askani, R. Chem. Ber. 1969, 102, 3304-3309.
(8) See Supporting Information for details.
(9) (a) Corey, E. J.; Mitra, R. B.; Uda, H. J. Am. Chem. Soc. 1963, 85, 362-
363. (b) Corey, E. J.; Bass, J. D.; Le Mahieu, R.; Mitra, R. B. J. Am.
Chem. Soc. 1964, 86, 5570-5583. (c) Eaton, P. E. Tetrahedron Lett. 1964,
3695-3698.
(10) (a) Engel, P. S. Chem. ReV. 1980, 80, 99-150. (b) Anderson, M. A.;
Grissom, C. B. J. Am. Chem. Soc. 1995, 117, 5041-5048. (c) Turro, N.
J.; Liu, J.-M.; Martin, H.-D.; Kunze, M. Tetrahedron Lett. 1980, 1299-
1302. (d) Jenkins, J. A.; Doehner, R. E.; Paquette, L. A. J. Am. Chem.
Soc. 1980, 102, 2131-2133. (e) Tanida, H.; Teratake, S.; Hata, Y.;
Watanabe, M. Tetrahedron Lett. 1969, 5341-5343.
1
(3) esterification with CH2N2 in ether (95% yield). The H NMR
(600 MHz) and 13C NMR (125 MHz) spectra of synthetic 1 as
well as nOe observed were in complete agreement with the data
reported1 for naturally derived 1, as was the mass spectrum; HRMS
calcd. for C21H33O2 (M + H+), 317.2480; found, 317.2475. Our
synthesis validates the proposed structure of anammoxic acid. An
authentic sample of 1 was not available from the original investiga-
tors.1
In the synthesis of (()-pentacycloanammoxic acid that is
summarized in Scheme 1, the 20-carbon target structure was
established from three building blocks: cyclooctatetraene, 2-cy-
clopentenone, and 7-bromoheptanoic acid via a relatively concise
pathway. The stereochemical selectivity was very good, as expected
from literature precedents. The [2 + 2]-photocycloaddition of
2-cyclopentenone to 4 was highly exo-selective.9b The photochemi-
cal extrusion of the ketal of 5 selectively produced the all-anti
pentacycle 6 in a process that must involve a ring flip prior to
(11) Regitz, M. Synthesis 1972, 351-373.
(12) Kato, K.; Ohkawa, S.; Terao, S.; Terashita, Z.; Nishikawa, K. J. Med.
Chem. 1985, 28, 287-294.
(13) (a) Corey, E. J.; Mock, W. L.; Pasto, D. J. Tetrahedron Lett. 1961, 347-
352. (b) Corey, E. J.; Pasto, D. J.; Mock, W. L. J. Am. Chem. Soc. 1961,
83, 2957-2958.
(14) It should be mentioned that experiments on the thermolysis of 5 yielded
no detectible amounts of 6.
JA044089A
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