Transannular Nitrone Cycloaddition. A Stereocontrolled Entry to the Spirocyclic Core of Pinnaic Acid

Article abstract of DOI:10.1021/ol000361j

(Equation Presented) Thermolysis of lactone 18 initiated a stereospecific transannular nitrone-olefin [3 + 2] cycloaddition to yield tetracycle 19. Methanolysis followed by reductive cleavage of the isoxazolidine yielded 20, representing the azaspirocycli

Full text of DOI:10.1021/ol000361j

ORGANIC
LETTERS
2001
Vol. 3, No. 3
413-415
Transannular Nitrone Cycloaddition. A
Stereocontrolled Entry to the Spirocyclic
Core of Pinnaic Acid
James D. White,* Paul R. Blakemore, Eric A. Korf, and Alexandre F. T. Yokochi
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003
james.white@orst.edu
Received November 27, 2000
ABSTRACT
Thermolysis of lactone 18 initiated a stereospecific transannular nitrone−olefin [3 + 2] cycloaddition to yield tetracycle 19. Methanolysis
followed by reductive cleavage of the isoxazolidine yielded 20, representing the azaspirocyclic core of pinnaic acid (1).
A cycloaddition in which the pair of addends are tethered to
each other at both termini represents a special class of
intramolecular reaction that offers unique advantages for
synthesis. If the ring formed by connecting the addends in
this manner is conformationally constrained, a predictable
stereochemical outcome from the process of transannular
cycloaddition should be possible in principle. This is not
always the case in conventional intramolecular cycloadditions
where only one tether links the two addends.
By far the best studied examples of transannular cyclo-
addition are transannular Diels-Alder (TADA) reactions.1
Deslongchamps has demonstrated the practical value of
TADA for the elaboration of complex polycyclic systems
with a high degree of stereocontrol from relatively simple
precursors.2 However, aside from a few other examples
involving [2 + 2] photoaddition,3 transannular cycloadditions
are a largely unexplored class of reactions.
We now report the first transannular nitrone cycloaddition
(TANCA) where both dipole and dipolarophile are within a
ring and show that it can proceed with a high degree of
stereoselectivity.4 We further demonstrate its applicability
to a stereocontrolled synthesis of the azaspirocyclic core of
the alkaloid family which includes pinnaic acid (1) and
tauropinnaic acid (2).5,6 In related studies directed toward
the azaspirocyclic core of 1, the conventional intramolecular
nitrone cycloaddition chemistry of Grigg7 gave isoxazolidines
of incorrect relative configuration.6e,f
(1) For a review, see: Deslongchamps, P. Pure Appl. Chem. 1992, 64,
1831.
(2) For some recent examples, see: (a) Marsault, E.; Deslongchamps,
P. Org. Lett. 2000, 2, 3317. (b) Toro, A.; L’Heureux, A.; Deslongchamps,
P. Org, Lett. 2000, 2, 2737. (c) Lavoie, R.; Ouellet, S. G.; Dallaire, C.;
Dory, Y. L.; Toro, A.; Deslongchamps, P. Tetrahedron 2000, 56, 5509. (d)
Frank, S. A.; Works, A. B.; Roush, W. R. Can. J. Chem. 2000, 78, 757. (e)
Toro, A.; Nowak, P.; Deslongchamps, P. J. Am. Chem. Soc. 2000, 122,
4526.
(4) Transannular nitrone cycloadditions in which the nitrone is external
to the ring have been reported: (a) Baggiolini, E. G.; Lee, H. L.; Pizzolato,
G.; Uskokovic, M.J. Am. Chem. Soc. 1982, 104, 6460. (b) Mihailovic, M.
L.; Rajkovic, M. M.; Lorenc, L. B.; Pavlovic, V. D.; Milovanovic, A. Z.;
Tinant, B.; Declercq, J.-P. Tetrahedron 1996, 52, 11995.
(5) Chou, T.; Kuramoto, M.; Otani, Y.; Shikano, M.; Yazawa, K.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3871.
(3) For a recent example, see: White, J. D.; Kim, J.; Drapela, N. E. J.
Am. Chem. Soc. 2000, 122, 8665.
10.1021/ol000361j CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/12/2001

A generalized representation of our TANCA strategy is
shown in Scheme 1, where a tetracyclic (x * 0) isoxazolidine
which was converted to its ethylene ketal prior to ring-closing
metathesis (RCM) with 20 mol % of Grubbs’ catalyst 10.11
Deleterious side reactions presumably involving the azido
moiety resulted in only a low yield of tridecanolide 11 which
was obtained as an inseparable mixture of alkene isomers
(E:Z ) 4:1).12 Staudinger reaction13 of the azide 11 followed
by aza-Wittig condensation of the resultant iminophospho-
rane with p-anisaldehyde yielded an imine which underwent
selective oxidation with m-chloroperoxybenzoic acid (m-
CPBA) to furnish oxaziridine 12.14 Diastereomers of the
oxaziridine moiety (dr ) 3:2) could be separated by column
chromatography, but subsequent chemistry made this un-
necessary.
Scheme 1. Transannular Nitrone-Olefin Cycloaddition
In an attempt to improve the efficiency of the RCM of 9,
azide 13 was converted to oxaziridine 14 (dr ) 1:1) before
ring closure (Scheme 3). However, treatment of 14 with 10
3 bearing three new stereocenters is produced from nitrone
4. The latter is itself prepared from transannular condensation
of a hydroxylamine and a ketone function in 5. An important
requirement for stereocontrol in this reaction is that y and z
must be large enough to permit flexibility in the approach
of the nitrone to its olefin partner, but not so large as to
allow the nitrone oxygen to pass through the plane of the
macrocycle. If these conditions are met, the face of the alkene
to which the nitrone adds will be determined by the single
stereocenter (*) in 4 and hence by the configuration of the
hydroxylamine in 5. A system designed to test this concept
was constructed using ring-closing metathesis8 to produce a
14-membered macrocycle. A hydroxylamine and a ketone,
both generated in situ, are positioned for transannular
condensation to give the nitrone precursor for TANCA.
Scheme 3. RCM of Oxaziridine 14
5-Oxo-9-decenal (6), prepared in four steps from cyclo-
pentanone,9 was subjected to a Wittig reaction with phos-
phoranylidene 7 to give the trans allylic ester 8 as the sole
stereoisomer (Scheme 2). Conjugate addition of hydrazoic
acid to 8 in the presence of triethylamine10 afforded azide 9
Scheme 2. Synthesis of Nitrone Precursor 12
mol % of catalyst 10 gave only the allyl dodecanoate 15
and the tridecanolide 16 (E:Z ) 4:1) in 7% and 36% yields,
(6) For alternative approaches to the azaspirocyclic core of pinnaic acid,
see: (a) Arimoto, H.; Asano, S.; Uemura, D. Tetrahedron Lett. 1999, 40,
3583. (b) Koviach, J. L.; Forsyth, C. J. Tetrahedron Lett. 1999, 40, 8529.
(c) Clive, D. L. J.; Yeh, V. S. C. Tetrahedron Lett. 1999, 40, 8503. (d)
Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1999,
38, 3542. (e) Lee, S.; Zhao, Z. Tetrahedron Lett. 1999, 40, 7921. (f) Shindo,
M.; Fukuda, Y.; Shishido, K. Tetrahedron Lett. 2000, 41, 929. (g) Wright,
D. L.; Schulte, J. P.; Page, M. A. Org. Lett. 2000, 2, 1847.
(7) Grigg, R.; Markandu, J.; Surendrakumar, S.; Thornton-Pett, M.;
Warnock, W. J. Tetrahedron 1992, 48, 10399.
(8) For recent reviews of olefin metathesis, see: (a) Grubbs, R. H.; Chang,
S. Tetrahedron 1998, 54, 4413. (b) Armstrong, S. K. J. Chem. Soc., Perkin
Trans. 1 1998, 371.
(9) Nishiyama, T.; Woodhall, J. F.; Lawson, E. N.; Kitching, W. J. Org.
Chem. 1989, 54, 2183.
(10) Lakshmipathi, P.; Rao, A. V. R. Tetrahedron Lett. 1997, 38, 2551.
(11) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100.
(12) Use of Grubbs’ recently reported olefin metathesis catalyst,
tricyclohexylphosphine[1,3-bismesityl-4,5-dihydroimidazol-2-ylidene]-
benzylideneruthenium(IV) dichloride, provided no advantage in yield, see:
Scholl, M.; Ding, S.; Lee, C. W.; Grubbs R. H. Org. Lett. 1999, 1, 953.
(13) For a review of the Staudinger reaction, see: Gololobov, Y. G.;
Kasukhin, L. F. Tetrahedron 1992, 48, 1353.
414
Org. Lett., Vol. 3, No. 3, 2001

respectively.15 TLC analysis of the reaction mixture sug-
gested that isomerization of the oxaziridine occurred before
RCM and none of the desired compound 12 was formed.
Interestingly, in a separate experiment 15 was converted to
16 in 95% yield (E:Z ) 6:1) by the action of just 5 mol %
of 10. 16
Exposure of 12 to p-toluenesulfonic acid in aqueous
MeOH resulted in simultaneous hydrolysis of the ethylene
ketal and the oxaziridine to give transiently the keto
hydroxylamine 17 (Scheme 4). The latter underwent spon-
Scheme 4. Transannular Cycloaddition of Nitrone 18
Figure 1. ORTEP diagram for 19. Ellipsoids are drawn at the 30%
probability level.
19 (Figure 1). As expected, the relative configuration of the
three new stereogenic carbons in this tetracyclic isoxazolidine
emanates from the single stereogenic center in 18 along with
the trans geometry of the alkene and affirms the proposition
that good stereocontrol can be realized in transannular dipolar
cycloadditions of this type.
Finally, base-catalyzed methanolysis of lactone 19 fol-
lowed by reductive cleavage of the isoxazolidine with
samarium diiodide17 gave the dihydroxy amino ester 20
representing the azaspirocyclic core of pinnaic acid (1). This
demonstration of TANCA not only opens a practical route
to 1 but should provide stereocontrolled access to a wide
variety of heterocycles. Further development of this new
principle of synthesis will be reported in due course.
taneous intramolecular condensation to produce nitrone 18
as a 4:1 mixture of E and Z isomers. It proved possible at
this stage to remove the minor Z isomer by careful column
chromatography. Conformational analysis of nitrone 18
indicates that the macrocycle is too small to allow the nitrone
oxygen to pass through the ring, and hence transannular
cycloaddition should occur preferentially at only the rear face
of the double bond as shown in 18. In fact, a solution of 18
in toluene heated to reflux afforded a single crystalline
product, X-ray analysis of which revealed its structure to be
Acknowledgment. Financial support was provided by the
National Institutes of Health (GM58889).
Supporting Information Available: Detailed experi-
mental procedures and characterization data for all new
compounds. X-ray crystallographic data for 19. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL000361J
(14) A similar transformation sequence has been reported by Holmes
and co-workers: Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes, L.
R.; Lidert, C.; Swithenbank, C. J. Org. Chem. 1991, 56, 1393.
(15) The isomerization of oxaziridines to amides is usually base
catalyzed: Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703.
(16) For macrocyclic RCM to yield other 14-membered lactones, see:
(a) Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942. (b) Lee, C.
W.; Grubbs, R. H. Org. Lett. 2000, 2, 2145.
(17) Keck, G. E.; Wager, T. T.; McHardy, S. F. Tetrahedron 1999, 55,
11755.
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