Nitrenium ion azaspirocyclization-spirodienone cleavage: A new synthetic strategy for the stereocontrolled preparation of highly substituted lactams and N-hydroxy lactams

Article abstract of DOI:10.1021/jo051252r

Although 1,4-cyclohexadienes 2, obtained through the Birch reduction of arenes 1, have found widespread use as masked β-oxo carbonyl synthons 3, the possibility that 2,5-cyclohexadienones 5 might also be employed to the same end has been overlooked despit

Full text of DOI:10.1021/jo051252r

Nitrenium Ion Azaspirocyclization-Spirodienone Cleavage:
A New Synthetic Strategy for the Stereocontrolled Preparation of
Highly Substituted Lactams and N-Hydroxy Lactams
Duncan J. Wardrop* and Matthew S. Burge
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
wardropd@uic.edu
Received June 17, 2005
Although 1,4-cyclohexadienes 2, obtained through the Birch reduction of arenes 1, have found
widespread use as masked â-oxo carbonyl synthons 3, the possibility that 2,5-cyclohexadienones 5
might also be employed to the same end has been overlooked despite their ready availability. As
part of our ongoing investigation of the synthetic chemistry of nitrenium ions, we have developed
a novel and efficient strategy for the stereoselective preparation of di- and trisubstituted azetidinone,
pyrrolidinone, and piperidinone derivatives, which features the ozonolytic cleavage of azaspirocyclic
2,5-cyclohexadienones 12. For example, ozonolysis of spirodienone 12c in CH2Cl2 and reductive
workup with dimethyl sulfide generated unstable â-formyl ester 21, whereas cleavage in MeOH
followed by reduction with thiourea led to hemiacetal 22. While both 21 and 22 partially decompose
upon exposure to silica gel, they can be trapped in situ, with a variety of weakly basic nucleophiles,
to usefully substituted products. The requisite spirodienone substrates are readily accessible through
the nitrenium ion cyclization of alkyl ω-arylhydroxamates 10, which proceeds with moderate to
high diastereoselectivity.
Introduction
Birch reduction of 1 and cleavage of one or both double
bonds in the resulting dihydroaromatic compound 2, most
commonly through ozonolysis, serves to unmask the
latent dicarbonyl system.4 This two-step protocol is
tolerant of a wide range of aryl substituents (R1, R2) and
has successfully been applied to the synthesis of â-keto
The synthetic equivalency of benzenoid systems and
carbonyl-based functional groups1 has been widely ex-
ploited since Woodward’s biosynthetically inspired use
of a veratryl group as a masked hexa-2,4-dienedioic acid
during his total synthesis of strychnine.2 Among the
numerous reports concerning the oxidative cleavage of
aromatic and heteroaromatic rings to form carboxylic
acids, lactones and other related functionality,3 the use
of disubstituted arenes 1 as latent 1,3-dicarbonyl groups
3 has proven to be particularly fruitful (Scheme 1).
Rather than involving a direct oxidation, in this case,
(3) For recent, representative reports concerning the oxidative
degradation of benzenoid systems, see: (a) Audouard, C.; Barsukov,
I.; Fawcett, J.; Griffith, G. A.; Percy, J. M.; Pintat, S.; Smith, C. A.
Chem. Commun. 2004, 1526 (b) Lee, Y.-S.; Choung, W.-K.; Kim, K.
H.; Kang, T. W.; Ha, D.-C. Tetrahedron 2004, 60, 867. (c) Miranda, L.
S. M.; Vasconcellos, M. L. A. A. Synthesis 2004, 1767. (d) Demir, A.;
Sesenoglu, O.; Ulku, D.; Arici, C. Helv. Chim. Acta 2003, 86, 91. (e)
Jaroch, S.; Holscher, P.; Rehwinkel, H.; Sulzle, D.; Burton, G.;
Hillmann, M.; McDonald, F. M. Bioorg. Med. Chem. Lett. 2003, 13,
1981. (f) Mander, L. N.; Williams, C. M. Tetrahedron 2003, 59, 1105
and references therein. (g) Colletti, S. L.; Li, C.; Fisher, M. H.; Wyvratt,
M. J.; Meinke, P. T. Tetrahedron Lett. 2000, 41, 7825. (h) Bringmann,
G.; Munchbach, M.; Michel, M. Tetrahedron: Asymmetry 2000, 11,
3167. (i) Zhou, W.-S.; Lu, Z.-H.; Xu, Y.-M.; Liao, L.-X.; Wang, Z.-M.
Tetrahedron 1999, 55, 11959.
* To whom correspondence should be addressed. Tel: 312-996-8542.
Fax: 312-996-0431.
(1) Ho, T.-L. Tactics of Organic Synthesis, 1st ed.; Wiley: New York,
1994; pp 50-53.
(2) (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.;
Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749. (b)
Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H.
U.; Schenker, K. Tetrahedron 1963, 19, 247.
(4) Birch, A. J.; Fitton, F.; Smith, D. C. C.; Steere, D. E.; Stelfox, A.
R. J. Chem. Soc. 1963, 2209.
10.1021/jo051252r CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/12/2005
J. Org. Chem. 2005, 70, 10271-10284
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Wardrop and Burge
acetate (8) in ethyl acetate,11c for example, provided keto
aldehyde 9 in low yield together with nine other products,
which were proposed to arise through anomalous ozo-
nolysis of 8, Baeyer-Villiger oxidation of aldehyde 9,14
and the partial ozonolytic cleavage of the dienone ring.15
SCHEME 1. 1,3-Disubstituted Arenes as Masked
â-Oxo Carbonyl Synthons
SCHEME 2. 2,5-Cyclohexadienones as Potential
Masked â-Oxo Carbonyl Synthons
Notwithstanding these unpromising observations, suc-
cessful ozonolytic cleavage of systems such as 5 remains
synthetically appealing for a number of reasons, not least
of which is the prospect that a route to 1,3-dicarbonyl
systems, which bear an asymmetric quaternary stereo-
center at C-2, might be established through the ozonoly-
sis of differentially 4,4-disubstituted 2,5-cyclohexadi-
enones 5.16 That the requisite dienones precursors 5 are
readily available, through with the oxidation of phenols
4 and other electron-rich arenes,17 is an additionally
attractive feature of this type of transformation.
Our interest in the ozonolytic cleavage of 2,5-cyclo-
hexadienones was spurred by this laboratory’s ongoing
study of the synthetic application of acyl nitrenium
ions.18-20 We have recently reported a stereoselective
nitrenium ion spirocyclization involving the treatment
of R- and â-substituted methyl 3-(methoxyphenyl)pro-
piohydroxamates 10 (n ) 1) with phenyliodine(III) bis-
(trifluoroacetate) (PIFA) to provide spirolactams 12 with
useful levels of diastereoselectivity (Scheme 3).21
esters,5 ω-formyl esters,6 malonate esters,7 â-diketones,8
â-formyl ketones,9 and even higher order polyketides.10
In contrast to cyclohexadienes 2, there are only a
handful of accounts documenting the ozonolytic cleavage
of 2,5-cyclohexadienones 5, their electron-deficient con-
geners, to form 1,3-dicarbonyl compounds 7 (Scheme 2).11
Given the complex nature of the reaction between di-
enones and ozone, the absence of reports concerning this
transformation is perhaps understandable. The ozonoly-
sis of cross-conjugated ketones was first studied by
Harries, who noted that while treatment of phorone with
excess ozone formed mesoxaldialdehyde (6) and acetone,12
exposure of this substrate to 1 equiv of ozone resulted in
anomalous ozonolysis13 to produce â,â-dimethylacrylic
acid.
More recently, Caspi11a-c and Rodig11d have indepen-
dently investigated the ozonolysis of steroidal ∆1,4-3-
ketones and found the outcome of this reaction to be
similarly complex. Ozonolysis of 1-dehydrotestosterone
(14) Story, P. R.; Burgess, J. R. Tetrahedron Lett. 1968, 1287.
(15) (a) Shibata, K.; Takegawa, S.; Koizumi, N.; Yamakoshi, N.;
Shimazawa, E. Chem. Pharm. Bull. 1992, 40, 935. (b) Koizumi, N.;
Takegawa, S.; Mieda, M.; Shibata, K. Chem. Pharm. Bull. 1996, 44,
2162. (c) Cambie, R. C.; Higgs, P. I.; Read, C. M.; Rutledge, P. S.; Ryan,
G. R.; Woodgate, P. D. Aust. J. Chem. 1990, 43, 681.
(16) For reviews covering the formation of quaternary stereogenic
center, see: (a) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001,
40, 4591. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed.
1998, 37, 388.
(17) For recent reviews of phenolic oxidation, see: (a) Wirth, T. In
Hypervalent Iodine Chemistry: Modern Developments in Organic
Synthesis; Wirth, T., Ed.; Springer: Berlin, 2003; Vol. 224. (b) Moriarty,
R. M.; Prakash, O. Org. React. 2001, 57, 327. (c) Pelter, A.; Ward, R.
S. Tetrahedron 2001, 57, 273.
(18) (a) Wardrop, D. J.; Basak, A. Org. Lett., 2001, 3, 1053. (b)
Wardrop, D. J.; Zhang, W. Org. Lett., 2001, 3, 2353. (c) Wardrop, D.
J.; Landrie, C. L.; Ort´ız, J. A. Synlett, 2003, 1352.
(19) For reviews concerning the chemistry of nitrenium ions, see:
(a) Falvey, D. E. In Reactive Intermediate Chemistry; Moss, R. A., Platz,
M. S., Jones, M., Eds.; Wiley-Interscience: Hoboken, NJ, 2004; Chapter
13. (b) Kikugawa, Y. Rev. Heteroatom Chem. 1996, 15, 263. (c)
Abramovitch, R. A.; Jeyaraman, R. In Azides and Nitrenes: Reactivity
and Utility; Scriven, E. F. V., Eds.; Academic Press: Orlando, FL, 1984;
Chapter 6.
(20) For the intramolecular reaction acylnitrenium ions and related
electron-deficient species with arenes, see: (a) Glover, S. A.; Goosen,
A.; McCleland, C. W.; Schoonraad, J. L. J. Chem. Soc., Perkin Trans.
1 1984, 2255. (b) Kikugawa, Y.; Kawase, M. J. Am. Chem. Soc. 1984,
106, 5728. (c) Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad,
J. L. Tetrahedron 1987, 43, 2577. (d) Kawase, M.; Kitamura, T.;
Kikugawa, Y. J. Org. Chem. 1989, 54, 3394. (e) Cherest, M.; Lusinchi,
X. Tetrahedron Lett. 1989, 30, 715. (f) Glover, S. A.; Rowbottom, C.
A.; Scott, A. P.; Schoonraad, J. L. Tetrahedron 1990, 46, 7247. (g) Prata,
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Branco, P. S. J. Chem. Soc., Perkin Trans. 1 2002, 513. (h) Miyazawa,
E.; Sakamoto, T.; Kikugawa, Y. Heterocycles 2003, 59, 149. (i)
Miyazawa, E.; Sakamoto, T.; Kikugawa, Y. J. Org. Chem. 2003, 68,
5429. (j) Kikugawa, Y.; Nagashima, A.; Sakamoto, T.; Miyazawa, E.;
Shiiya, M. J. Org. Chem. 2003, 68, 6739.
(5) (a) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1986, 27, 3119.
(b) Evans, D. A.; Gauchet-Prunet, J. A.; Carreira, E. M. and Charette,
A. B. J. Org. Chem. 1991, 56, 741. (c) Rao, A. V. R.; Gurjar, M. K.;
Islam, A. Tetrahedron Lett. 1993, 34, 4993.
(6) (a) Corey, E. J.; Katzenellenbogen, J. A.; Gilman, N. W.; Roman,
S. A.; Erickson, B. W. J. J. Am. Chem. Soc. 1968, 90, 5618. (b) Moody,
C. J.; Toczek, J. Tetrahedron Lett. 1986, 27, 5253. (c) Moody, C. J.;
Toczek, J. J. Chem. Soc.-Perkin Trans. 1 1988, 1397. (d) Kammler, R.;
Polborn, K.; Wanner, K. T. Tetrahedron 2003, 59, 3359.
(7) (a) Mittelbach, M.; Poklukar, N.; Junek, H. Liebigs Ann. Chem.
1990, 185. (b) Bringmann, G.; Kuenkel, G.; Geuder, T. Synlett 1990,
253. (c) Bringmann, G.; Geuder, T. Synthesis 1991, 829.
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Org. Chem. 2001, 1899.
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(b) Bringmann, G. Liebigs Ann., Chem. 1985, 2105.
(11) For reports concerning the ozonolysis of 2,5-cyclohexadienones,
see: (a) Caspi, E.; Schmid, W.; Khan, B. T. Tetrahedron 1962, 18, 767.
(b) Caspi, E.; Khan, B. T.; Balasubrahmanyam, S. N. Tetrahedron 1962,
18, 1013. (c) Balasubrahmanyam, S. N.; Caspi, E.; Khan, B. T. J. Chem.
Soc. 1963, 761. (d) Rodig, O. R.; Zanati, G. J. Org. Chem. 1968, 33,
914. (e) Okamoto, K.; Nitta, I.; Shingu, H. Bull. Chem. Soc. Jpn. 1970,
43, 1768. (f) Bailey, P. S.; Ferrell, T. M. J. Org. Chem. 1981, 46, 5028.
(12) (a) Harries, C.; Turk, H. Chem. Ber. 1905, 38, 1630. (b) Harries,
C. Ann. 1910, 374, 288. (c) For an account of Harries' introduction of
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86, 930.
(13) Bailey, P. S. Ozonation in Organic Chemistry, Vol. 1; Traha-
novsky, W., Ed.; Academic Press: New York, 1978; Vol. I, pp 153-
162.
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Nitrenium Ion Azaspirocyclization-Spirodienone Cleavage
SCHEME 3. Spirocyclic Lactams as Masked Heterocyclic â-Oxo Carbonyl Synthons
Given the ease with which spirocycles 12 can be
accessed and our ability to control the configuration of
the spirocyclic center, we were prompted to consider the
possibility that ozonolytic cleavage of the dienone ring
would offer convenient access to lactams 13 that possess
a nitrogen-bearing quaternary stereogenic center. Since
spiroazetidinone, pyrrolidinone and piperidinone systems
12 (n ) 0, 1, 2) are all accessible through the oxidative
cyclization of alkyl hydroxamates 10,19b and given the fact
that this reaction is tolerant of a wide range of aryl and
side chain substituents, this strategy potentially offers
a route to a diverse array of target molecules. Among the
heterocyclic systems that might potentially be accessed
through application of the two-step sequence outlined in
Scheme 3, the targets shown in Figure 1 are of particular
interest.
kainate toxicity.24 Salinosporamide (17) and lactacystin
(18), on the other hand, are both inhibitors of the
proteasome, while the latter is additionally a potent
cytotoxic agent.25 That the dienone cleavage strategy
might also lend itself to the development of an expedient
synthetic route to 4,4-disubstituted â-lactams (13, n )
0) is also appealing in view of the pharmacological
importance of these systems. Tigemonam (19), for ex-
ample, is a potent oral antibiotic that is resistant to
â-lactamase-mediated hydrolysis.26
Having recently reported the application of the reaction
sequence shown in Scheme 3 to the total synthesis of (-)-
dysibetaine,27 in this paper, we now disclose a full account
of our development of two complementary strategies for
the ozonolytic cleavage of spirolactams 2,5-cyclohexadi-
enones 12 and the implementation of this transformation,
together with the stereoselective nitrenium ion spirocy-
clization reaction, as a valuable strategy for the synthesis
of di- and trisubstituted lactams and N-hydroxy lactams.
Results and Discussion
1. Substrate Preparation. Given Caspie and Rodig’s
observations concerning the cleavage of steroidal systems,
our initial choice of spirodienone substrate was guided
by the recognition that in order to promote efficient
ozonolysis, it would be necessary to address the inherent
electron-deficiency of these cross-conjugated ketones.
Since it is well-known that electron-releasing substitu-
ents increase the reactivity of alkenes toward ozone,28,29
we opted to examine the cleavage of dienone substrates
activated by the presence of a â-methoxy substituent. Our
investigation therefore commenced with the preparation
of a series of dienones 12, which where accessed through
the oxidative spirocyclization of alkyl hydroxamates 10,30
(24) (a) Shin-ya, K.; Kim, J. S.; Furihata, K.; Hayakawa, Y.; Seto,
H. Tetrahedron Lett. 1997, 38, 7079. (b) Okue, M.; Kobayashi, H.; Shin-
ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.; Watanabe, H.; Kitahara,
T. Tetrahedron Lett. 2002, 43, 857.
FIGURE 1. Synthetic targets potentially accessible via ni-
trenium ion cyclization-dienone cleavage strategy.
(25) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355.
(26) (a) Gordon, E. M.; Ondetti, M. A.; Pluscec, J.; Cimarusti, C.
M.; Bonner, D. P.; Sykes, R. B. J. Am. Chem. Soc. 1982, 104, 6053. (b)
Koster, W. H.; Bonner, D. P. In Frontiers of Antibiotic Research;
Umezawa, H., Ed.; Academic Press: New York, 1987; p 211
(27) Wardrop, D. J.; Burge, M. S. Chem. Commun. 2004, 1230.
(28) (a) Clark, R. D.; Heathcock, C. H. J. Org. Chem. 1976, 41, 1396.
(b) Keul, H.; Kuczkowski, R. L. J. Am. Chem. Soc. 1984, 106, 5370. (c)
Keul, H.; Kuczkowski, R. L.; Choi, H.-S. J. Org. Chem. 1985, 50, 3365.
(d) Wojciechowski, B. J.; Pearson, W. H.; Kuczkowski, R. L. J. Org.
Chem. 1989, 54, 115. (e) Griesbaum, K.; Kim, W. S.; Nakamura, N.;
Mori, M.; Nojima, M.; Kusabayashi, S. J. Org. Chem. 1990, 55, 6153.
(f) Bunnelle, W. H. Chem. Rev. 1991, 91, 335. (g) Griesbaum, K.; Kim,
W. S. J. Org. Chem. 1992, 57, 5574. (h) Hillers, S.; Niklaus, A.; Reiser,
O. J. Org. Chem. 1993, 58, 3169. (i) Schank, K.; Beck, H.; Pistorius, S.
Helv. Chim. Acta 2004, 87, 2025.
The marine natural product (-)-dysibetaine (14) is a
neuroexcitotoxin, which is believed to bind to the
glutamate receptors present in the central nervous
system of mice,22,23 while kaitocephalin (15), an AMPA/
NMDA antagonist isolated from the fungus Eupenicil-
lium shearii PF1191, protects hippocampal neurons from
(21) Wardrop, D. J.; Burge, M. S.; Zhang, W.; Ort´ız, J. A. Tetrahe-
dron. Lett., 2003, 44, 2587.
(22) Sakai, R.; Oiwa, C.; Takaishi, K.; Kamiya, H.; Tagawa, M.
Tetrahedron Lett. 1999, 40, 6941.
(23) For syntheses of dysibetaine, see: (a) Langlois, N.; Le Nguyen,
B. K. J. Org. Chem. 2004, 69, 7558. (b) Le Nguyen, B. K.; Langlois, N.
Tetrahedron Lett. 2003, 44, 5961. (c) Snider, B. B.; Gu, Y. Org. Lett.
2001, 3, 1761.
(29) For reports of the efficient ozonolysis of dihydropyrones, see:
(a) Danishefsky, S.; Kato, N.; Askin, D.; Kerwin, J. F., Jr. J. Am. Chem.
Soc. 1982, 104, 360. (b) Sugiyama, T.; Yamakoshi, H.; Nojima, M. J.
Org. Chem. 1993, 58, 4212.
J. Org. Chem, Vol. 70, No. 25, 2005 10273

Wardrop and Burge
TABLE 1. Preparation of Dienone Substrates 12 through Spirocyclization of Alkyl Hydroxamates 10a
a Reaction conditions: PIFA (1.2 equiv), CH2Cl2-MeOH (1:1), -78 f -15 °C, 1.5 h; H2O, 10 min. b Isolated yield, after purification by
flash chromatography. c Diastereomeric ratio (dr) determined by NMR analysis of the appropriate, characteristic proton signals in the
unpurified product mixture. d Methanol adduct 20 (26%) was also isolated.31 e Reaction performed in the absence of MeOH. f Isolated
yield of anti diastereomer, after separation by flash chromatography and recrystallization. g Isolated yield of inseparable 92:8 mixture of
anti and syn diastereomers. h Isolated yield of an inseparable 93:7 mixture of anti and syn diastereomers. i Isolated yield of an inseparable
90:10 mixture of anti and syn diastereomers.
under conditions previously developed in this laboratory
(Table 1).21 Thus, upon treatment of a solution of 10 in
CH2Cl2 at -78 °C with 1.2 equiv of phenyliodine(III) bis-
(trifluoroacetate) (PIFA) in methanol followed by warm-
ing to -15 °C, spirocyclization took place smoothly to
afford the desired azaspirans 12 in good to excellent
yield.31
As anticipated from our investigation of the stereo-
chemistry of this reaction,21 substrates 10g-m under-
went spirocyclization to provide the anti spirolactam
diastereomers with reasonable selectivity. Figure 2 shows
a possible rationale for this general observation. We
believe that spirocyclization of the nitrenium ion gener-
ated from 10 preferentially proceeds via conformer B to
form anti-12. Conformer A, on the other hand, is desta-
bilized due to nonbonding interactions (benzylic strain)32
(30) For details of the preparation of 10, see the Supporting
Information.
10274 J. Org. Chem., Vol. 70, No. 25, 2005

Nitrenium Ion Azaspirocyclization-Spirodienone Cleavage
SCHEME 4. Exploratory Dienone Ozonolysis
Studies
and the formation of a less polar product, as indicated
by thin-layer chromatography. Subsequent reduction of
this ozonide intermediate with dimethyl sulfide (10 equiv)
at room temperature for 12 h gave, upon concentration
of the reaction mixture, â-formyl ester 21. While the
spectroscopic data (1H NMR, 13C NMR, IR, and MS) from
this compound were fully consistent with the structure
assigned, purification of 21 by flash chromatography
resulted in partial decomposition, and the product was
isolated in moderate yield. The instability of 21 was
further apparent from its rapid decomposition, upon
standing at room temperature, to form an intractable
mixture of products. That the sterically congested alde-
hyde group in this compound is highly reactive is also
evident from its spontaneous reaction with methanol to
generate adduct 22. Ozonolysis of 12c in methanol,
followed by reduction of the putative R-methoxy hydro-
peroxide intermediate36 with thiourea (1.25 equiv),37
proceeded cleanly to yield hemiacetal 22 as a 1:1 mixture
of epimers. While this reaction was highly efficient, as
evidenced by NMR analysis of the crude product mixture,
attempts to purify 22 by flash chromatography resulted
in loss of methanol and formation of aldehyde 21, which
was also isolated in diminished yield (60%). Fortunately
in this case, there was no need for purification since
filtration of the reaction mixture through a plug of Celite
after ozonolysis served to remove the precipitated thio-
urea S-dioxide and provided material of sufficient purity
to be utilized in subsequent manipulations. In view of
the instability of both aldehyde 21 and hemiacetal 22,
we now examined the possibility that these compounds
might be intercepted in situ, either through reduction or
reaction with nucleophiles in general, to provide more
tractable products (Scheme 5).
FIGURE 2. Benzylic strain in the putative nitrenium ion
intermediate leads to selective formation of anti-12.
between the substituents on the side chain and the ortho
position of the aromatic ring.33
After separation by chromatography and/or crystal-
lization, the relative stereochemistry of the individual
diastereomers was readily assigned on the basis of
correlations observed in the 2D-NOESY spectra. In the
case of products 12i and 12k, separation of the individual
spirodienone diastereomers was not possible, and con-
sequently, the mixtures were used in the subsequent
step.
The successful cyclization of benzyl hydroxamates34
10b, 10d, and 10f is noteworthy from a synthetic
standpoint since it adds additional flexibility to our
methodology: in these cases, hydrogenolysis of the benzyl
ether, after dienone cleavage, provides access to N-
hydroxy lactams, which are important bioactive targets
(vide infra).35
2. Exploratory Dienone Ozonolysis Studies. Pro-
ceeding now to examine cleavage of the dienone system,
we chose spiropyrrolidinone 12c for the purposes of this
exploratory study (Scheme 4).
Exposure of a solution of 12c in CH2Cl2 (0.12 M) at
-78 °C to a stream of ozonated oxygen for 30 min
resulted in complete consumption of starting material
(31) (a) In the case of substrate 10a (entry 1), the formation of
â-lactam 12a was also accompanied by compound 20, which arises from
the conjugate addition of methanol to the dienone system.31b Although
isolated as a single diastereomer, we were unable to unequivocally
establish the relative stereochemistry of 20 via spectroscopic means.
The formation of this undesired byproduct was simply avoided by
carrying out the cyclization of 10a and 10b in CH2Cl2, in the absence
of methanol (entries 2 and 3).
Encouragingly, ozonolysis of 12c in methanol, reduc-
tion with thiourea, and then treatment of the reaction
(35) For examples of biologically active N-hydroxy lactams and their
derivatives, see: (a) Higashide, E.; Horii, S.; Ono, H.; Mizokami, N.;
Yamazaki, T.; Shibata, M.; Yoneda, M. J. Antibiot. 1985, 38, 285. (b)
Schlemminger, I.; Mole, D. R.; McNeill, L. A.; Dhanda, A.; Hewitson,
K. S.; Tian, Y. M.; Ratcliffe, P. J.; Pugh, C. W.; Schofield, C. J. Bioorg.
Med. Chem. Lett. 2003, 13, 1451. (c) Wendenbaum, S.; Demange, P.;
Dell, A.; Meyer, J. M.; Abdallah, M. A. Tetrahedron Lett. 1983, 24,
4877. (d) Sware´n, P.; Massova, I.; Bellettini, J. R.; Bulychev, A.;
Maveyraud, L.; Kotra, L. P.; Miller, M. J.; Mobashery, S.; Samama, J.
P. J. Am. Chem. Soc. 1999, 121, 5353. (e) Bulychev, A.; O’Brien, M.
E.; Massova, I.; Teng, M.; Gibson, T. A.; Miller, M. J.; Mobashery, S.
J. Am. Chem. Soc. 1995, 117, 5938. (f) Bulychev, A.; Bellettini, J. R.;
O’Brien, M.; Crocker, P. J.; Samama, J.-P.; Miller, M. J.; Mobashery,
S. Tetrahedron 2000, 56, 5719.
(b) Nilsson, A.; Ronla´n, A.; Parker, V. D. Tetrahedron Lett. 1975, 1107.
(32) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(33) Analogous rationalizations of π-facial diastereoselectivity are
proposed in: (a) Wender, P, A.; Ternansky, R. J. Tetrahedron Lett.
1985, 26, 2625. (b) Adam, W.; Peters, E. M.; Peters, K.; Prein, M.; von
Schnering, H. G. J. Am. Chem. Soc. 1995, 117, 6686. (c) Kamikawa,
K.; Furusyo, M.; Uno, T.; Sato, Y.; Konoo, A.; Bringmann, G.; Uemura,
M. Org. Lett. 2001, 3, 3667.
(34) The oxidative Ar2-5 cyclization of 3-substituted 3-aryl-1-ben-
zyloxyureas has previously been noted: Romero, A. G.; Darlington,
W. H.; Jacobsen, E. J.; Mickelson, J. W. Tetrahedron Lett. 1996, 37,
2361 (footnote 7).
(36) Schreiber, S. L.; Claus, R. E.; Reagan, J. Tetrahedron Lett. 1982,
23, 3867.
(37) Gupta, D.; Soman, R.; Dev, S. Tetrahedron 1982, 38, 3013.
J. Org. Chem, Vol. 70, No. 25, 2005 10275

Wardrop and Burge
SCHEME 5. One-Pot Dienone Ozonolysis and
Trappinga
in situ reduction of 21 with sodium borohydride gave
unsatisfactory results, concentration of the ozonolysis
reaction mixture and reduction with LiBH4 in THF
provided the corresponding bis(hydroxymethyl)pyrroli-
dinone,40 which because of its polarity was converted to
bis-O-acetate 29 prior to purification. Treatment of
hemiacetal 22 with NaBH4 or LiBH4, on the other hand,
failed to provide any useful results. Reasoning that a
weaker reducing agent might prove selective for the
hemiacetal group, without affecting the methyl ester or
promoting decomposition, sodium triacetoxyborohydride
in acetic acid was evaluated.41 Thus, after ozonolysis of
12c and reductive workup with thiourea, the reaction
mixture was concentrated under reduced pressure and
then treated with NaBH(OAc)3 (4 equiv) in acetic acid.
Reduction of latent aldehyde 22 proceeded smoothly at
room temperature and was complete within 24 h. Treat-
ment of the reaction mixture with aqueous HCl for 20
min, extractive workup and purification by flash chro-
matography then provided â-hydroxy ester 30c in 81%
overall yield from 12c (Table 2, entry 3).
3. Establishing the Scope and Limitations of
Dienone Cleavage. Having successfully established the
practical viability of dienone cleavage and in situ deriva-
tization, we now proceeded to extend our study to include
the remaining dienone substrates 12 in order to evaluate
the scope and limitations of this chemistry. In view of
the synthetic value of â-hydroxy esters of general struc-
ture 30, as both masked 2-hydroxymethyl amino acids42
and potential building blocks for the preparation of the
natural products dysibetaine (14) and lactacystin (18),
we opted to focus our attention on in situ reduction of
the ozonolysis products with sodium triacetoxyborohy-
dride. The results of this study are detailed in Table 2.
Encouragingly, the reactivity of spiropyrrolidinone 12c
toward ozone appeared to be general: cleavage of the
homologous azaspiro[3.5]nonadienone (entries 1 and 2)
and azaspiro[5.5]undecadienone (entries 5 and 6) systems
proceeded to furnish the respective disubstituted azeti-
dinone and piperidinone products 30. The successful
ozonolysis of spiroazetidinones 12a and 12b is of par-
ticular note since this transformation provides expedient
access to usefully functionalized 4,4-disubstituted â-lac-
tams.43 The disparity in yield observed during the forma-
tion of 30a and 30b appears to result from the greater
polarity of the former product, which hampers its puri-
fication by flash chromatography. While the beneficial
a Reagents and conditions: (a) O3/O2, MeOH, -78 °C, 30 min;
thiourea, -78 °C f rt, 30 min; (b) O3/O2, CH2Cl2, -78 °C, 30 min;
Me2S, -78 °Cfrt, 4 h; (c) H2NOH‚HCl, NaOAc, MeOH, rt, 3 h
(75%); (d) 2,4-DNPH, HCl (concd), MeOH, 3 Å ms, reflux, 3 h
(67%); (e) Me2C(CH2OH)2, TsOH, 3 Å ms, CH2Cl2, reflux, 16 h dec;
(f) (CH2SH)2, HCl (concd), rt, 16 h (47%); (g) Ph3PdCHCO2Et,
PhCH3, reflux, 2 h (88%); (h) Ph3PdCH2, THF, rt, 14 h dec; (i)
LiBH4, THF, rt, 16 h then Ac2O, py, rt 24 h (27%); (j) NaBH(OAc)3,
AcOH, rt, 20 h (81%).
mixture with hydroxylamine hydrochloride (2.4 equiv)
and sodium acetate (1.8 equiv) provided stable aldoxime
23 in good yield (75%). Likewise, hemiacetal 22 also
underwent condensation with 2,4-dinitrophenylhydrazine
to form hydrazone 24, albeit under somewhat more
forcing conditions. Although attempts to prepare 4,4-
dimethyldioxane acetal 25 under a variety of dehydrating
conditions were unsuccessful, treatment of 22 with 1,2-
ethanedithiol in the presence of concentrated hydrochlo-
ric acid did provide 1,2-dithiolane 26 albeit in modest
yield (47%). Homologation of 22, on the other hand,
proved to be more successful. Horner-Wittig reaction of
22 with (carboethoxymethylene)triphenylphosphorane
(2.2 equiv) proceeded efficiently to provide enoate 27 as
a single geometrical isomer.38 In this case, the ozonolysis
reaction mixture was concentrated to remove methanol,
and the carboethoxymethylenation was then carried out
in toluene. Interestingly, 22 did not undergo methylena-
tion with the ylide generated from methyltriphenylphos-
phonium bromide and n-butyllithium. In fact, treatment
of either 21 or 22 with strongly basic nucleophiles,
including Grignard and organozinc reagents, failed to
provide the expected addition products. This general
observation may be due to decomposition of these sub-
strates through retro-aldol or retro-Claisen processes,
which could occur upon deprotonation of the hydroxyl
group, in the case of 22, or upon nucleophilic addition to
the aldehyde group in 21.39
(38) Duhamel, P.; Kotera, M.; Monteil, T.; Marabout, B.; Davoust,
D. J. Org. Chem. 1989, 54, 4419.
(39) The instablity of related systems to basic conditions has been
noted: (a) Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc.
2004, 126, 6230. (b) Trancard, D.; Tout, J.-B.; Giard, T.; Chichaoui, I.;
Cahard, D.; Plaquevent, J.-C. Tetrahedron Lett. 2000, 41, 3843. (c)
Duhamel, P.; Kotera, M. J. Org. Chem. 1982, 47, 1688.
(40) Bis(hydroxymethyl)pyrrolidinones and their derivatives are of
interest as neuraminidase inhibitors: (a) Brouillette, W. J.; Bajpai, S.
N.; Ali, S. M.; Velu, S. E.; Atigadda, V. R.; Lommer, B. S.; Finley, J.
B.; Luo, M.; Air, G. M. Bioorg. Med. Chem. 2003, 11, 2739. (b)
Schieweck, F.; Altenbach, H. J. J. Chem. Soc., Perkin Trans. 1 2001,
3409. (c) Atigadda, V. R.; Brouillette, W. J.; Duarte, F.; Ali, S. M.; Babu,
Y. S.; Bantia, S.; Chand, P.; Chu, N.; Montgomery, J. A.; Walsh, D. A.;
Sudbeck, E. A.; Finley, J.; Luo, M.; Air, G. M.; Laver, G. W. J. Med.
Chem. 1999, 42, 2332.
(41) (a) Ishmuratov, G. Y.; Kharisov, R. Y.; Yakovleva, M. P.;
Botsman, O. V.; Muslukhov, R. R.; Tolstikov, G. A. Russ. J. Org. Chem.
2001, 37, 37. (b) Gribble, G. W. Chem. Soc. Rev. 1998, 27, 395.
(42) Zhang, J.; Flippen-Anderson, J. L.; Kozikowski, A. P. J. Org.
Chem. 2001, 66, 7555.
We next turned our attention to the reduction of the
initial ozonolysis products and, in particular, to the
transformation of these compounds to â-hydroxy ester
30c via selective reduction of the aldehyde and hemi-
acetal groups. While attempts to generate 30c through
10276 J. Org. Chem., Vol. 70, No. 25, 2005

Nitrenium Ion Azaspirocyclization-Spirodienone Cleavage
TABLE 2. Ozonolytic Cleavage of Spirodienones 12 and In Situ Reduction
a
Method A: O3/O2, MeOH, -78 °C, 30 min; thiourea, -78 °C f rt; NaBH(OAc)3, AcOH, rt, 24 h. b Method B: NaBH4, CeCl3‚7H2O,
MeOH, 0 °C, 1 min; O3/O2, MeOH, -78 °C, 30 min; thiourea, -78 °C f rt, 1 h; NaBH(OAc)3, AcOH, rt, 24 h. c Duration of ozonolysis.
d Overall, isolated yield, after purification of the final product by flash chromatography. e A complex, intractable mixture of products was
isolated after ozonolysis and reduction. f Isolated yield, after conversion of alcohol to the corresponding O-acetate derivative and purification
by flash chromatography. g Isolated as a 91:9 mixture of diastereomers. h A complex, intractable mixture of products was recovered.
i Ozonolysis carried out for 1 h and the product converted to acetate 30m derivative before purification.
effect of O-benzyl groups, upon the efficiency of dienone
cleavage, was also apparent during the ozonolysis of
spiropyrrolidinones 12c and 12d, this effect did not
extend to compounds 12e and 12f.
A remarkable structure-reactivity relationship emerged
during the cleavage of substrates 12a-e. While the
reaction of spiroazetidinones 12a and 12b with ozone was
complete within 30 min, ozonolysis of the corresponding
J. Org. Chem, Vol. 70, No. 25, 2005 10277

Wardrop and Burge
SCHEME 6. Alternative, Two-Step Protocol for the Cleavage of Spirodienone Lactams 12
pyrrolidinones 12c and 12d was significantly slower,
requiring 1 h. Even more strikingly, piperidinones 12e
and 12f reacted very sluggishly with cleavage not reach-
ing completion even after exposure to ozone for 3 h.
Purification of the product mixtures, in the case of this
latter pair of substrates, also proved to be problematic
due to the presence of several minor byproducts. Fortu-
nately, acetylation of the reaction mixtures, using Ac2O
in pyridine, provided the corresponding O-acetate deriva-
tives, which where more amenable to purification by flash
chromatography. Rather unexpectedly, spiropiperidinone
12n proved to be considerably more reactive toward ozone
than either 12e or 12f and underwent rapid ozonolysis
to provide 30n in excellent yield, after in situ reduction.
The successful cleavage of 12n is notable since it opens
a possible route to quaternary tetrahydroisoquinoline-3-
carboxylic acid (Tic) derivatives,44 which are of interest
as conformationally restricted amino acids. A more
detailed discussion of the possible origins of this struc-
ture-reactivity pattern is presented in section 5.
Having established the viability of cleavage in unsub-
stituted 4-, 5-, and 6-membered spirolactams, attention
now turned to the R- and â-substituted spiropyrrolidino-
nes 30g-l. We were encouraged to find, in fact, that the
presence of R-substituents in the pyrrolidinone ring was
tolerated with cleavage giving the corresponding 2,4-
disubstituted pyroglutamate derivatives with moderate
to excellent efficiency. That attempts to ozonize 12m, the
isomer of compound 12g, failed to provide any trace of
compound 30m is likely a consequence of the increased
steric encumbrance imposed upon the dienone ring by
the â-methyl substituent in this substrate.
electron-deficient congeners, the logical course of action
at this stage seemed to be to reduce the dienone carbonyl
group and subject the resulting dienylic alcohol(s) 31 to
ozonolysis (Scheme 6).
Although the 1,2-reduction of 2,5-cyclohexadienones is
well documented,45 a potential caveat with this plan was
the propensity of the reduction products 31 to potentially
undergo rearrangement during purification.46 Fortu-
nately, reduction of dienone 12c, under Luche conditions
(NaBH4, CeCl3, MeOH),47 proceeded rapidly at 0 °C to
give a mixture of diastereomers 31, which could be
isolated with excellent mass recovery. As these alcohols
proved to be highly acid sensitive and decomposed upon
exposure to silica gel, they were immediately submitted
to ozonolysis without further purification (Table 2).
Gratifyingly, ozonolysis of diene 31 in CH2Cl2 at -78
°C occurred rapidly, with the starting material being
consumed within 30 min as opposed to 1 h for dienone
12c. Sequential reduction of the peroxidic intermediates
with thiourea (1.25 equiv) and sodium triacetoxyborohy-
dride (5 equiv) in acetic acid then proceeded without
incident to furnish â-hydroxy ester 30c in good yield.
While this two-step protocol was slightly less efficient
than direct dienone ozonolysis in this case (76 vs 81%),
its application to the remaining substrates in Table 2
proved to be considerably more rewarding. With the
exception of 12a, 12b, and 12n, improvements in yield
and a decrease in reaction time were observed in all
cases. Indeed, ozonolysis of the intermediate dienylic
alcohols was complete within 30 min for all substrates,
including spiropiperidinones 12e and 12f. The transfor-
mation of hindered 12m to compound 30m,48 albeit in
low yield, under these conditions is also of note, since
this product could not be prepared through direct ozo-
nolysis of the dienone system. In the case of compounds
12a and 12n, complex mixtures of products where
obtained, which we believe arise from decomposition of
the intermediate dienylic alcohols prior to ozonolysis.
5. Assessment of Spirodienone Structure-Reac-
tivity Relationships. Steric effects are known to play
a significant role in determining the rate of 1,3-dipolar
cycloaddition between ozone and unsaturated systems,
including alkenes and arenes.49 We have rationalized the
marked variation in reactivity toward ozone displayed
by spirodienones 12 in terms of steric hindrance above
4. An Alternative Strategy for Dienone Cleavage.
The extended reaction times and modest yields encoun-
tered during the ozonolysis of substrates 12e and 12f,
coupled with the failure of â-substituted spiropyrrolidi-
none 12m to undergo cleavage, prompted a search for
an alternative, more efficient strategy for cleavage of the
dienone ring system. Given the greater reactivity of 1,4-
cyclohexadienes toward ozone as compared to their
(43) For selected routes to 4,4-disubtituted azetidinones, see: (a)
Ageno, G.; Banfi, L.; Cascio, G.; Guanti, G.; Manghisi, E.; Riva, R.;
Rocca, V. Tetrahedron 1995, 51, 8121. (b) DeKimpe, N.; Tehrani, K.
A.; Fonck, G. J. Org. Chem. 1996, 61, 6500. (c) Palomo, C.; Aizpurua,
J. M.; Garc´ıa, J. M.; Galarza, R.; Legido, M.; Urchegui, R.; Roma´n, P.;
Luque, A.; Server-Carrio, J.; Linden, A. J. Org. Chem. 1997, 62, 2070.
(d) Gerona-Navarro, G.; Garcia-Lo´pez, M. T.; Gonza´lez-Mniz, R. J. Org.
Chem. 2002, 67, 3953. (e) Campomanes, P.; Menendez, M. I.; Sordo,
T. L. J. Org. Chem. 2003, 68, 6685.
(44) For the preparation of quaternary tetrahydroisoquinoline-3-
carboxylic acid derivatives, see: (a) Vicario, J. L.; Badia, D.; Carrillo,
L.; Etxebarria, J. Curr. Org. Chem. 2003, 7, 1775. (b) Kawabata, T.;
Ozturk, O.; Suzuki, H.; Fuji, K. Synthesis 2003, 505. (c) Alezra, V.;
Bonin, M.; Micouin, L.; Husson, H. P. Tetrahedron Lett. 2001, 42, 2111.
(d) Chinchilla, R.; Galindo, N.; Najera, C. Synthesis 1999, 704. (e) Ma,
D.; Ma, Z.; Kozikowski, A. P.; Pshenichkin, S.; Wroblewski, J. T. Bioorg.
Med. Chem. Lett. 1998, 8, 2447. (f) Seebach, D.; Dziadulewicz, E.;
Behrendt, L.; Cantoreggi, S.; Fitzi, R. Liebigs Ann. Chem. 1989, 1215.
(g) Bajgrowicz, J.; El Achquar, A.; Roumestant, M.-L.; Pigie`re, C.;
Viallefont, P. Heterocycles 1986, 24, 2165.
(45) (a) Kondo, K.; Sodeoka, M.; Mori, M.; Shibasaki, M. Tetrahedron
Lett. 1993, 34, 4219. (b) Kondo, K.; Sodeoka, M.; Mori, M.; Shibasaki,
M. Synthesis 1993, 920. (c) Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994,
116, 11678. (d) Blades, K.; Cockerill, G. S.; Easterfield, H. J.; Lequeux,
T. P.; Percy, J. M. Chem. Commun. 1996, 1615.
(46) Banerjee, A. K.; Azocar, J. A.; Vera, W. Synth. Commun. 1999,
29, 2995.
(47) (a) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226. (b)
Abruscato, G. J.; Tidwell, T. T. J. Org. Chem. 1972, 37, 4151.
(48) Acetylation of the crude product was necessary in this case to
facilitate chromatographic purification.
(49) Nakagawa, T. W.; Andrews, L. J.; Keefer, R. M. J. Am. Chem.
Soc. 1960, 82, 269.
10278 J. Org. Chem., Vol. 70, No. 25, 2005

Nitrenium Ion Azaspirocyclization-Spirodienone Cleavage
TABLE 3. Relationship between Spirodienone
Reactivity and Structure
none is apparent from the decrease in the angle (φ)
formed between the methylene group, spirocenter and the
carbonyl carbon of the dienone ring. That the dienone
rings in spiroazetidinones 12a and 12b are more acces-
sible to attack is also evident from the fact only these
substrates undergo conjugate addition of methanol dur-
ing azaspirocyclization. While the dramatic increase in
reactivity of dienylic alcohols 31, as compared to their
corresponding dienone partners can be rationalized in
terms of the attenuation of the electron-withdrawing
properties of the carbonyl group, it is not immediately
apparent why this should result in loss of the structure
reactivity relationship.
6. Reductive Cleavage of N-Methoxy and N-Ben-
zyloxy Lactams. To confirm the practical utility of the
nitrenium ion cyclization-dienone cleavage strategy, it
was necessary now to address the issue of N-O bond
scission in the cleavage products 30. Although the
reduction of hydroxylamines, hydroxamic acids, and
N-hydroxy lactams can readily be accomplished with a
variety of reagents, metal ion-mediated reduction of
N-alkoxy lactams is often more demanding since these
systems lack an acidic chelation site.52 While this trans-
formation has been accomplished with a number of
reagents, including hydrogenolysis over heterogeneous
catalysts53 or reduction with Raney nickel,54 SmI2,55
sodium56 and aluminum amalgam,57 LDA,58 tert-bu-
tyldimethylsilyl triflate,59 Li/4,4′-di-tert-butylbiphenyl,60
and Birch reduction,61 few are entirely general. From
previous studies, we have found the most dependable
reducing agent for our relatively hindered substrates to
be molybdenum hexacarbonyl.62
Reductive cleavage of 30 proceeds most efficiently
when the substrate is heated with 1.2 equiv of Mo(CO)6
in a degassed mixture of acetonitrile and water (15:1) for
24 h and the reaction then exposed to air at room
temperature for an equivalent period of time (Table 4).
Concentration of the black reaction mixture and purifica-
tion of the residue by flash chromatography then provides
the desired lactams 32 in good yield. Exposure of the
reaction mixture to air greatly facilitates purification, and
failure to carry out this step often results in the con-
a Optimized geometries were obtained through the MMMF force
field implemented in Spartan. b Duration of ozonolysis.
(â) and below (R) the plane of the dienone ring system,
which varies as a function of the size of the adjoining
lactam ring (Table 3).
Notwithstanding possible dipole and stereoelectronic
effects,50 we believe that ozone approaches the spirocyclic
cyclohexadienones from the R face, anti to the N-methoxyl
group, which in all substrates bisects the dienone ring
and thereby disfavors â attack. Our assumption that the
N-OMe group is more sterically demanding than the
methylene group appears to be born out by the observa-
tion that substrate 12m, which possesses a methyl
substituent at the â position of the pyrrolidinone ring, is
quite inert to ozone. Molecular mechanics minimization
(MMMF) of the geometries of dienones 12a, 12c, 12e, and
12n using the SPARTAN computational interface51 re-
veals that methylene group attached to the spirocenter
progressively shields the â face of the adjoining dienone
ring from ozone cycloaddition as the lactam ring increases
in size. The increasing steric influence played by the
methylene group in going from azetidinone to piperidi-
(52) Mattingly, P. G.; Miller, M. J. J. Org. Chem. 1980, 45, 410.
(53) (a) Chang, C. Y.; Yang, T. K. Tetrahedron: Asymmetry 2003,
14, 2081. (b) Romero, A. G.; Darlington, W. H.; McMillan, M. W. J.
Org. Chem. 1997, 62, 6582.
(54) Qabar, M. N.; Kahn, M. Tetrahedron Lett 1996, 37, 965.
(55) (a) Chiara, J. L.; Destabel, C.; Gallego, P.; Marco-Contelles, J.
J. Org. Chem. 1996, 61, 359. (b) Yang, H. W.; Romo, D. J. Org. Chem.
1999, 64, 7657. (c) Keck, G. E.; Wager, T. T.; McHardy, S. F.
Tetrahedron 1999, 55, 11755
(56) (a) Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1994,
59, 1358. (b) Blakemore, P. R.; Kim, S.-K.; Schulze, V. K.; White, J.
D.; Yokochi, A. F. T. J. Chem. Soc., Perkin Trans. 1 2001, 1831. (c)
Chow, C. P.; Shea, K. J.; Sparks, S. M. Org. Lett. 2002, 4, 2637
(57) (a) King, S. B.; Ganem, B. J. Am. Chem. Soc. 1991, 113, 5089.
(b) Malpass, J. R.; Smith, C. Tetrahedron Lett. 1992, 33, 273.
(58) (a) Graham, S. L.; Scholz, T. H. Tetrahedron Lett. 1990, 31,
6269. (b) Anderson, J. C.; Flaherty, A.; Swarbrick, M. E. J. Org. Chem.
2000, 65, 9152.
(59) Keck, G. E.; McHardy, S. F.; Murry, J. A. Tetrahedron Lett.
1994, 34, 6215
(60) Yus, M.; Radivoy, G.; Alonso, F. Synthesis 2001, 914
(61) (a) Cardani, S.; Gennari, C.; Scolastico, C.; Villa, R. Tetrahedron
1989, 45, 7397. (b) Williams, R. M.; Lee, B. H.; Miller, M. M.; Anderson,
O. P. J. Am. Chem. Soc. 1989, 111, 1073.
(62) (a) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351. (b) Gouverneur, V.; Ghosez, L.
Tetrahedron Lett. 1991, 32, 5349. (c) Ritter, A. R.; Miller, M. J. J. Org.
Chem. 1994, 59, 4602.
(50) (a) Wipf, P.; Jung, J.-K. Chem. Rev. 1999, 99, 1469. (b) Ohkata,
K.; Tamura, Y.; Shetuni, B. B.; Takagi, R.; Miyanaga, W.; Kojima, S.;
Paquette, L. A. J. Am. Chem. Soc. 2004, 126, 16783.
(51) The calculations were performed with Spartan′04 for Macintosh,
Wavefunction Inc., Irvine, CA 92612.
J. Org. Chem, Vol. 70, No. 25, 2005 10279

Wardrop and Burge
TABLE 4. Reductive N-O Bond Cleavage of N-Methoxy Lactams 30
a Reaction conditions: Mo(CO)6 (1.2 equiv), CH3CN, H2O reflux, 24 h; air, rt, 24 h. b Isolated yield, after purification by flash
chromatography.
tamination of the lactam products with unidentified,
nonpolar molybdenum complexes. As documented in
Table 4, reductive cleavage of the N-methoxy lactams
proceeded without incident to provide the corresponding
pyroglutamate derivatives in good to excellent yield. The
successful reduction of N-methoxy-2-azetidinone 30a
under these mild conditions is notable since direct
cleavage of this class of substrate has previously only
been accomplished under more stringent conditions
involving alkali metals in ammonia.61
N-Hydroxy lactams are important synthetic targets,
imbued with a wide range of biological activities, for
which there are relatively few methods of preparation
available.63 In this regard, the successful cyclization of
the benzyl hydroxamate substrates 12b, 12d, and 12f
and the subsequent compatibility of the O-benzyl groups
10280 J. Org. Chem., Vol. 70, No. 25, 2005

Nitrenium Ion Azaspirocyclization-Spirodienone Cleavage
TABLE 5. Hydrogenolysis of N-Benzyloxy Lactams 30
of dienone cleavage in the context of other types of
spirodienone.
Experimental Section
Reagents. Flash column chromatography was performed
according to the method of Still65 using silica gel 60 (mesh
230-400). Phenyliodine(III) bis(trifluoroacetate) (PIFA) was
prepared according to the procedure reported by Loudon.66
Solutions of sodium triacetoxyborohydride were prepared
freshly by reacting sodium borohydride with acetic acid.
General Procedure A (Preparation of Spirodienones
12 in CH2Cl2). (()-1,5-Methoxy-1-azaspiro[3.5]nona-5,8-
diene-2,7-dione (12a) (Entry 2, Table 1). To a stirred
suspension of phenyliodine(III) bis(trifluoroacetate) (PIFA)
(580 mg, 1.35 mmol, 1.2 equiv) in CH2Cl2 (1 mL), under an
atmosphere of N2 at -78 °C, was added a cold (-78 °C) solution
of alkyl hydroxamate 10a (253 mg, 1.12 mmol) in CH2Cl2 (5
mL) via cannula. The reaction mixture was then allowed to
warm to -15 °C (bath temperature) over 1.5 h, whereupon
H2O (3 mL) was added and the cooling bath removed. After
being stirred for 10 min, the biphasic mixture was partitioned
between CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (5
mL). The aqueous phase was separated and extracted with
CH2Cl2 (3 × 10 mL), and the combined organic extracts were
dried (Na2SO4), filtered, and concentrated under reduced
pressure to provide a yellow oil. Purification by flash chroma-
tography (SiO2, EtOAc/hexanes, 1:3) then afforded 12a (158
mg, 67%): white crystals; mp 100-103 °C (EtOAc/hexanes);
entry substrate
R
n
product reaction time (h) yielda (%)
1
2
3
30b
30d
30f
H
0
1
2
34b
34d
34f
0.1
0.5
1.5
99
90
99
H
Ac
a
Isolated yield, after purification by flash chromatography.
with the dienone cleavage protocol now provided an
opportunity to access these target molecules, through
selective hydrogenolysis of the benzyl ether in N-benzyl-
oxy lactams 30 (Table 5).
Hydrogenation of 30b, 30d and 30f in ethyl acetate
proceeded smoothly at atmospheric pressure, in the
presence of 10% Pd-C, to provide the desired N-hydroxy
lactams 34 in excellent yield. In all cases, the reaction
stopped after debenzylation, and no trace of the lactam
products, resulting from N-O bond cleavage,64 could be
detected.
Conclusions
Rf 0.55 (EtOAc); FTIR (film) νmax 1785, 1676, 1600, 1222 cm-1
;
1H NMR (500 MHz, CDCl3) δ 6.72 (d, J ) 9.9 Hz, 1 H), 6.36
(dd, J ) 1.6, 9.9 Hz, 1 H), 5.78 (d, J ) 1.6 Hz, 1 H), 3.84 (s, 3
H), 3.74 (s, 3 H), 3.15 (d, J ) 13.7 Hz, 1 H), 2.83 (d, J ) 13.7
Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 186.7, 169.3, 163.4,
142.2, 132.0, 105.7, 65.4, 61.2, 56.7, 43.8; HRMS-ESI calcd for
C10H11NO4Na [M + Na]+ 232.0586, found 232.0591.
In conclusion, we have reported a novel and efficient
strategy for the stereoselective preparation of di- and
trisubstituted azetidinone, pyrrolidinone, and piperidi-
none derivatives, which features the ozonolytic cleavage
of azaspirocyclic 2,5-cyclohexadienones. Notable features
of this methodology include (a) the rapidity with which
structural complexity is established; (b) flexibility (4-, 5-,
and 6-membered lactams and N-hydroxy lactams can be
accessed); and (c) the accessibility of the spirodienone
substrates, which can be prepared through the nitrenium
ion cyclization of alkyl ω-arylhydroxamates with excellent
efficiency and moderate to high diastereoselectivity. The
results presented herein demonstrate, for the first time,
that the ozonolytic cleavage of 2,5-cyclohexadienones is
a synthetically viable and potentially powerful method.
Since, in addition to the cyclization of nitrenium ions,
spirocyclic 2,5-cyclohexadienones, including lactones, lac-
tams, and oxazolines, are readily accessible, through the
oxidative spirocyclization of phenol derivatives, we an-
ticipate that the chemistry reported herein may offer a
general route to R,R-disubstituted heterocycles. Future
directions for this work will include application of the
current method to the synthesis of the natural products
lactacystin and kaitocephalin as well as an examination
General Procedure B (Preparation of Spirodienones
12 in CH2Cl2-MeOH). (()-1,6-Dimethoxy-1-azaspiro[4.5]-
deca-6,9-diene-2,8-dione (12c) (Entry 4, Table 1). To a
suspension of phenyliodine(III) bis(trifluoroacetate) (PIFA)
(863 mg, 2.01 mmol, 1.2 equiv) in MeOH (2 mL), under an
atmosphere of N2 at -78 °C, was added a cold (-78 °C) solution
of 10c (400 mg, 1.67 mmol) in CH2Cl2 (8 mL) via cannula. The
reaction mixture was then allowed to warm to -20 °C (internal
temperature) over 1.5 h, whereupon H2O (3 mL) was added
and the cooling bath removed. After being stirred for 10 min,
the biphasic mixture was partitioned between CH2Cl2 (10 mL)
and saturated aqueous NaHCO3 (5 mL). After separation, the
aqueous phase was extracted with CH2Cl2 (3 × 10 mL), and
the combined organic extracts were dried (MgSO4), filtered,
and concentrated under reduced pressure to provide a yellow
oil. Purification by flash chromatography over silica gel
(EtOAc) then afforded 12c (301 mg, 81%): white crystals; mp
133-135 °C (EtOAc/hexanes); Rf 0.24 (EtOAc); FTIR (film) νmax
1728, 1665, 1633, 1602, 1369, 1226 cm-1; 1H NMR (400 MHz,
CDCl3) δ 6.61 (d, J ) 9.9 Hz, 1 H), 6.28 (dd, J ) 1.5, 9.9 Hz,
1 H), 5.61 (d, J ) 1.5 Hz, 1 H), 3.76 (s, 3 H), 3.75 (s, 3 H),
2.65-2.55 (m, 1 H), 2.48-2.40 (m, 1 H), 2.26-2.19 (m, 1 H),
2.16-2.08 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 186.4, 173.2,
172.7, 144.3, 130.3, 103.2, 64.7, 62.8, 56.2, 27.3, 26.2; HRMS-
ESI calcd for C11H13NO4Na [M + Na]+ 246.0742, found
246.0750.
(63) (a) Black, D. S. C.; Brown, R. F. C.; Wade, A. M. Aust. J. Chem.
1972, 25, 2155. (b) Black, D. S. C.; Brown, R. F. C.; Wade, A. M. Aust.
J. Chem. 1972, 25, 2429. (c) Keck, G. E.; Webb, R. R.; Yates, J. B.
Tetrahedron 1981, 37, 4007. (d) Crossley, M. J.; Crumbie, R. L.; Fung,
Y. M.; Potter, J. J.; Pegler, M. A. Tetrahedron Lett. 1987, 28, 2883. (e)
Baldwin, J. E.; Adlington, R. M.; Gollins, D. W.; Schofield, C. J. J.
Chem. Soc., Chem. Commun. 1990, 720. (f) Baldwin, J. E.; Adlington,
R. M.; Godfrey, C. R. A.; Gollins, D. W.; Schofield, C. J. Tetrahedron
1991, 47, 5835 (g) Leeson, P. D.; Williams, B. J.; Rowley, M.; Moore,
K. W.; Baker, R.; Kemp, J. A.; Priestley, T.; Foster, A. C.; Donald, A.
E. Bioorg. Med. Chem. Lett. 1993, 3, 71. (h) Tiecco, M.; Testaferri, L.;
Tingoli, M.; Marini, F. J. Chem. Soc., Chem. Commun. 1994, 221. (i)
Thomas, A.; Rajappa, S. Tetrahedron 1995, 51, 10571. (j) Forzato, C.;
Nitti, P.; Pitacco, G.; Valentin, E.; Morganti, S.; Rizzato, E.; Spinelli,
D.; Dell′Erba, C.; Petrillo, G.; Tavani, C. Tetrahedron 2004, 60, 11011.
(64) Dong, L.; Miller, M. J. J. Org. Chem. 2002, 67, 4759.
Methyl (()-2-Formyl-1-methoxy-5-oxopyrrolidine-2-
carboxylate (21). A stream of oxygen and ozone was passed
through a solution of 12c (83 mg, 0.37 mmol) in CH2Cl2 (3 mL)
at -78 °C for 30 min. The blue solution was then purged with
a stream of argon for 5 min, Me2S (546 µL, 7.44 mmol) added,
(65) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(66) Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.; Blodgett,
J. K.; Boutin, R. H. J. Org. Chem. 1984, 49, 4272.
J. Org. Chem, Vol. 70, No. 25, 2005 10281

Wardrop and Burge
the cooling bath removed, and the mixture stirred room
temperature for 12 h. The reaction mixture was then concen-
trated under reduced pressure and the residual oil purified
by flash chromatography (SiO2, EtOAc) to provide a crude
sample of unstable 21 (45 mg, 61%): yellow oil; Rf 0.23
(EtOAc); IR (film) νmax 2951, 1734, 1296, 1246, 1059 cm-1; 1H
NMR (400 MHz, CDCl3) δ 9.92 (s, 1 H, CHO), 3.94 (s, 3 H),
3.89 (s, 3 H), 2.49-2.26 (m, 4 H); 13C NMR (100 MHz, CDCl3)
δ 194.5, 172.6, 168.9, 64.5, 53.5, 42.6, 25.6, 23.3; HRMS-ESI
calcd for C8H11NO5Na [M + Na]+ 224.0535, found 224.0538.
Methyl (2S*,6RS*)-2-(Hydroxymethoxymethyl)-1-meth-
oxy-5-oxopyrrolidine-2-carboxylate (22). A stream of oxy-
gen and ozone was passed through a solution of 12c (160 mg,
0.72 mmol) in MeOH (5 mL) at -78 °C for 30 min. The blue
solution was then purged with a stream of argon for 5 min,
thiourea (68 mg, 0.90 mmol, 1.25 equiv) was added, the cooling
bath was removed, and the solution was stirred at room
temperature for 5 h. The reaction mixture was then filtered
through a pad of Celite and the filtrate concentrated under
reduced pressure to provide crude 22 (180 mg) as an ap-
Hz, 1 H), 3.94 (s, 3 H), 3.90 (s, 3 H), 2.72-2.65 (m, 1 H), 2.61-
2.45 (m, 2 H), 2.40-2.33 (m, 1 H); 13C NMR (100 MHz, CDCl3)
δ 172.7, 170.1, 144.6, 144.3, 138.9, 130.3, 129.8, 123.2, 116.6,
69.3, 64.5, 53.7, 25.9, 25.4; HRMS-ESI calcd for C14H14N5O8
[M - H]- 380.0842, found 380.0844.
(()-2-[1,3]Dithiolan-2-yl-1-methoxy-5-oxopyrrolidine-
2-carboxylic Acid Methyl Ester (26). A stream of oxygen
and ozone was passed through a solution of 12c (123 mg, 0.55
mmol) in MeOH (3 mL) at -78 °C for 30 min. The blue solution
was then purged with a stream of argon for 10 min, thiourea
(52 mg, 0.69 mmol) added, the cooling bath removed, and the
solution then allowed to warm to room temperature over 40
min. The reaction mixture was then filtered through a plug of
Celite and the filtrate concentrated under reduced pressure.
The resulting colorless oil was taken up in CH2Cl2 (6 mL), and
ethane-1,2-dithiol (58 µL, 0.69 mmol) and concentrated HCl
(300 µL) were added sequentially. The reaction mixture was
stirred for 16 h at room temperature, concentrated under
reduced pressure, and purified by flash chromatography (SiO2,
EtOAc/hexanes, 1:5) to provide dithioacetal 26 (72 mg, 47%):
colorless oil; Rf 0.66 (EtOAc); FTIR (film) νmax 1735, 1433, 1271,
1057 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.37 (s, 1 H), 3.90 (s,
3 H), 3.81 (s, 3 H), 3.32-3.19 (m, 4 H), 2.51-2.46 (m, 2 H),
2.38-2.29 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ 173.6, 171.5,
72.0, 64.2, 55.5, 53.2, 39.4, 39.0, 26.4, 21.8; HRMS-ESI calcd
for C10H16NO4S2 [M + H]+ 278.0521, found 278.0526.
Methyl (()-E-2-(2-Ethoxycarbonylvinyl)-1-methoxy-5-
oxopyrrolidine-2-carboxylate (27). A stream of oxygen and
ozone was passed through a solution of 12c (200 mg, 0.90
mmol) in MeOH (5 mL) at -78 °C for 30 min. The blue solution
was then purged with a stream of argon for 10 min, thiourea
(85 mg, 1.11 mmol) added, the cooling bath removed, and the
solution then allowed to warm to room temperature over 40
min. The reaction mixture was then concentrated under
reduced pressure to provide 22 as an oil, which was dissolved
in toluene (5 mL). (Carbethoxymethylene)triphenylphosphorane
(687 mg, 1.97 mmol) was then added and the mixture heated
at reflux for 2 h. The reaction was then cooled and concen-
trated under reduced pressure and the resulting oil partitioned
between CH2Cl2 (10 mL) and saturated aqueous NH4Cl (7 mL).
The organic phase was separated and the aqueous portion
extracted with CH2Cl2 (3 × 10 mL), The combined organic
extracts were dried (Na2SO4), filtered, and concentrated under
reduced pressure, and the residue was purified by flash
chromatography (SiO2, EtOAc/hexanes, 1:1) to provide 27 (213
mg, 88%) as a single geometrical isomer: yellow oil; Rf 0.52
(EtOAc); IR (film) νmax 1726, 1659, 1313, 1266, 1184, 1053, 979
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J ) 16.0 Hz, 1 H),
6.10 (d, J ) 16.0 Hz, 1 H), 4.20 (q, J ) 7.2 Hz, 2 H), 3.93 (s, 3
H), 3.82 (s, 3 H), 2.44-2.15 (m, 4 H), 1.28 (t, J ) 7.2 Hz, 3 H);
13C NMR (100 MHz, CDCl3) δ 172.2, 170.3, 165.5, 142.0, 123.5,
69.6, 64.2, 60.9, 53.4, 28.4, 25.7, 14.1; HRMS-ESI calcd for
C12H17NO6Na [M + Na]+ 294.0954, found 294.0945.
1
proximately 1:1 mixture of hemiacetal diastereomers (by H
NMR): colorless oil; Rf 0.50 (EtOAc); IR (film) νmax 3373 (br),
1741, 1702, 1694, 1440, 1253, 1059 cm-1; 1H NMR (500 MHz,
CD3OD) δ (mixture of diastereomers) δ 5.11 (s, 0.5 H), 5.09 (s,
0.5 H), 3.80 (s, 3.8 H), 3.79 (s, 2.2 H), 3.42 (s, 1.2 H), 3.35 (s
1.5 H), 2.35-2.31 (m, 5 H); 13C NMR (125 MHz, CD3OD) δ
(mixture of diastereomers) 174.5, 174.4, 170.8, 170.7, 96.5,
96.3, 71.7, 71.4, 63.4, 63.3, 55.1, 54.8, 52.3, 49.0, 26.2, 26.1,
20.7, 20.1; HRMS-ESI calcd for C9H15NO6Na [M + Na]+
256.0797, found 256.0791.
(()-2-(Hydroxyiminomethyl)-1-methoxy-5-oxopyrroli-
dine-2-carboxylic Acid Methyl Ester (23). A stream of
oxygen and ozone was passed through a solution of 12c (200
mg, 0.90 mmol) in MeOH (5 mL) at -78 °C for 30 min. The
blue solution was then purged with a stream of argon for 10
min, thiourea (85 mg, 1.11 mmol) added, and the mixture then
allowed to warm to room temperature over 40 min. Sodium
acetate (132 mg, 1.61 mmol) and NH2OH‚HCl (149 mg, 2.15
mmol) were added and the mixture stirred at room tempera-
ture for 3 h. The reaction mixture was then concentrated under
reduced pressure and the residue purified by flash chroma-
tography (SiO2, EtOAc/hexane, 1:1) to provide 23 (146 mg,
75%) as a 12:1 mixture of geometrical isomers: yellow oil; Rf
0.68 (EtOAc); IR (film) νmax 3293 (br), 1745, 1703, 1439, 1268,
1
1070, 974 cm-1; H NMR (400 MHz, CDCl3) δ (major isomer)
8.96 (br s, 1 H), 7.74 (s, 1 H), 3.89 (s, 3 H), 3.83 (s, 3 H), 2.59-
2.51 (m, 1 H), 2.47-2.42 (m, 2 H), 2.26-2.19 (m, 1 H); 13C NMR
(100 MHz, CDCl3) δ (major isomer) 173.1, 170.3, 145.9, 68.3,
64.4, 53.5, 26.0, 25.1; HRMS-ESI calcd for C8H12N2O5Na [M
+ Na]+ 239.0644, found 239.0647.
(()-2-[(2,4-Dinitrophenyl)hydrazonomethyl]-1-methoxy-
5-oxopyrrolidine-2-carboxylic Acid Methyl Ester (24). A
stream of oxygen and ozone was passed through a solution of
12c (178 mg, 0.80 mmol) in MeOH (4 mL) at -78 °C for 30
min. The blue solution was then purged with a stream of argon
for 10 min, thiourea (76 mg, 1.00 mmol) added, the cooling
bath removed, and the solution allowed to warm to room
temperature over 40 min. After the reaction mixture was
filtered through a plug of Celite, the filtrate was sequentially
treated with activated 3 Å molecular sieve beads (500 mg),
2,4-dinitrophenylhydrazine (316 mg, 1.59 mmol), and concen-
trated HCl (300 µL). The reaction mixture was then heated
at reflux for 1.5 h, whereupon it was cooled to room temper-
ature, filtered through a plug of Celite, and concentrated under
reduced pressure. The resulting oil was purified by flash
chromatography (SiO2, EtOAc/hexanes, 1:5) to provide hydra-
zone 24 (204 mg, 67%): orange crystals; mp 174-176 °C
(EtOAc/hexanes); Rf 0.67 (EtOAc); FTIR (film) νmax 3296 (br),
Acetic Acid (()-2-Acetoxymethyl-1-methoxy-5-oxopyr-
rolidin-2-ylmethyl Ester (29). A stream of oxygen and ozone
was passed through a solution of 12c (148 mg, 0.66 mmol) in
CH2Cl2 (4 mL) at -78 °C for 30 min. The blue solution was
then purged with a stream of argon for 10 min, Me2S (730 µL,
9.94 mmol) added, the cooling bath removed, and the mixture
stirred at room temperature for 4 h. The reaction mixture was
then concentrated under reduced pressure, the residue dis-
solved in Et2O (5 mL), and this solution then treated with
LiBH4 (72 mg). After being stirred at room temperature for
16 h, the reaction was quenched with H2O (4 mL) and then
stirred for an additional 1 h. The organic layer was then
separated and the aqueous layer extracted with EtOAc (5 ×
10 mL). The combined organic extracts were dried (Na2SO4),
filtered through Celite, and concentrated under reduced pres-
sure. The resulting solid was dissolved in pyridine (1 mL) and
Ac2O (500 µL), and this mixture then stirred at room temper-
ature for 24 h. The reaction mixture was then concentrated
1
1735, 1616, 1593, 1514, 1431, 1335, 751 cm-1; H NMR (500
MHz, CDCl3) δ 11.26 (s, 1 H), 9.10 (d, J ) 2.5 Hz, 1 H), 8.34
(dd, J ) 2.5, 9.5 Hz, 1 H), 7.89 (s, 1H, NH), 7.87 (d, J ) 9.5
10282 J. Org. Chem., Vol. 70, No. 25, 2005

Nitrenium Ion Azaspirocyclization-Spirodienone Cleavage
under reduced pressure and the resulting residue purified by
flash chromatography (SiO2, EtOAc) to provide 29 (47 mg,
27%): colorless oil; Rf 0.32 (EtOAc); IR (film) νmax 1743, 1724,
additional 10 min, the reaction was concentrated under
reduced pressure and the residue dissolved in AcOH (500 µL).
This solution was added to a solution of NaBH(OAc)3 in AcOH
(0.17 M, 5 mL). After being stirred for 24 h at room temper-
ature, the reaction was concentrated under reduced pressure
and the residue dissolved in pyridine (1 mL) and acetic
anhydride (500 µL, 5 mmol). The mixture was stirred at room
temperature for 8 h and then concentrated under reduced
pressure and the residue purified by flash chromatography
(SiO2, EtOAc) to provide 30e (32 mg, 58%) and starting
material 12e (18 mg): white crystals; mp 72-74 °C (EtOAc/
hexanes); Rf 0.37 (EtOAc); FTIR (film) νmax 1745, 1689, 1238,
1051 cm-1; 1H NMR (500 MHz, CDCl3) δ 4.54 (d, J ) 11.9 Hz,
1 H), 4.49 (d, J ) 11.9 Hz, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H),
2.54-2.47 (m, 2 H), 2.19-2.16 (m, 1 H), 2.12 (s, 3 H), 2.11-
2.05 (m, 1 H), 1.82-1.78 (m 2 H); 13C NMR (125 MHz, CD3-
OD) δ 171.0 (2 C), 170.7, 70.9, 63.9, 63.7, 53.5, 33.5, 31.3, 21.2,
18.1; HRMS-ESI calcd for C11H17NO6Na [M + Na]+ 282.0954,
found 282.0958.
General Procedure E (Luche Reduction-Ozonolysis
of Spirodienones 12). Methyl (2S*,4S*)-2-Hydroxy-
methyl-1-methoxy-5-oxo-4-phenylpyrrolidine-2-carbox-
ylate (30j) (Entry 10, Table 2). To a solution of 12j (117 mg,
0.39 mmol) and CeCl3‚7H2O (117 mg, 0.39 mmol) in MeOH (8
mL) at 0 °C was added NaBH4 (16 mg, 0.41 mmol). After being
stirred for 1 min, the reaction was quenched with water (2
mL) and concentrated under reduced pressure and the re-
maining aqueous portion extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were dried (Na2SO4), filtered,
and concentrated to provide the unstable dienylic alcohol as a
colorless oil, which was immediately subjected to ozonolysis.
Thus, a stream of oxygen and ozone was passed through a
solution of the dienylic alcohol in MeOH (4 mL) at -78 °C for
30 min. The blue solution was then purged with a stream of
argon for 10 min, thiourea (37 mg, 0.49 mmol, 1.25 equiv) was
added, and the solution was then allowed to warm to room
temperature over 30 min. After being stirred for an additional
30 min, the reaction was concentrated under reduced pressure,
the residue dissolved in AcOH (1 mL), and this mixture added
to a solution of NaBH(OAc)3 in AcOH (0.65 M, 3 mL, 5 equiv).
After being stirred for 24 h at room temperature, the reaction
was concentrated under reduced pressure, the residual oil
diluted with CH2Cl2 (10 mL), and 2 M aqueous HCl (5 mL)
added. After being allowed to stand for 20 min, the organic
layer was separated and the aqueous layer extracted with CH2-
Cl2 (3 × 15 mL). The combined organic extracts were concen-
trated under reduced pressure, and the resulting oil was
purified by flash chromatography (SiO2, EtOAc) to provide 30j
(107 mg, 98%).
1
1225, 1045 cm-1; H NMR (400 MHz, CDCl3) δ 4.26 (d, J )
11.6 Hz, 2 H), 4.12 (d, J ) 11.6 Hz, 2 H), 3.84 (s, 3 H), 2.38
(m, 2 H), 2.10 (s, 6 H), 2.03 (m, 2 H); 13C NMR (100 MHz,
CDCl3) δ 172.4, 170.3, 64.3, 64.2, 63.8, 26.3, 22.6, 20.7; HRMS-
ESI calcd for C11H17NO6Na [M + Na]+ 282.0954, found
282.0958.
Methyl (()-2-Hydroxymethyl-1-methoxy-5-oxopyrro-
lidine-2-carboxylate (30c). A stream of oxygen and ozone
was passed through a solution of 12c (139 mg, 0.62 mmol) in
CH2Cl2 (7 mL) at -78 °C for 30 min. The blue solution was
then purged with a stream of argon for 10 min, Me2S (686 µL,
9.34 mmol) added, the cooling bath removed, and the mixture
stirred at room temperature for 4 h. The reaction mixture was
then filtered through a plug of Celite and the filtrate concen-
trated under reduced pressure. The resulting residue was
dissolved in AcOH (2 mL) and this mixture added to a solution
of NaBH(OAc)3 in AcOH (0.8 M, 7.8 mL). After being stirred
for 24 h at room temperature, the reaction was concentrated
under reduced pressure, the residual oil diluted with CH2Cl2
(5 mL), and 2 M aqueous HCl (2 mL) added. After being
allowed to stand for 10 min, the organic layer was separated
and the aqueous layer extracted with CH2Cl2 (3 × 10 mL). The
combined organic extracts were concentrated under reduced
pressure, and the resulting oil was purified by flash chroma-
tography (SiO2, EtOAc) to provide 30c (62 mg, 49%): colorless
oil; Rf 0.32 (EtOAc); FTIR (film) νmax 3410 (br), 1737, 1706,
1432, 1251, 1056, 969 cm-1; 1H NMR (500 MHz, CDCl3) δ 3.97
(d, J ) 11.9 Hz, 1 H), 3.87 (d, J ) 11.9 Hz, 1 H), 3.84 (s, 3 H),
3.73 (s, 3 H), 3.35 (br s, 1 H), 2.38-2.34 (m, 2 H), 2.28-2.22
(m, 1 H), 2.08-2.03 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ
173.8, 172.2, 70.0, 64.3, 62.9, 53.2, 26.7, 24.1; HRMS-EI calcd
for C8H14NO5 [M + H]+ 204.0872, found 204.0881
General Procedure C (Ozonolysis-Reduction of Spiro-
dienones 12). Methyl (()-2-Hydroxymethyl-1-methoxy-
4-oxoazetidine-2-carboxylate (30a) (Entry 1, Table 2). A
stream of oxygen and ozone was passed through a solution of
12a (50 mg, 0.24 mmol) in MeOH (3 mL) at -78 °C for 30
min. The blue solution was then purged with a stream of argon
for 10 min, thiourea (23 mg, 0.30 mmol) was added, and the
solution then allowed to warm to room temperature over 30
min. After being stirred for an additional 10 min, the reaction
was concentrated under reduced pressure, the residue dis-
solved in AcOH (500 µL), and this mixture added to a solution
of NaBH(OAc)3 in AcOH (0.51 M, 2 mL). After being stirred
for 24 h at room temperature, the reaction was concentrated
under reduced pressure, the residual oil diluted with CH2Cl2
(5 mL), and 2 M aqueous HCl (2 mL) added. After being
allowed to stand for 10 min, the organic layer was separated
and the aqueous layer extracted with CH2Cl2 (3 × 10 mL). The
combined organic extracts were concentrated under reduced
pressure, and the resulting oil was purified by flash chroma-
tography (SiO2, EtOAc) to provide 30a (35 mg, 78%): colorless
oil; Rf 0.44 (EtOAc); IR (film) νmax 3445 (br), 1778, 1742, 1072,
1031 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.16 (d, J ) 12.4 Hz,
1 H), 4.02 (d, J ) 12.4 Hz, 1 H), 3.90 (s, 3 H; OCH3), 3.84 (s,
3 H; OCH3), 2.93 (d, J ) 13.8 Hz, 1 H), 2.88 (d, J ) 13.8 Hz,
1 H) 2.51 (br s, 1 H); 13C NMR (100 MHz, CDCl3) δ 170.3, 164.4,
67.5, 65.0, 61.4, 53.0, 39.6; HRMS-ESI calcd for C7H11NO5Na
[M + Na]+ 212.0535, found 212.0543.
General Procedure F (Reductive Cleavage of N-Meth-
oxy Lactams). Methyl (()-2-Hydroxymethyl-4-oxoazeti-
dine-2-carboxylate (32a) (Entry 1, Table 4). A mixture of
30a (210 mg, 1.11 mmol) and Mo(CO)6 (352 mg, 1.33 mmol,
1.2 equiv) in degassed CH3CN-H2O (15:1, 5 mL) was heated
at reflux, under N2, for 24 h, whereupon the black reaction
mixture was cooled to room temperature, opened to the
atmosphere, and stirred for 24 h. The reaction was then
concentrated under reduced pressure and the resulting residue
purified by flash chromatography (SiO2, EtOAc) to yield 32a
(133 mg, 75%): colorless oil; Rf 0.37 (EtOAc); FTIR (film) νmax
1
3312 (br), 1750, 1277, 1228, 1045 cm-1; H NMR (400 MHz,
CDCl3) δ 6.80 (br s, 1 H), 4.14 (d, J ) 11.7 Hz, 1 H), 3.85-
3.82 (m, 4 H), 3.12 (d, J ) 14.9 Hz, 1 H), 3.04 (d, J ) 14.9 Hz,
1 H), 2.71 (br s, 1 H); 13C NMR (100 MHz, CD3OD) δ 172.4,
167.1, 65.1, 59.3, 53.5, 45.2; HRMS-ESI calcd for C6H9NO4 [M
+ Na]+ 182.0429, found 182.0426.
General Procedure G (Hydrogenolysis of N-Benzyloxy
Lactams). Methyl (()-1-Hydroxy-2-hydroxymethyl-4-
oxoazetidine-2-carboxylate (34b) (Entry 1, Table 5). A
mixture of 30b (40 mg, 0.15 mmol) and 10% Pd/C (2 mg) in
EtOAc (2 mL) was stirred under an atmosphere of H2 for 10
General Procedure D (Ozonolysis-Reduction-Acetyla-
tion of Spirodienones 12). Methyl (()-2-Acetoxymethyl-
1-methoxy-6-oxopiperidine-2-carboxylate (30e) (Entry 5,
Table 2). A stream of oxygen and ozone was passed through
a solution of 12e (50 mg, 0.21 mmol) in MeOH (5 mL) at -78
°C for 3 h. The blue solution was then purged with a stream
of argon for 10 min, thiourea (20 mg, 0.26 mmol) was added
in one portion, and the solution was then allowed to warm to
room temperature over 30 min. After being stirred for an
J. Org. Chem, Vol. 70, No. 25, 2005 10283

Wardrop and Burge
min and then filtered through a pad of Celite. The filtrate was
concentrated under reduced pressure and the residue purified
by flash chromatography (SiO2, EtOAc) to yield 34b (26 mg,
99%): colorless oil; Rf 0.25 (EtOAc); FTIR (film) νmax 3390 (br),
Acknowledgment. We thank the National Insti-
tutes of Health (GM-67176) for financial support.
1
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1770, 1745, 1247, 1037 cm-1; H NMR (400 MHz, CD3OD) δ
4.02 (d, J ) 12.4 Hz, 1 H), 3.95 (d, J ) 12.4 Hz, 1 H), 3.79 (s,
3 H), 2.89 (d, J ) 13.2 Hz, 1 H), 2.82 (d, J ) 13.2 Hz, 1 H); 13
C
NMR (100 MHz, CD3OD) δ 170.0, 164.7, 67.9, 58.4, 51.7, 38.0;
HRMS-ESI calcd for C6H9NO5Na [M + Na]+ 198.0378, found
198.0373.
JO051252R
10284 J. Org. Chem., Vol. 70, No. 25, 2005