An enantioselective ring expansion route leading to furanose and pyranose nucleosides featuring spirodiketopiperazines at the anomeric position

Article abstract of DOI:10.1021/jo982259u

A study directed at the enantioselective synthesis of spirodiketopiperazine homologues of hydantocidin is described. Furanoid glycals, systems that are amenable to C-5 metalation in the presence of tert- butyllithium, are readily coupled to N-protected 2,3-azetidinediones provided that at least 1 equiv of BF₃·OEt₂ is present to curb enolization. The resulting 1:1 mixtures of carbinols undergo smooth ring expansion to spirocyclic keto amides when heated with pyridinium p-toluenesulfonate in benzene. 1,2-Acyl shifts operate exclusively. Since attempts to engage these products in Beckmann rearrangement proved singularly unsuccessful, recourse was alternatively made to new methodology based upon sequential Baeyer- Villiger oxidation and ammonolysis. The data show that the first of these steps occurs with exclusive migration of the quaternary carbon. Furthermore, nucleophilic attack by NH₃ can be directed regioselectively to the anomeric region. If heating is supplied during acid-promoted cyclization to the spirodiketopiperazines, spiropyranose derivatives are produced in a complementary process. The central issue of this synthesis effort was the utilization of 4-phenylseleno-substituted furanoid glycals so as to ultimately enable introduction of the cis-diol functionality at C-3 and C-4 (hydantocidin numbering).

Full text of DOI:10.1021/jo982259u

2010
J . Org. Chem. 1999, 64, 2010-2025
An En a n tioselective Rin g Exp a n sion Rou te Lea d in g to F u r a n ose
a n d P yr a n ose Nu cleosid es F ea tu r in g Sp ir od ik etop ip er a zin es a t
th e An om er ic P osition
Leo A. Paquette,* Stephen Brand, and Carsten Behrens
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received November 13, 1998
A study directed at the enantioselective synthesis of spirodiketopiperazine homologues of hydan-
tocidin is described. Furanoid glycals, systems that are amenable to C-5 metalation in the presence
of tert-butyllithium, are readily coupled to N-protected 2,3-azetidinediones provided that at least
1 equiv of BF3‚OEt2 is present to curb enolization. The resulting 1:1 mixtures of carbinols undergo
smooth ring expansion to spirocyclic keto amides when heated with pyridinium p-toluenesulfonate
in benzene. 1,2-Acyl shifts operate exclusively. Since attempts to engage these products in Beckmann
rearrangement proved singularly unsuccessful, recourse was alternatively made to new methodology
based upon sequential Baeyer-Villiger oxidation and ammonolysis. The data show that the first
of these steps occurs with exclusive migration of the quaternary carbon. Furthermore, nucleophilic
attack by NH3 can be directed regioselectively to the anomeric region. If heating is supplied during
acid-promoted cyclization to the spirodiketopiperazines, spiropyranose derivatives are produced
in a complementary process. The central issue of this synthesis effort was the utilization of
4-phenylseleno-substituted furanoid glycals so as to ultimately enable introduction of the cis-diol
functionality at C-3 and C-4 (hydantocidin numbering).
(+)-Hydantocidin (1) is an architecturally unusual
observations have understandably stimulated consider-
able interest not only in the synthesis of 16 but also in a
variety of its analogues. Included in this group are the
levorotatory C-5 epimer (2),7 several deoxy derivatives,4,8
as well as carbocyclic9 and sulfur-containing isosteres.10
Additional preparative work has focused on the elabora-
tion of pyranose derivatives of various types (e.g., 3)11 or
of more diverse spiroheterocyclic subunits (e.g., 4).12
spirohydantoin D-ribofuranose nucleoside recently iso-
lated from fermentation broths of Streptomyces hygro-
scopicus SANK 63584,1 Tu-2474,2 and A1491.3 This
(6) (a) Mio, S.; Ichinose, R.; Goto, K.; Sugai, S.; Sato, S. Tetrahedron
1991, 47, 2111. (b) Mio, S.; Shiraishi, M.; Sugai, S.; Haruyama, H.;
Sato, S. Tetrahedron 1991, 47, 2121. (c) Mio, S.; Kumagawa, Y.; Sugai,
S. Tetrahedron 1991, 47, 2133. (d) Mio, S.; Ueda, M.; Hamura, M.;
Kitagawa, J .; Sugai, S. Tetrahedron 1991, 47, 2145. (e) Chemla, P.
Tetrahedron Lett. 1993, 34, 7391. (f) Harrington, P. M.; J ung, M. E.
Tetrahedron Lett. 1994, 35, 5145. (g) Dondoni, A.; Scherrmann, M.-
C.; Marra, A.; Dele´pine, J .-L. J . Org. Chem. 1994, 59, 7517. (h)
Nakajima, N.; Matsumoto, M.; Kirihara, M.; Hashimoto, M.; Katoh,
T.; Terashima, S. Tetrahedron 1996, 52, 1177.
(7) (a) Fairbanks, A. J .; Ford, P. S.; Watkin, D. J .; Fleet, G. W. J .
Tetrahedron Lett. 1993, 34, 3327. (b) Fairbanks, A. J .; Fleet, G. W. J .
Tetrahedron 1995, 51, 3881. (c) Nakajima, N.; Kirihara, M.; Matsu-
moto, M.; Hashimoto, M.; Katoh, T.; Terashima, S. Heterocycles 1996,
42, 503.
(8) Renard, A.; Kotera, M.; Lhomme, J . Tetrahedron Lett. 1998, 39.
3129.
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(b) Sano, H.; Sugai, S. Tetrahedron 1995, 51, 4635.
(10) (a) Sano, H.; Mio, S.; Kitagawa, J .; Shindou, M.; Honma, T.;
Sugai, S. Tetrahedron 1995, 51, 12563. (b) Lamberth, C.; Blarer, S.
Synth. Commun. 1996, 26, 75.
substance was quickly recognized to be an extremely
potent herbicide devoid of toxicity to animals and micro-
organisms.1,4 This plant-growth regulator functions as a
proherbicide to a metabolite that inhibits purine biosyn-
thesis at the adenylosuccinate synthase site.5 These
(1) (a) Haruyama, H.; Takayama, T.; Kinoshita, T.; Kondo, M.;
Nakajima, M.; Haneishi, T. J . Chem. Soc., Perkin Trans. 1 1991, 1637.
(b) Nakajima, M.; Itoi, K.; Takamatsu, Y.; Okazaki, T.; Kinoshita, T.;
Shindou, M.; Kawakubo, K.; Honma, T.; Toujigamori, M.; Haneishi,
T. J . Antibiot. 1991, 44, 293. (c) Sankyo, Eur. Pat. Appl. 0 23 572 A,
19.08.1989. (d) Sankyo, US Pat. 4,952,234, 29/07/1988.
(2) Ciba-Geigy, DE Pat. 41 29 616 A, 10/09/1990.
(3) Mitsubishi Kasei, J pn. Pat. 04222589 A, 19/12/1990.
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Biol. Chem. 1991, 55, 1105. (b) Mio, S.; Sugai, S. Annu. Rep. Sankyo
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(11) (a) Bichard, C. J . F.; Mitchell, E. P.; Wormald, M. R.; Watson,
K. A.; J ohnson, L. N.; Zographos, S. E.; Koutra, D. D.; Oikonomakos,
N. G.; Fleet, G. W. J . Tetrahedron Lett. 1995, 36, 2145. (b) Brandstetter,
T. W.; Kim, Y.-H.; Son, J . C.; Taylor, H. M.; Lilley, P. M. de Q.; Watkin,
D. J .; J ohnson, L. N.; Oikonomakos, N. G.; Fleet, G. W. J . Tetrahedron
Lett. 1995, 36, 2149. (c) Brandstetter, T. W.; Wormald, M. R.; Dwek,
R. A.; Butters, T. D.; Platt, F. M.; Tsitsanou, K. E.; Zographos, S. E.;
Oikonomakos, N. G.; Fleet, G. W. J . Tetrahedron: Asymmetry 1996,
7, 157. (d) Esteves, J . C.; Smith, M. D.; Wormald, M. R.; Besra, G. S.;
Brennan, P. J .; Nash, R. J .; Fleet, G. W. J . Tetrahedron: Asymmetry
1996, 7, 391. (e) Kru¨lle, T. M.; de la Fuente, C.; Watson, K. A.;
Gregoriou, M.; J ohnson, L. N.; Tsitsanou, K. E.; Zographos, S. E.;
Oikonomakos, N. G.; Fleet, G. W. J . Synlett 1997, 211. (f) Osz, E.;
So´s, E.; Somsa´k, L.; Szila´gyi, L.; Dinya, Z. Tetrahedron 1997, 53,
5813.
(5) (a) Heim, D. R.; Cseke, C.; Gerwick, B. C.; Murdoch, M. G.; Green,
S. B. Pesticide Biochem. Physiol. 1995, 53, 138. (b) Siehl, D. L.;
Subramanian, M. V.; Walters, E. W.; Lee, S. F.; Anderson, R. J .; Toschi,
A. G. Plant Physiol. 1996, 110, 753.
10.1021/jo982259u CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/03/1999

Enantioselective Ring Expansion Route
J . Org. Chem., Vol. 64, No. 6, 1999 2011
The fact that naturally occurring13 and synthetic
diketopiperazines14 constitute a class of bioactive pep-
tides15 has not escaped attention. Fleet and co-workers
have recently reported the incorporation of a spirodike-
topiperazine ring into the anomeric position of furanose16
and pyranose sugars17 in an effort to mimic 1. Our
interest in constrained nucleosides of this type arose in
the same context18 and as a result of new ring expansion
methodology being developed in this laboratory.19 This
paper explores the synthesis of a member of this com-
pound class in which an acid-catalyzed rearrangement
of a 3-hydroxy â-lactam and the ammonolysis of a spiro
keto lactone are featured.
luded to by Palomo and co-workers.22 These include a
pronounced tendency to undergo enolization23 and, in
protic solvents, hemiacetal formation. Our investigation
into both of these concerns revealed that 9a was 70%
enolized in CDCl3 at room temperature (1H NMR analy-
sis). In D2O, only the keto form was observed. The
addition of Lewis acids, most notably boron trifluoride
etherate, to CDCl3 solutions likewise had the effect of
driving the equilibrium strongly in the keto direction. As
a consequence, all of the addition reactions reported
herein were performed in the presence of BF3‚OEt2.
Furthermore, as the double bond cleavage in 8 is
performed in aqueous methanol, the oxidation results in
initial formation of the methyl hemiketal derivative. To
avoid low yields in the ensuing glycal coupling step, care
must be exercised to ensure complete removal of the
methanol, either by prolonged warming under high
vacuum or by recrystallization.
Resu lts a n d Discu ssion
Cou p lin g of F u r a n oid Glyca ls to N-P r otected
Azetid in ed ion es. N-p-Methoxybenzyl-2,3-azetidinedi-
one (9b) was prepared starting from methyl acrylate and
acetaldehyde in a manner parallel to that developed
earlier for the N-benzyl derivative 9a (Scheme 1).20,21
Entirely comparable yields were realized in steps b-e.
(S)-(+)-Dihydro-5-(hydroxymethyl)-2-(3,4)-furanone (10)
was prepared in 97% enantiomeric excess from L-glutam-
ic acid according to precedent.24,25 Although the robust
trityl protecting group was utilized in the early phases
of this investigation, recourse was subsequently made to
the tert-butyldimethylsilyl alternative in order to facili-
tate later unmasking of this hydroxyl.26
Sch em e 1a
Dibal-H reduction of 10a and 10b followed by acetyl-
ation of the resulting lactols and vacuum pyrolysis in a
Kugelrohr apparatus27 gave rise efficiently to 12a and
12b, respectively (Scheme 2). In keeping with the kinetic
acidity exhibited by the parent dihydrofuran28 and alkyl
derivatives thereof,27b 12a and 12b could be metalated
at C-5 by exposure to tert-butyllithium at low tempera-
ture. Deprotonation R to silicon is reportedly a problem
in the presence of this alkyllithium.29 However, a deu-
terium labeling study designed to measure the regio-
chemistry and extent of lithiation of 12b under standard
conditions (t-BuLi, 30 min at -78 °C followed by 30 min
at -20 to 0 °C to give a near-colorless solution) revealed
that the dihydrofuran undergoes approximately 90%
deprotonation at C-1 during this time frame. No deu-
teration of the CH3Si groups was noted. Also, exposure
a
Key: (a) CH3CHO, DABCO, MeOH; (b) ArCH2NH2, MeOH;
(c) t-BuMgCl, THF; (d) MsCl, Et3N, CH2Cl2; DBU; (e) NaIO4,
(OsO4), MeOH, H2O.
Possible complications associated with the addition of
carbon nucleophiles to R-keto-â-lactams have been al-
(21) For another application of this sequence, see: Paquette, L. A.;
Rothhaar, R. R.; Isaac, M.; Rogers, L. M.; Rogers, R. D. J . Org. Chem.
1998, 63, 5463.
(22) Palomo, C.; Aizpurua, J . M.; Lopez, M. C.; Aurrekoetxea, N.;
Oiarbide, M. Tetrahedron Lett. 1990, 31, 6425.
(23) Chiba, K.; Mori, M.; Ban, Y. Tetrahedron 1985, 41, 387.
(24) Ezquerra, J .; He, W.; Paquette, L. A. Tetrahedron Lett. 1990,
31, 6979 and relevant references therein.
(25) It is strongly recommended that the carboxy lactone precursor
to 10 not be purified by distillation (165 °C, 0.1 Torr) as this appears
to be the main cause of a loss in optical purity in subsequent
intermediates (variations from 92 to 30% ee have been measured). This
unwanted consequence can be avoided by utilizing the unpurified acid
directly in further transformations or by recrystallization of the
material from benzene. If the crude material is used, it should be dried
sufficiently (MgSO4, then azeotropic removal of benzene solvent) prior
to subsequent reduction with the borane-dimethyl sulfide reagent.
The reduction of crude acid is even more vigorous, and gr ea t ca r e
must be taken to ensure controlled addition of reducing agent so as to
avoid an uncontrollable exotherm. HPLC analysis of 10 prepared in
this manner demonstrates that if these precautions are taken the
original optical purity of the L-glutamic acid (97% ee) is retained.
(26) The triisopropylsilyl and tert-butyldiphenylsilyl groups were
introduced with equal success. In retrospect, the high crystallinity and
UV activity imparted by the TBDPS functionality to its derivatives
may cause its selection to be the most practical one.
(12) (a) Ferris, J . P.; Devadas, B. J . Org. Chem. 1987, 52, 2355. (b)
Yokoyama, M.; Yamada, N. Tetrahedron Lett. 1989, 30, 3675. (c)
Yokoyama, M.; Yamada, N.; Togo, H. Chem. Lett. 1990, 753. (d) Mellor,
J . M.; Mohammed, S. Tetrahedron Lett. 1991, 32, 7111. (e) Kittaka,
A.; Tanaka, H.; Odanaka, Y.; Ohnuki, K.; Yamaguchi, K.; Miyasaka,
T. J . Org. Chem. 1994, 59, 3636. (f) Sano, H.; Mio, S.; Tsukaguchi, N.;
Sugai, S. Tetrahedron 1995, 51, 1387. (g) Brandstetter, T. W.; de la
Fuente, C.; Kim, Y.-h.; J ohnson, L. N.; Crook, S.; Lilley, P. M. de Q.;
Watkin, D. J .; Tsitsanou, K. E.; Zographos, S. E.; Chrysina, E. D.;
Oikonomakos, N. G.; Fleet, G. W. J . Tetrahedron 1996, 52, 10721.
(13) (a) Funabashi, Y.; Horiguchi, T.; Iinuma, S.; Tanida, S. J .
Antibiot. 1994, 47, 1202. (b) Alvarez, M. E.; Houck, D. R.; White, C.
B.; Brownell, J . E.; Bobko, M. A.; Rodger, C. A.; Stawicki, M. B.; Sun,
H. H.; Gillum, A. M.; Cooper, R. J . Antibiot. 1994, 47, 1196. (c)
Adamczeski, M.; Reed, A. R.; Crews, P. J . Nat. Prod. 1995, 58, 201.
(14) Barrow, C. J .; Musza, L. L.; Cooper, R. Bioorg. Med. Chem. Lett.
1995, 5, 377.
(15) Prasad, C. Peptides 1995, 16, 151.
(16) Estevez, J . C.; Smith, M. D.; Lane, A. L.; Crook S.; Watkin, D.
J .; Besra, G. S.; Brennan, R. J .; Nash, R. J .; Fleet, G. W. J .
Tetrahedron: Asymmetry 1996, 7, 387.
(17) (a) Estevez, J . C.; Long, D. D.; Wormald, M. R.; Dwek, R. A.;
Fleet, G. W. J . Tetrahedron Lett. 1995, 36, 8287. (b) Kru¨lle, T. M.;
Watson, K. A.; Gregoriou, M.; J ohnson, L. N.; Crook, S.; Watkin, D.
J .; Griffiths, R. C.; Nash, R. J .; Tsitsanou, K. E.; Zographos, S. E.;
Oikonomakos, N. G.; Fleet, G. W. J . Tetrahedron Lett. 1995, 36, 8291.
(18) (a) Paquette, L. A.; Behrens, C. Heterocycles 1997, 46, 31. (b)
Behrens, C. Unpublished observations.
(27) (a) Zhang, H.-C.; Daves, G. D., J r. J . Org. Chem. 1993, 58, 2557.
(b) Paquette, L. A.; Lanter, J . C.; J ohnston, J . N. J . Org. Chem. 1997,
62, 1702.
(28) Boeckman, R. K., J r.; Bruza, K. J . Tetrahedron Lett. 1977, 4187.
(29) Friesen, R. W.; Sturino, C. F.; Daljeet, A. K.; Kolaczewska, A.
J . Org. Chem. 1991, 56, 1944.
(19) Paquette, L. A. Recent Res. Dev. Chem. Sci. 1997, 1.
(20) Behrens, C.; Paquette, L. A. Org. Synth. 1998, 75, 106.

2012 J . Org. Chem., Vol. 64, No. 6, 1999
Paquette et al.
Sch em e 2a
in yield was noted, a phenomenon that was directly
linked to the quantity of furanoid glycal recovered.
Quenching of the lithiated intermediate by the enol tau-
tomer of the 2,3-azetidinedione or incomplete lithiation
during the preceding operation are believed to be contrib-
utory factors. The adducts proved not to be extraordinar-
ily sensitive and were generally amenable to full char-
acterization as inseparable 1:1 diastereomeric mixtures.
Isom er iza tion of th e 3-Hyd r oxya zetid in on es. Py-
ridinium p-toluenesulfonate in benzene solution proved
suitable for promoting the key spirocyclization-ring
expansion transformation. When 15a was stirred at 20
°C for 24 h under these conditions, the chromatographi-
cally purified lactams 19a and 20a were obtained in a
1:2 ratio and a combined isolated yield of 51% (Scheme
3). The rearrangement of 15b, performed at the reflux
Sch em e 3
a
Key: (a) TrCl, DMAP, Et3N; (b) TBSCl, imid, DMF; (c) Dibal-
H, CH2Cl2, Et2O; (d) Ac2O, py, CH2Cl2; (e) 190 °C 0.5 (11a ) or 70
Torr (11b); (f) t-BuLi, THF, -78 °C; n-Bu3SnCl; (g) PhSCl, THF,
-78 °C; KO-t-Bu; (h) PhSeCl, THF, -78 °C; KO-t-Bu.
of the lithium derivative of 12a to excess tri-n-butyltin
chloride afforded 13 in 60% yield. Subsequent transmeta-
lation of this stannane with n-butyllithium made possible
clean reconversion to the lithium species without con-
tamination by an excess of n-BuLi.18b
temperature for a shorter time period (80 min), proceeded
more efficiently (92%) to deliver 19b and 20b. Like 15a ,
15b afforded the more polar spirocyclic isomer predomi-
nantly (1:1.6). Stereochemical distinction between 19a
and 20a was achieved by their independent Wittig olefin-
ation. Access to 21 and 22 in this manner was followed
by detailed analysis of NOE effects in C6D6 solution (see
The formation of 14a from 12b via an intermediate
chloro sulfide adduct with subsequent dehydrochlorina-
tion by means of DBU proved troublesome, giving rise
to a complex reaction mixture from which only 17% of
the desired product could be retrieved. However, the
replacement of DBU by potassium tert-butoxide signifi-
cantly improved the yield (87%) and rate of this conver-
sion. Application of this modification to the phenylsele-
nenyl derivative afforded 14b without difficulty (78%
yield).
In every case examined, coupling of the lithiated di-
hydrofuran to 9a and 9b at low temperature in THF con-
taining boron trifluoride etherate gave the desired epimer-
ic mixture of carbinols, i.e., 15-18. Considerable variation
1
formulas). Other revealing H NMR changes were fully
consistent with the indicated structural assignments.
Thus, the ∆νAB of the protons in the TrOCH2- group was
more than doubled following the conversion of 20a (53.4
Hz) to 22 (108.8 Hz). The associated effects in 19a and
21 are only marginal (29.3 Hz f 26.5 Hz). Of equal
importance was the fact that chemical shift and infrared
data showed the carbonyl groups not to be vicinal. The
relative configuration at the spirocyclic center in 19b and
20b was initially assigned by analogy and later confirmed
unambiguously by X-ray crystallography (see below).
The available evidence supports the working assump-
tion that expansion of the azetidinone ring proceeds
exclusively with migration of the carbonyl carbon. This
selectivity in favor of 1,2-acyl transfer conforms to
observations recorded for many related acid-catalyzed
isomerizations, the most exhaustively studied of which
relate to R,â-epoxy ketones.30 Once the glycal double bond
has been protonated with formation of the cyclic oxonium
(30) Rosowsky, A. In Heterocyclic Compounds with Three- and Four-
Membered Rings, Part One, Weissberger, A., Ed.; Interscience: New
York, 1964; pp 253-261.

Enantioselective Ring Expansion Route
J . Org. Chem., Vol. 64, No. 6, 1999 2013
ion, the acyl shift can occur either syn (as in A) or anti
to the substituent residing at C-2 (see B). The intuitive
expectation based on steric considerations is that path-
way A should be impeded to some degree. Significantly,
the partitioning of these reaction trajectories gives no
evidence of being linked to the diastereomeric ratio
present in the starting 3-hydroxy-â-lactams 15-18.
Comparable rearrangement of the model system 16
resulted in efficient conversion to 23 as the only product
(Scheme 4). The structural features of 23 were originally
F igu r e 1. Computer-generated perspective drawing of 26 as
Sch em e 4
determined by X-ray crystallography.
The acid-catalyzed isomerization of 17a occurs at a
considerably slower rate than the unsubstituted analogue
15b under comparable conditions (48 h versus 80 min).
This phenomenon may result because 17a offers two pos-
sible sites for protonation. Although placement of the pos-
itive charge adjacent to oxygen is more likely, competitive
protonation with generation of a sulfur-stabilized cation
would obviate the course of the reaction. A similar rate
reduction in spirocyclization is not observed for 16, 17b,
and 18 since Se-stabilized carbocation generation is less
likely. Notwithstanding, comparable yields are realized.
Chromatographic purification of this reaction mixture
gave two fractions defined as 28 and 29, 1H NMR analy-
sis of which indicated the presence in each of two coelu-
ting anomers in the approximate ratio of 1:1 (Scheme 5).
Whether these anomers vary at C-5 (the spirocyclic
center) or at the adjacent sulfur-substituted position
would be demonstrated by their conversion to the 3,4-
Sch em e 5
deduced on the assumption that the 1,2-acyl shift would
be directed by the phenylseleno substituent (possibly via
an episelenonium ion), such that they would have an anti
relationship. Conclusive proof of this assignment began
with chemoselective sodium borohydride reduction of the
ketone carbonyl in 23. Hydride delivery under these
circumstances is relegated predominantly to the π-sur-
face distal to the selenide substituent. Indeed, 24 pre-
dominates by a ratio of 5:1. Selenoxide elimination then
afforded olefin 25, the hydroxyl group in which was
utilized to effect syn delivery of OsO431 and m-chloroper-
benzoic acid.32 Conversion to the triol occurred in a few
hours with a selectivity of 4.7:1. Subsequent acetylation
of the major isomer furnished the highly crystalline
triacetate 26, the stereochemical features of which were
corroborated by X-ray structural analysis (Figure 1). The
hydroxyl group in 25 also cleanly directs epoxidation to
provide 27.33
(31) The most successful conditions found for these dihydroxylations
are those reported by: Paquette, L. A.; Lowinger, T. B.; Bolin, D. G.;
Branan, B. M. J . Org. Chem. 1996, 61, 7486.
(32) Somasekar Rao, A.; Rama Mohan, H. In Encyclopedia of
Organic Reagents; Paquette, L. A., Editor-in-Chief; J ohn Wiley and
Sons: Chichester, 1995; pp 1192-1198.
(33) Brand, S. Unpublished observations.

2014 J . Org. Chem., Vol. 64, No. 6, 1999
Paquette et al.
dehydro analogues via syn-sulfoxide elimination. The
inefficiencies experienced for the conversions of 28 and
29 into 30 and 31, respectively, arise in large part
because of the low solubilities of these substances in the
aqueous methanol reaction medium. Still more problem-
atic was the thermal extrusion step. No reaction was
observed in refluxing toluene (111 °C) or chlorobenzene
(132 °C) after extended heating (up to 48 h), and only
substrate decomposition was seen in refluxing 1,2-dichlo-
robenzene (180 °C). For these reasons, the greater ease
of selenoxide elimination as foreshadowed by the conver-
sion of 24 to 25 was now exploited.
As before, the exposure of 17b to PPTS in hot benzene
afforded all four isomers, albeit with a greater prepon-
derance for two of the four possibilities (approximate ratio
9:1:1:9). This mixture could be separated chromatographi-
cally into two fractions denoted as 34 and 35, each of
which consisted of a major and minor component (ratio
9:1, Scheme 6). Subsequent oxidation of each of these
In light of the stereoselectivity exhibited during the
rearrangement of 17b, it may be concluded that there is
no facial preference associated with initial protonation
of the double bond. The direct consequence of this lack
of discrimination is the positioning of the PhSe group on
both faces of the furanose ring. After the protonation step,
however, the incoming acyl migrant exhibits almost
complete selectivity for the face opposite to that occupied
by the selenium, possibly because of the transient
intervention of an episelenonium intermediate.
Ela bor a tion of th e Sp ir od ik etop ip er a zin e Rin g.
Dideoxy spironucleoside 19b proved amenable to oxima-
tion as long as pyridine (and not sodium acetate) was
present. A single geometric isomer was formed (Scheme
7). As a result of the sensitivity of the TBS protecting
group to cleavage in the presence of hydroxylamine
hydrochloride, this functionality can be preserved or
removed at this stage depending on the order of addition
of the reagents. The significantly reduced accessibility
to the carbonyl group in 20b required that high-pressure
conditions be utilized to obtain 42. In contrast, the
dehydro congeners 36 and 37 undergo rapid oximation
at room temperature.
Sch em e 6
X-ray crystallographic analysis of 44 revealed the
presence of an “R-face” oxime with geometry well suited
for the planned regioselective Beckmann rearrangement.
The presence of an intramolecular hydrogen bond was
also noted (Figure 2). Catalytic hydrogenation of 44 gave
rise to 40, thereby intercorrelating all necessary stereo-
chemical assignments.
F igu r e 2. Computer-generated perspective drawing of 44 as
determined by X-ray crystallography.
Exposure of either 41 or 42 to widely varying concen-
trations of hydrogen chloride in acetic acid failed to
induce Beckmann rearrangement.34,35 A ring-expanded
diketopiperazine was likewise not obtained when these
conditions were applied to 45. On the basis of spectro-
scopic evidence, the crystalline products recovered from
these attempts proved to be the simple O-acylated
derivatives. Treatment of these products with potassium
carbonate in aqueous methanol resulted in reconversion
to the starting oximes.
When more forcing conditions such as saturated HCl
in HOAc/Ac2O for 1 week or activation of 46 with
phosphorus pentachloride in CHCl3 at 0 °C led to no
recognizable reaction or in slow decomposition, attention
was turned to activation with sulfonyl chlorides.36 To test
this strategy, oximes which retained the TBS protecting
fractions with sodium metaperiodate gave the corre-
sponding olefin as a diastereomeric mixture (9:1), thus
indicating that the two components of each fraction are
epimeric at the spirocyclic center. Fortuitously, since 36
and 37 are separable by chromatography, no need exists
to deal directly with the 34/35 mixtures.
NOE analysis of the major anomer of 35 indicated that
the TBSOCH2 and PhSe substituents have a syn rela-
tionship. For the purpose of ascertaining the absolute
configuration of the spirocyclic center, 36 and 37 were
converted to their exo-methylene derivatives and sub-
jected to NOE analysis as before. The structural assign-
ment to 38 is fully consistent with that inferred from the
crystal structure of its oxime derivative (see below).
(34) (a) Donaruma, L. G.; Heldt, W. Z. Org. React. 1960, 11, 1. (b)
Gawley, R. E. Org. React. 1988, 35, 1.
(35) McCarty, C. G. In Chemistry of the Carbon-Nitrogen Double
Bond, Patai, S., Ed.; Interscience: New York, 1970; pp 408-439.

Enantioselective Ring Expansion Route
J . Org. Chem., Vol. 64, No. 6, 1999 2015
Sch em e 7
Sch em e 9
group were required as substrates. When pyridine addi-
tion was carried out prior to introduction of the hydrox-
ylamine hydrochloride, 47a was conveniently generated
from 20b. Although tosylation of this intermediate proved
to be sluggish, the derived mesylate 47b did form at a
convenient rate (Scheme 8). Attempted in situ rearrange-
Sch em e 8
ment merely by allowing the reaction mixture to warm
to 20 °C resulted in an unexpected Beckmann fragmen-
tation. Amide 48 was recovered as the only product. In
all likelihood, such undesirable fragmentations were
expected to be an unavoidable property of these systems.
Therefore, an alternative strategy was sought in order
to circumvent the problem.
The diketopiperazine ring was successfully installed
by means of the protocol outlined in Scheme 9. Baeyer-
Villiger oxidation of all spiro systems examined in this
study proceeded rapidly and with complete regioselec-
tivity37 to form the corresponding spirolactones, thereby
intimating exclusive quaternary carbon migration. The
requisite formal O to NH exchange was achieved simply
by ammonolysis, a process that bears some similarity to
the regioselective deprotection of a polyacetylated sugar
at its anomeric center,38 followed by acid-promoted re-
cyclization. The conversion of 19b and 20b into 49 and
50, respectively, with efficiencies approaching 100% is
(36) Corey, E. J .; Ueda, Y.; Ruden, R. A. Tetrahedron Lett. 1975,
4347.
(37) Paquette, L. A.; Kinney, M. J .; Dullweber, U. J . Org. Chem.
1997, 62, 1713.

2016 J . Org. Chem., Vol. 64, No. 6, 1999
Paquette et al.
Sch em e 11
illustrative of the first step. Subsequent ring cleavage of
either product with NH3 furnished the lactol amide 51
as a 1:1 mixture of epimers. The ring closure of this
material, in a reaction patterned after the spiroketaliza-
tion of a keto diol,39 has been scrutinized under various
conditions. In CDCl3 solution, spontaneous cyclization
1
can be observed by H NMR to proceed to a 1:1 mixture
of 52 and 53 with a half-life of approximately 72 h.
Alternatively, this process can be completed within 48 h
in 95% yield by stirring in benzene containing PPTS and
4 Å molecular sieves. Although 1:1 mixtures again result,
the diastereomers are chromatographically separable. At
80 °C, ring closure is complete within 1 h. However,
under these more forcing conditions, approximately 30%
of a new product with an Rf midway between those of 52
and 53 is generated. Spectroscopic analysis (including
NOE) clearly defines this product to be the pyranose
spirodiketopiperazine 57 (Scheme 10). The competing
Sch em e 10
ization (58/60 ) 5:1), likely due to the presence of
adventitious moisture in the commercial fluoride reagent.
The potential for configurational lability within 58 was
further demonstrated by epimerization of the 5:1 ano-
meric mixture to the 1:1 level upon heating at 50 °C with
PPTS in benzene. The anomers are indistinguishable by
TLC. A related base-catalyzed isomerization of hydan-
tocidin to the thermodynamically more stable 2-epi
derivative is precedented.7a Attempted N-deprotection of
this mixture by hydrogenolysis proceeded very sluggishly
over several days to give 61 and not the intact diketopi-
perazine. Consequently, recourse was made to lithium
in liquid ammonia for this purpose.40 The debenyzylation
proceeded rapidly (<5 min) to give the mixture 62 and a
trace of ring-opened compound (≡ 63). The latter was
readily cyclized to 62. As foreshadowed by earlier results,
samples of 62 underwent hydrolysis to 63 in a matter of
hours when stored at 0 °C in CDCl3.
Ar r iva l a t F u lly F u n ction a lized F u r a n ose Sys-
tem s. The relatively low reactivity of 25, 36, and 37
toward osmylation led us to consider elaboration of the
spirodiketopiperazine ring prior to olefin dihydroxylation.
As anticipated, the peracid oxidation of 25 occurred very
cleanly and rapidly (<2 min at -5 °C) as evidenced by
TLC analysis. However, the resulting 64 turned out to
be unstable upon attempted chromatography. During
purification in this manner, complete conversion to furan
65 materialized. This option was therefore not further
investigated.
mechanism associated with the appearance of 57 likely
involves preliminary equilibration of 51 with its open-
chain tautomer 54 followed by primary to secondary silyl
group migration as in 55, and relactonization to the
corresponding pyran 57, possibly via an N-acyliminium
ion intermediate. The sterically unfavorable migration
of the TBS group is considered to be driven by subsequent
formation of the assumedly more thermodynamically
stable spiro[5,5]pyranose ring resident in 57.
The effect of prolonged heating on lactol 51 is very
predominant conversion to 57. This being the case, 49,
50, and analogues thereof may serve as useful precursors
to pyranose as well as furanose systems. Furthermore,
this observation raises intriguing questions relating to
the dynamic properties and configurational stabilities of
these spirocyclic nucleosides.
When attempted hydrogenolytic debenzylation of 52
(10% Pd/C in methanol) was found to cause partial loss
of the silyl ether protecting group, the order of deprotec-
tion was reversed (Scheme 11). Quantitative desilylation
was effected with TBAF in THF, but with partial epimer-
(38) (a) Mehta, S.; J ordan, K. L.; Weimar, T.; Kreis, U. C.; Batchelor,
R. J .; Einstein, F. W. B.; Pinto, B. M. Tetrahedron: Asymmetry 1994,
5, 2367. (b) Excoffier, G.; Gagnaire, D.; Utille, J .-P. Carbohydr. Res.
1975, 39, 368.
(39) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617.
(40) Kocienski, P. J .; Street, S. D. A.; Yeates, C.; Campbell, S. F. J .
Chem. Soc., Perkin Trans. 1 1987, 2171.
At this stage, attention was directed to 18, acid-
catalyzed rearrangement of which in the predescribed

Enantioselective Ring Expansion Route
J . Org. Chem., Vol. 64, No. 6, 1999 2017
Sch em e 12
manner provided a mixture of four ring-expanded se-
lenides (ratio 10:1:1:10). Their direct oxidation with
sodium periodate in the presence of sodium bicarbonate
at 0 °C proceeded cleanly and allowed for the chromato-
graphic separation of 66 from 67 (Scheme 12). Relative
stereochemistry was determined by the conversion of 66
to its exo-methylene derivative 68, which exhibited the
diagnostic NOE shown.
Dihydroxylation of 66 proceeded with disappointing
π-facial stereoselectivity (1:4 ratio of 69:70) despite the
presence of two groups having face-directing potential.
Acetylation of this mixture gave the separable diacetates
69 and 70. Both of these intermediates underwent facile
and clean Baeyer-Villiger oxidation to form the corre-
sponding spirolactones 73 and 74. The latter exhibits a
stereochemically diagnostic NOE effect. The ammonolysis
of 73 occurred regioselectively without cleavage of the
C-3 and C-4 acetates, due to the greater reactivity of the
anomeric carboxylate, giving a mixture of lactol amides
(1:1 by 1H NMR). Subsequent acid-promoted ring closure
resulted in formation of the single spirodiketopiper-
azine 77 in good yield. The anologous transformation of
74 likewise gave rise to an anomerically pure spiro-
amide, viz. 78. In neither case has the absolute config-
uration of the anomeric center been unequivocally de-
fined.
Additionally, 67 was converted via an identical path-
way into 71 and 72 (ratio 1:3). Transformation of the
major diastereomer into 76 allowed for the ultimate
production of 78. In the final synthetic maneuver, 77 was
found to undergo sluggish oxidative debenzylation with
ceric ammonium nitrate.41

2018 J . Org. Chem., Vol. 64, No. 6, 1999
Paquette et al.
121.1, 114.0, 55.2, 46.1 45.2, 14.1; MS m/z (M+) calcd 217.1103,
obsd 217.1109.
Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96. Found: C,
71.65; H, 7.04.
In summary, application of the oxonium ion-initiated
pinacol rearrangement to carbinols 15-18 easily ob-
tained by the coupling of 5-lithiated furanoid glycals to
2,3-azetidinediones serves as a useful device for accessing
spirocyclic keto lactams such as 19 and 20. Added versa-
tility is gained when a 4-phenylseleno substituent is
present, since this modification allows for the ready intro-
duction of a double bond as in 25, 36, 37, 66, and 67.
Possibilities for differentiating the two anomeric series
at this stage have been identified. The optimal version
of the end game involves Baeyer-Villiger oxidation of
the derived diacetates followed by regioselective amina-
tion of the anomeric carbon. This chemistry defines a con-
cise de novo strategy for the construction of hydantocidin
homologues based on L-glutamic acid as the starting
material. Further details on the biological actions of these
and other compounds will be published elsewhere.
1-(p-Meth oxyben zyl)-2,3-a zetid in ed ion e (9b). The pro-
cedure developed for 9a 20 was followed. From 30.0 g (0.138
mmol) of 8b in methanol (900 mL) and distilled water (500
mL), finely ground sodium periodate (80.0 g), and osmium
tetraoxide (40 mg) was obtained 23.1 g (82%) of 9b as a
crystalline solid: mp 96-97.5 °C (from ethyl acetate); IR (neat,
cm-1) 3325, 1730, 1607; 1H NMR (300 MHz, CDCl3) δ 7.19 (d,
J ) 8.6 Hz, 2 H), 6.89 (d, J ) 8.6 Hz, 2 H), 4.69 (s, 2 H), 3.79
(s, 3 H), 3.76 (s, 2 H); 13C NMR (75 MHz, CDCl3) δ 193.0, 163.3,
159.7, 129.8, 125.4, 114.5, 58.8, 55.3, 46.4; MS m/z (M+) calcd
205.0739, obsd 205.0758.
Anal. Calcd for C11H11NO3: C, 64.38; H, 5.40. Found: C,
64.74; H, 5.53.
(S)-2,3-Dih yd r o-2-[(tr ityloxy)m eth yl]fu r a n (12a ). A so-
lution of the lactol from 10a 42 (750 mg, 2.08 mmol) in pyridine
(25 mL) was treated with acetic anhydride (0.5 mL, 5.20
mmol), stirred overnight, diluted with ether (50 mL), washed
with saturated NaHCO3 solution (2×) and brine, dried, and
evaporated in vacuo. Chromatographic purification on silica
gel (elution with 10% ethyl acetate in hexanes) gave 11a (620
mg, 74%) as a 1:3 mixture of R- and â-anomers: 1H NMR (300
MHz, CDCl3) δ (less polar anomer) 7.46-7.16 (series of m, 15
H), 6.38 (d, J ) 6.5 Hz, 1 H), 4.45 (m, 1 H), 3.14 (AB, J ) 4.6,
3.2 Hz, ∆ν ) 14.3 Hz, 2 H), 2.23-2.10 (m, 2 H), 2.05 (s, 3 H),
2.02-1.61 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ (less polar
anomer) 170.5, 143.9, 128.2, 127.7, 127.0, 99.5, 86.6, 79.3, 65.6,
31.8, 25.3, 21.4; [R]2D0 +11.76 (c 1.27, CH2Cl2).
Exp er im en ta l Section
Gen er a l In for m a tion . Melting points are uncorrected.
Magnetic stirring was used for all reactions. Yields were
calculated for material judged to be homogeneous by TLC and
NMR. Thin-layer chromatography was performed on Merck
Kieselgel 60 F254 aluminum-backed plates. Flash column
chromatography was accomplished in glass columns with
Woelm silica gel (230-400 mesh). Solvents were reagent grade
and in most cases dried prior to use. The high-resolution mass
spectra were obtained at The Ohio State University Chemical
Instrumentation Center. Elemental analyses were performed
by the Scandinavian Microanalytical Laboratory, Herlev,
Denmark, and Atlantic Microlab, Norcross, GA.
Anal. Calcd for C26H26O4: C, 77.59; H, 6.51. Found: C, 77.47;
H, 6.59.
A 850 mg (2.48 mmol) sample of 11a was heated at 190 °C
and 0.5 Torr in a Kugelrohr apparatus for 90 min. The
resulting clear oil was purified on silica gel (eluting with 10%
ethyl acetate and 2% triethylamine in hexanes) to provide 660
mg (91%) of 12a , which exhibited spectra identical to those
reported in the literature.
ter t-Bu tyl[[(S)-2,3-d ih yd r o-2-fu r yl]m eth oxy]d im eth yl-
sila n e (12b). A solution of (S)-(+)-10b (20.0 g, 0.087 mmol)
in ether (200 mL) and CH2Cl2 (200 mL) was blanketed with
N2, cooled to -78 °C, and treated dropwise with Dibal-H (130.0
mL of 1 M in hexanes, 0.13 mol). The reaction mixture was
maintained at -78 °C for 3 h, quenched with methanol (30
mL), and allowed to warm gradually to room temperature.
After dilution with saturated Rochelle’s salt solution and
another hour of stirring, the product was extracted into ether
(3 × 150 mL), and the combined organic extracts were dried
and concentrated to give the lactol as a colorless oil (20.1 g,
100%).
A solution of the lactol (40.0 g, 0.17 mmol) in CH2Cl2 (500
mL) and pyridine (50 mL) was treated with acetic anhydride
(19.3 g, 0.19 mol), stirred for 48 h, and processed in the
predescribed manner to furnish 11b (45.4 g, 96%). Heating of
a 2.7 g (9.8 mmol) sample of this material as detailed earlier
for 12a gave 12b (2.03 g, 96%) as a volatile colorless oil that
was used without further purification.
t er t -Bu t yl [[(S )-2,3-d ih yd r o-4 -(p h e n ylt h io)-2-fu r yl]-
m eth oxy]d im eth yl sila n e (14a ). A cold (-78 °C), magneti-
cally stirred solution of 12b (1.54 g, 7.20 mmol) in THF (15
mL) was treated dropwise with phenylsulfenyl chloride until
a faint yellow coloration just persisted (ca 1 mL). The reaction
mixture was agitated for 15 min prior to the addition of finely
divided potassium tert-butoxide (1.18 g, 1.5 equiv) with vigor-
ous stirring, allowed to warm to room temperature during 1
h, and added to a mixture of ethyl acetate (40 mL) and
saturated NaHCO3 solution (40 mL). The separated aqueous
layer was extracted with ethyl acetate (3 × 50 mL), and the
combined organic phases were dried and concentrated. Puri-
fication of the residue by chromatography on silica gel (elution
with 5% ethyl acetate in hexanes) gave 14a as a colorless oil
3-Eth ylid en e-1-(p-m eth oxyben zyl)-2-a zetid in on e (8b).
A solution of 520 (49.8 g, 0.38 mol) in methanol (385 mL) was
treated dropwise with p-methoxybenzylamine (50 mL, 0.38
mol) and stirred for 24 h prior to concentration in vacuo. Flash
chromatography of the residue on silica gel (elution with ethyl
acetate) gave 6b as a faintly yellowish oil (100 g, 98%); IR
1
(neat, cm-1) 3325, 1730, 1607; H NMR (200 MHz, CDCl3) δ
7.16 (d, J ) 8.8 Hz, 2 H), 6.81 (d, J ) 8.8 Hz, 2 H), 4.22-4.12
(m, 1 H), 3.74 (s, 3 H), 3.66 (s, 2 H), 3.65 (s, 3 H), 3.09-2.90
(m, 2 H), 2.47-2.38 (m, 1 H), 1.13 (d, J ) 6.3 Hz, 3 H); 13C
NMR (50 MHz, CDCl3) δ 173.4, 158.6, 130.0, 129.2, 113.6, 69.1,
55.0, 53.0, 51.6, 50.7, 48.2, 21.7; MS m/z (M+) calcd 267.1471,
obsd 267.1460.
Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92. Found: C,
63.22; H, 8.15.
A procedure entirely parallel to that developed for the
preparation of 7a 20 was employed. From 56.0 g (0.21 mmol) of
6b, 28.0 g of magnesium turnings, and 120 mL of tert-butyl
chloride was obtained 48.6 g (98%) of 7b as a colorless oil: IR
1
(neat, cm-1) 3412, 1729, 1612; H NMR (200 MHz, CDCl3) δ
7.11 (d, J ) 12.0 Hz, 2 H), 6.78 (d, J ) 12.0 Hz, 2 H), 4.30 (d,
J ) 16 Hz, 1 H), 4.19 (d, J ) 16 Hz, 2 H), 4.20-3.97 (m, 1 H),
3.72 (s, 3 H), 3.62 (d, J ) 4.0 Hz, 1 H), 3.14-2.80 (m, 2 H),
1.18 (d, J ) 9.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ168.3,
159.0, 129.3, 127.4, 114.0, 64.8, 56.8, 55.1, 45.2, 41.0, 21.3; MS
m/z (M+) calcd 235.1208, obsd 235.1215.
Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28. Found: C,
66.08; H, 7.53.
A similar procedure to that used for 8a 20 was followed.
Reaction of 7b (48.6 g, 0.206 mmol) in CH2Cl2 (750 mL) with
methanesulfonyl chloride (20 mL) followed by DBU (35 mL)
in benzene (500 mL) gave 8b as a pale yellow oil (37.1 g, 83%)
following chromatography on silica gel (elution with 50% ethyl
acetate in hexanes); IR (neat, cm-1) 1743, 1612, 1513; 1H NMR
(300 MHz, CDCl3) δ (major isomer) 7.15 (d, J ) 8.7 Hz, 2 H),
6.84 (d, J ) 8.7 Hz, 2 H), 6.12 (m, 1 H), 4.39 (s, 2 H), 3.77 (s,
3 H), 3.57 (m, 2 H), 1.66 (d, J ) 7.0 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ (major isomer) 163.7, 159.0, 138.1, 136.7, 129.3,
(41) Shin, C.-g.; Okamoto, T.; Yoshimura, J .; Hashimoto, H.; Suzuki,
T.; Yamaura, M. Bull. Chem. Soc. J pn. 1985, 58, 1413.
(42) These assignments could be reversed.

Enantioselective Ring Expansion Route
J . Org. Chem., Vol. 64, No. 6, 1999 2019
(2.06 g, 89%): IR (neat, cm-1) 1693, 1607, 1472; 1H NMR (300
MHz, CDCl3) δ 7.31-7.23 (m, 5 H), 6.66 (t, J ) 2.0 Hz, 1 H),
4.85-4.75 (m, 1 H), 3.75 (d, J ) 4.8 Hz, 2 H), 2.71 (ddd, J )
14.6, 10.4, 2.0 Hz, 1 H), 2.57 (ddd, J ) 14.6, 7.8, 2.0 Hz, 1 H),
0.91 (s, 9 H), 0.089 (s, 3 H), 0.085 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 151.9, 128.9, 127.1, 125.5, 102.6, 83.7, 77.3, 77.24,
77.21, 76.7, 65.0, 34.2, 25.9, 25.6, 18.4, -5.3; MS m/z (M+) calcd
322.1423, obsd 322.1458; [R]2D5 +48.7 (c 3.7, CHCl3).
dry THF (5 mL) under argon at -78 °C was treated dropwise
with a solution of tert-butyllithium in pentane (2.60 mL of 1.7
M, 4.38 mmol). The solution was stirred for 1 h at this
temperature prior to warming quickly to -10 °C whereupon
the solution became clear. The reaction mixture was returned
to -78 °C, transferred via a cold cannula into a stirred solution
of 9a (400 mg, 2.28 mmol) and boron trifluoride etherate (4.66
mL of 0.49 M solution in ether, 2.28 mmol) in THF (15 mL),
and stirred at -78 °C for 30 min and at -10 °C for 30 min
before being quenched with saturated NaHCO3 solution (5
mL). The product was extracted into ether (3 × 30 mL), the
combined extracts were dried, concentrated, and passed
through a small pad of silica gel (washed with 30% ethyl
acetate and 2% triethylamine in hexanes) to deliver 830 mg
(58%) of 15a . A total of 407 mg of 12a was recovered: 1H NMR
(300 MHz, CDCl3) δ 7.70-6.95 (m, 20 H), 5.25-5.10 (m, 1 H),
4.95-4.68 (m, 1 H), 4.28-4.05 (m, 2 H), 3.65-3.28 (m, 2 H),
3.28-3.06 (m, 3 H), 2.65-2.28 (dd, J ) 14, 5.5 Hz, 2 H); MS
m/z (M+) calcd 517.2253, obsd 517.2269.
Anal. Calcd for C17H26O2SSi: C, 63.31; H, 8.12. Found: C,
63.08; H, 8.35.
ter t-Bu t yl[[(S)-2,3-d ih yd r o-4-(p h en ylselen o)-2-fu r yl]-
m eth oxy]d im eth ylsila n e (14b). A solution of 12b (1.84 g,
8.60 mmol) in dry THF (40 mL) was cooled to -78 °C, treated
dropwise with a solution of phenylselenenyl chloride (1.65 g,
8.61 mmol) in THF (5 mL) until a faint yellow color persisted,
and stirred for 30 min prior to the addition of finely divided
potassium tert-butoxide (1.30 g, 1.5 equiv) with vigorous
stirring. Workup in a manner identical to that just described
afforded 2.48 g (78%) of 14b as a colorless oil: IR (neat, cm-1
)
1609, 1578, 1475; 1H NMR (300 MHz, CDCl3) δ 7.42-7.38 (m,
2 H), 7.29-7.18 (m, 3 H), 6.61 (t, J ) 2.1 Hz, 1 H), 4.77 (m, 1
H), 3.74 (m, 2 H), 2.76 (ddd, J ) 14.8, 10.4, 2.1 Hz, 1 H), 2.60
(ddd, J ) 14.8, 7.7, 2.1 Hz, 1 H), 0.91 (s, 9 H), 0.88 (s, 6 H);
13C NMR (75 MHz, CDCl3) δ 152.2, 129.9, 129.2, 126.3, 97.6,
83.5, 65.0, 36.2, 25.9 (2 C), 18.4, -5.3; MS m/z (M+) calcd
370.0867, obsd 370.0886; [R]2D5 +46.7 (c 1.23, CHCl3).
Anal. Calcd for C17H26O2SeSi: C, 55.27; H, 7.09. Found: C,
55.54; H, 7.36.
ter t-Bu t yl[[(S)-2,3-d ih yd r o-4-(p h en ylselen o)-2-fu r yl]-
m eth oxy]d ip h en ylsila n e. A solution of 10 (55.0 g, 0.47 mol)
and imidazole (65.0 g, 0.95 mol) in DMF at 20 °C was treated
portionwise with tert-butyldiphenylsilyl chloride (130.0 g, 0.47
mol). The reaction mixture was stirred for 48 h with warming
to 60 °C for the last 4 h and prior to the addition of saturated
NaHCO3 solution (2 L) and extraction with ether (4 × 600 mL).
The combined organic phases were dried and concentrated to
give a white solid (126.3, 75%), which was dissolved in CH2-
Cl2 (600 mL) under N2, cooled to -78 °C and treated dropwise
with Dibal-H (180 mL of 1.0 M in hexanes, 0.18 mol). The
reaction mixture was maintained at -78 °C for 16 h prior to
quenching with methanol (20 mL) and gradual warming to
room temperature. Following the addition of saturated Roch-
elle salt solution and overnight stirring, the product was
extracted into ether (3 × 150 mL), and the combined organic
phases were dried and concentrated to give the lactol as a
colorless oil (56.1 g, 97%).
A 52.0 g (0.146 mol) sample of this material was dissolved
in CH2Cl2 (500 mL) and pyridine (50 mL), treated with acetic
anhydride (25 mL) and DMAP (500 mg), and stirred for 48 h.
After the removal of all volatiles in vacuo, the residue was
purified by flash chromatography on silica gel (elution with
10% ethyl acetate in hexanes) to give the acetate as a colorless
oil (53.4 g, 92%).
A 55.0 g (0.138 mol) sample of this oil was heated in 5 g
lots in a Kugelrohr apparatus at 185-190 °C and 70 Torr. The
distillate was purified in flash chromatography (SiO2, elution
with 2% ethyl acetate in hexanes) to give 12c as a thick
colorless oil (42.7 g, 91%).
B. 1-Ben zyl-3-[(S)-5-[(ter t-bu tyldim eth ylsiloxy)m eth yl]-
4,5-d ih yd r o-2-fu r yl]-3-h yd r oxy-2-a zetid in on e (15b). The
coupling of 12b (1.14 g, 5.33 mmol) to 9a (789 mg, 4.51 mmol)
in this manner afforded 1.12 g (64%) of 15b alongside 271 mg
of recovered 12b. For the 1:1 mixture of diastereomers: IR
(neat, cm-1) 3378, 1740, 1670, 1471; 1H NMR (300 MHz,
CDCl3) δ 7.37-7.20 (m, 5 H), 5.08-5.05 (m, 1 H), 4.73-4.65
(m, 1 H), 4.48-4.42 (m, 2 H), 4.17 and 4.11 (br s, 1 H), 3.74-
3.59 (m, 2 H), 3.48 (d, J ) 5.3 Hz, 0.5 H), 3.47 (d, J ) 5.4 Hz,
0.5 H), 3.25 (d, J ) 5.4 Hz, 0.5 H), 3.24 (d, J ) 5.3 Hz, 0.5 H),
2.77-2.66 (m, 1 H), 2.57-2.46 (m, 1 H), 0.89 and 0.87 (s, 9
H), 0.06, 0.05, 0.04, 0.03 (s, 6 H); 13C NMR (75 MHz, CDCl3)
δ 168.2, 168.0, 153.3, 134.7, 128.6, 128.5, 128.0, 127.8, 127.7,
97.3, 82.5, 82.4, 81.5, 81.4, 65.0, 64.9, 53.3, 45.7, 32.1, 32.0,
25.9, 25.84, 25.81, -5.29, -5.31, -5.35; MS m/z (M+) calcd
389.2022, obsd 389.2022; [R]2D5 +39.2 (c 1.3, CHCl3).
Anal. Calcd for C21H31NO4Si: C, 64.75; H, 8.03. Found: C,
64.69; H, 7.96.
C. 1-Ben zyl-3-[4,5-d ih yd r o-3-(p h en ylselen o)-2-fu r yl]-3-
h yd r oxy-2-a zetid in on e (16). A stirred solution containing
2,3-dihydrofuran (35 mL) in THF (1000 mL) at -78 °C was
treated dropwise with a solution of phenylselenenyl chloride
(50.0 g, 0.26 mol) and stirred for 1 h prior to the addition of
potassium tert-butoxide (34.95 g, 0.312 mol) in several portions.
The resulting slurry was gradually warmed to room temper-
ature during 1 h, poured into water (1 L), and extracted with
ether (4 × 150 mL). The combined extracts were dried and
concentrated prior to distillation in a Kugelrohr apparatus.
There was obtained 53.0 g (90%) of the 4-phenylseleno deriva-
tive as a pale yellow oil: bp 160-165 °C (0.7 Torr); IR (neat,
1
cm-1) 1604, 1575, 1476, 1438; H NMR (300 MHz, CDCl3) δ
7.44-7.40 (m, 2 H), 7.30-7.18 (m, 3 H), 6.65 (t, J ) 2.0 Hz, 1
H), 4.48 (t, J ) 9.5 Hz, 2 H), 2.74 (td, J ) 9.5, 2.0 Hz, 2 H);
13C NMR (75 MHz, CDCl3) δ 152.7, 131.0, 130.0, 129.1, 126.4,
98.3, 71.6, 34.5; MS m/z (M+) calcd 225.9897, obsd 225.9888.
Anal. Calcd for C10H10OSe: C, 53.35; H, 4.48. Found: C,
53.37; H, 4.52.
Coupling of the above selenide (8.15 g, 36.2 mmol) to 9a
(6.02 g, 34.4 mmol) as indicated above provided for the recovery
of 2.17 g (27%) of unreacted dihydrofuran and isolation of 16
(5.95 g, 41%) as a colorless solid: mp 87-92 °C dec; IR (neat,
cm-1) 3398, 1760; 1H NMR (300 MHz, CDCl3) δ 7.50-7.21 (m,
10 H), 4.53-4.25 (m, 5 H), 3.73 (d, J ) 5.4 Hz, 1 H), 3.28 (d,
J ) 5.4 Hz, 1 H), 2.82 (t, J ) 9.8 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 166.9, 155.2, 134.7, 131.0, 129.4, 128.9, 128.8, 128.5,
128.1, 128.0, 127.9, 127.8, 127.3, 95.6, 83.8, 70.2, 53.7, 45.8,
37.1; MS m/z (M+) calcd 401.0530, obsd 401.0522.
A cold (-78 °C) solution of 12c (22.2 g, 0.066 mol) in dry
THF (800 mL) was treated dropwise with
a solution of
phenylselenenyl chloride (12.5 g, 0.066 mol) in THF (50 mL)
until a faint yellow coloration just persisted. The reaction
mixture was allowed to stir at this temperature for 30 min
prior to the addition of finely divided potassium tert-butoxide
under conditions of vigorous agitation, allowed to warm to
room temperature over 2 h, and poured into ethyl acetate (1
L) and water (600 mL). The separated aqueous phase was
extracted with ethyl acetate (3 × 10 mL), and the combined
organic phases were dried and concentrated to give 27.2 g
(84%) of a pale yellow oil that was used directly.
Anal. Calcd for C20H19NO3Se: C, 59.88; H, 4.79. Found: C,
59.97; H, 4.71.
1-Ben zyl-3-[(S)-5-[(ter t-b u t yld im et h ylsiloxy)m et h yl]-
4,5-d ih yd r o-3-(p h en ylth io)-2-fu r yl]-3-h yd r oxy-2-a zetid i-
n on e (17a ). Metalation of 14a (1.80 g, 5.59 mmol) and
coupling with 9a (880 mg, 5.00 mmol) as detailed earlier
returned 620 mg of unreacted 14a and afforded 1.38 g (56%)
of 17a as a colorless oil: IR (neat, cm-1) 3378, 1767, 1473; 1H
Gen er a l P r oced u r e for th e Cou p lin g of F u r a n oid
Glyca ls to N-P r otected Azetid in e-2,3-d ion es. A. 1-Ben zyl-
3-[(S)-4,5-dih ydr o-5-[(tr ityloxy)m eth yl]-2-fu r yl]-3-h ydr oxy-
2-a zetid in on e (15a ). A solution of 12a (1.00 g, 2.92 mmol) in

2020 J . Org. Chem., Vol. 64, No. 6, 1999
Paquette et al.
NMR (300 MHz, CDCl3) δ 7.38-7.18 (m, 10 H), 4.79-4.71 (m,
1 H), 4.51-4.40 (m, 2 H), 3.76-3.65 (m, 3 H), 3.48 (d, J ) 7.0
Hz, 1 H), 2.81-2.67 (m, 2 H), 0.88 and 0.87 (2s, total 9 H),
0.06, 0.04, 0.02 (3s, total 6 H); 13C NMR (75 MHz, CDCl3) δ
134.7, 133.9, 129.2, 128.7, 128.3, 128.2, 128.1, 127.7, 126.6,
99.9, 81.7, 64.5, 53.6, 53.5, 45.8, 36.5, 25.8, 25.7, 18.3, -5.4;
MS m/z (M+) calcd 497.2056, obsd 497.2067; [R]2D5 +28.7 (c
1.35, CHCl3).
28.1 Hz, 2 H), 2.01-1.59 (m, 4 H); 13C NMR (75 MHz, C6D6) δ
206.5, 170.6, 144.7, 135.7, 129.3-127.1 (multiple signals), 87.1,
82.6, 81.3, 66.4, 52.6, 46.1, 32.9, 28.7; MS m/z (M+) calcd
517.2253, obsd 517.2253; [R]D20
-28.6 (c 1.41, CHCl3).
For 20a : colorless oil; IR (neat, cm-1) 1768, 1684; 1H NMR
(300 MHz, C6D6) δ 7.67-6.89 (m, 20 H), 4.73-4.65 (m, 1 H),
4.12 (AB, J ) 14.6 Hz, ∆ν ) 127.9 Hz, 2 H), 3.36 (AB, J ) 4.2,
9.8 Hz, ∆ν ) 29.3 Hz, 2 H), 2.91 (AB, J ) 17.3 Hz, ∆ν ) 21.7
Hz, 2 H), 2.01-1.62 (m, 4 H); 13C NMR (75 MHz, C6D6) δ 205.6,
171.3, 144.7, 135.7, 129.3-127.1 (multiple signals), 87.0, 82.5,
81.4, 66.3, 52.7, 46.1, 33.5, 28.7; MS m/z (M+) calcd 517.2253,
obsd 517.2253; [R]2D0 +18.2 (c 1.82, CHCl3).
Anal. Calcd for C27H35NO4SSi: C, 65.16; H, 7.09. Found:
C, 65.19; H, 7.02.
1-Ben zyl-3-[(S)-5-[(ter t-b u t yld im et h ylsiloxy)m et h yl]-
4,5-d ih yd r o-3-(p h en ylselen o)-2-fu r yl]-3-h yd r oxy-2-a zeti-
d in on e (17b). Metalation of 14b (5.80 g, 15.7 mmol) and
addition of the lithium derivative of 9a (2.74 g, 15.7 mmol) in
the conventional way returned 1.27 g of unreacted 14b and
provided 6.06 g (71%) of 17b as a colorless gum: IR (neat,
cm-1) 3381, 1766; 1H NMR (300 MHz, CDCl3) δ 7.50-7.44 (m,
2 H), 7.36-7.18 (m, 8 H), 4.71-4.62 (m, 1 H), 4.51-4.36 (m, 2
H), 3.77-3.65 (m, 3 H), 3.26 (m, 1 H), 2.94-2.62 (m, 2 H), 1.25
(br s, 1 H), 0.87 and 0.85 (2s, total 9 H), 0.05, 0.04, 0.03, 0.01
(4s, total 6 H); 13C NMR (75 MHz, CDCl3) δ 166.9, 166.7, 154.8,
154.6, 134.8, 131.0, 130.9, 129.4, 129.0, 128.7, 128.4, 128.1,
127.7, 127.2, 94.8, 84.0, 83.8, 81.9, 64.6, 64.5, 53.6, 53.5, 45.8,
39.1, 38.7, 25.84, 25.81, 18.3, -5.4; MS m/z (M+) calcd
545.1501, obsd 545.1457; [R]2D5 +15.3 (c 2.5, CHCl3).
Anal. Calcd for C34H31NO4: C, 78.89; H, 6.04. Found: C,
78.62; H, 6.00.
(2S,5S)-7-Ben zyl-2-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-
1-oxa -7-a za sp ir o[4.4]n on a n e-6,9-d ion e (19b) a n d (2S,5R)-
Ben zyl-2-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-1-oxa -7-a za -
sp ir o[4.4]n on a n e-6,9-d ion e (20b). A solution of 15b (700 mg,
1.78 mmol) in benzene (50 mL) containing 70 mg of pyridinium
p-toluenesulfonate was heated at 75-80 °C for 80 min under
N2. The cooled reaction mixture was quenched with saturated
NaHCO3 solution and processed as described above to furnish
273 mg of the less polar 20b, 165 mg of 19b, and 210 mg of
the mixture (92% total).
For 19b: colorless oil; IR (neat, cm-1) 1778, 1694; 1H NMR
(300 MHz, CDCl3) δ 7.38-7.22 (m, 5 H), 4.65 (d, J ) 14.6 Hz,
1 H), 4.58 (d, J ) 14.6 Hz, 1 H), 4.51 (m, 1H), 3.77 (dd, J )
10.6, 5.3 Hz, 1 H), 3.70-3.59 (m, 3 H), 2.34-1.96 (m, 4 H),
0.89 (s, 9 H), 0.060 (s, 3 H), 0.056 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 206.0, 171.5, 134.6, 129.0, 128.4, 128.2, 83.7, 81.4,
65.3, 52.8, 46.5, 33.6, 28.4, 18.4, -5.3; MS m/z (M+) calcd
389.2022, obsd 389.2047; [R]2D5 +4.5 (c 2.0, CHCl3).
3-[(S)-5-[(ter t-Bu tyldiph en ylsiloxy)m eth yl]-4,5-dih ydr o-
3-(ph en ylselen o)-2-fu r yl]-3-h ydr oxy-1-(p-m eth oxyben zyl)-
2-a zetid in on e (18). Furanoid glycal 12c (22.2 g, 66 mmol)
was exposed sequentially to phenylselenenyl chloride (12.5 g,
66 mmol) in cold (-78 °C) THF (850 mL) and then to
potassium tert-butoxide as described earlier for 16. The
selenide was obtained as a faint yellow oil (27.2 g, 84%): IR
1
(neat, cm-1) 1608, 1578, 1475; H NMR (300 MHz, CDCl3) δ
For 20b: colorless oil; IR (neat, cm-1) 1776, 1688; 1H NMR
(300 MHz, CDCl3) δ 7.37-7.19 (m, 5 H), 4.60 (s, 2 H), 4.41 (m,
1 H), 3.83 (dd, J ) 10.5, 5.5 Hz, 1 H), 3.67 (dd, J ) 10.5, 6.5
Hz, 1 H), 3.66 (s, 2 H), 2.28-1.97 (m, 4 H), 0.89 (s, 9 H), 0.08
(s, 3 H), 0.06 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 206.5, 171.0,
134.6, 129.0, 128.8, 128.4, 83.6, 81.3, 65.4, 52.8, 46.5, 33.0, 28.4,
25.93, 25.89, 25.86, 18.4, -5.3; MS m/z (M+) calcd 389.2022,
obsd 389.2047; [R]2D5 -5.1 (c 2.3, CHCl3).
7.75-7.61 (m, 4 H), 7.42-7.23 (m, 8 H), 7.23-7.17 (m, 3 H),
6.62 (br s, 1 H), 4.86-4.79 (m, 1 H), 3.80-3.72 (m, 2 H), 2.83-
2.63 (m, 2 H), 1.09 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 152.2,
135.6, 135.5, 133.4, 131.5 (2 C), 129.9, 129.7, 129.13, 129.08,
127.7, 126.2, 97.6, 83.4, 65.5, 36.2, 26.82, 26.76, 19.3; MS m/z
(M+) calcd 494.1180, obsd 494.1198; [R]D25 +35.2 (c 0.8, CHCl3).
Anal. Calcd for C27H30O2SeSi: C, 65.70; H, 6.13. Found: C,
65.77; H, 6.07.
Anal. Calcd for C21H31NO4Si: C, 64.75; H, 8.03. Found: C,
64.61; H, 7.95.
Lithiation of this furanoid glycal (10.0 g, 20.2 mmol) and
coupling to 9b (4.16 g, 20.3 mmol) as described earlier returned
5.1 g (51%) of unreacted seleno derivative and gave 11.24 g
(79%) of 18 as a colorless gum: IR (neat, cm-1) 3396, 1758,
1514; 1H NMR (300 MHz, CDCl3) δ (single isomer) 7.71-7.20
(m, 15 H), 7.14 (d, J ) 8.7 Hz, 2 H), 6.78 (d, J ) 8.7 Hz, 2 H),
4.77-4.71 (m, 1 H), 4.53 (s, 1 H), 4.42 (d, J ) 15.0 Hz, 1 H),
4.27 (d, J ) 15.0 Hz, 1 H), 3.81-3.74 (m, 2 H), 3.76 (s, 3 H),
3.70 (d, J ) 5.3 Hz, 1 H), 3.23 (d, J ) 5.3 Hz, 1 H), 2.85 (dd,
J ) 15.1, 11.2 Hz, 1 H), 2.74 (dd, J ) 15.1, 8.0 Hz, 1 H), 1.09
(s, 9 H); 13C NMR (75 MHz, CDCl3) δ (single isomer) 166.4,
159.1, 154.8, 135.5, 133.1, 132.8, 130.9, 129.9, 129.7, 129.5,
129.3, 129.1, 127.7, 127.07, 127.06, 126.7, 114.1, 114.0, 94.6,
83.4, 81.8, 65.2, 55.2, 53.4, 45.2, 39.0, 26.7, 19.24, 19.19; MS
m/z (M+) calcd 699.1765, obsd 699.1722; [R]2D5 +17.6 (c 1.2,
CHCl3).
(2S,5R)-7-Ben zyl-9-m eth ylen e-2-[(tr ityloxy)m eth yl]-1-
oxa -7-a za sp ir o[4.4]n on a n -6-on e (22). A slurry of methyl-
triphenylphosphonium iodide (234 mg, 0.58 mmol) in dry THF
(10 mL) was cooled to 0 °C, treated with n-butyllithium (0.45
mL of 1.3 M in hexanes, 0.58 mmol), stirred at this temper-
ature for 20 min and at room temperature for 30 min, and
returned to -78 °C. A solution of 20a (30 mg, 0.58 mmol) in
dry THF (2 mL) was introduced dropwise, and the reaction
mixture was stirred at -78 °C for 30 min, allowed to reach rt
overnight, quenched with saturated NaHCO3 solution, and
diluted with ether. The separated organic phase was dried and
evaporated to leave a residue, chromatography of which on
silica gel (elution with 20% ethyl acetate in hexanes) yielded
16 mg (54%) of 22 as a colorless oil: IR (neat, cm-1) 1703, 1448;
1H NMR (300 MHz, C6D6) δ 7.69-6.95 (m, 20 H), 5.17 (t, J )
2.2 Hz, 1 H), 4.70 (d, J ) 1.8 Hz, 1 H), 4.45 (m, 1 H), 4.18 (AB,
J ) 14.7 Hz, ∆ν ) 43.4 Hz, 2 H), 3.63 (AB, J ) 9.5, 6.3, 4.9
Hz, ∆ν ) 108.9 Hz, 2 H), 3.24 (AB, J ) 1.8, 2.2, 13.5 Hz, ∆ν )
39.0 Hz, 2 H), 2.26-2.02 (m, 2 H), 1.82-1.71 (m, 1 H), 1.63-
1.52 (m, 1 H); 13C NMR (75 MHz, C6D6) δ 173.6, 145.4, 134.0,
136.7, 129.7-127.1 (multiple signals), 120.1, 115.8, 109.5, 87.1,
84.7, 81.2, 67.5, 48.5, 46.5, 36.8, 29.3; MS m/z (M+) calcd
515.2460, obsd 515.2456; [R]2D0 -33.9 (c 0.59, CHCl3).
(2S,5S)-7-Ben zyl-9-m eth ylen e-2-[(tr ityloxy)m eth yl]-1-
oxa -7-a za sp ir o[4.4]n on a n -6-on e (21). The analogous olefi-
Anal. Calcd for C38H41NO2SeSi: C, 65.32; H, 5.91. Found:
C, 65.30; H, 5.91.
(2S,5S)-7-Ben zyl-2-[(tr ityloxy)m eth yl]-1-oxa-7-azaspir o-
[4.4]n on a n e-6,9-d ion e (19a ) a n d (2S,5R)-Ben zyl-2-[(tr i-
t yloxy)m et h yl]-1-oxa -7-a za sp ir o[4.4]n on a n e-6,9-d ion e
(20a ). A solution of 15a (830 mg, 1.60 mmol) in benzene (60
mL) was treated with pyridinium p-toluenesulfonate (30 mg),
stirred overnight at room temperature, washed with saturated
NaHCO3 solution, dried, and concentrated. Chromatography
of the residue on silica gel (elution with 30% ethyl acetate in
hexanes) provided 255 mg (35%) of the less polar isomer 20a ,
102 mg (14%) of the more polar 19a , and 69 mg (10%) of a 1:1
mixture of both.
For 19a : colorless oil; IR (neat, cm-1) 1779, 1709; 1H NMR
(300 MHz, C6D6) δ 7.68-6.91 (series of m, 20 H), 4.55 (m, 1
H), 4.17 (AB, J ) 14.9 Hz, ∆ν ) 115.4 Hz, 2 H), 3.45 (AB, J )
5.3, 9.8 Hz, ∆ν ) 53.4 Hz, 2 H), 2.87 (AB, J ) 7.4 Hz, ∆ν )
nation of 19a gave rise to 21 in 95% yield: IR (neat, cm-1
)
1
1703, 1596, 1078; H NMR (300 MHz, C6D6) δ 7.81-7.11 (m,
20 H), 5.54 (s, 1 H), 4.98 (m, 1H), 4.89 (s, 1 H), 4.34 (AB, J )
14.7 Hz, ∆ν ) 60.4 Hz, 2 H), 3.44 (AB, J ) 3.9, 9.7 Hz, ∆ν )
26.5 Hz, 2 H), 3.39 (AB, J ) 13.8 Hz, ∆ν ) 24 Hz, 2 H), 2.40-
2.25 (m, 2 H), 1.92-1.82 (m, 2 H); 13C NMR (75 MHz, C6D6) δ
174.3, 144.9, 144.8, 136.7, 129.3, 128.9, 128.5, 128.3, 128.0,

Enantioselective Ring Expansion Route
J . Org. Chem., Vol. 64, No. 6, 1999 2021
127.8, 127.7, 127.1, 110.0, 86.9, 80.5, 66.5, 48.6, 46.4, 36.5, 28.6;
MS m/z (M+) calcd 515.2460, obsd 515.2448; [R]2D0 +23.1 (c
0.92, CHCl3).
Anal. Calcd for C35H33NO3: C, 81.52; H, 6.45. Found: C,
81.68; H, 6.38.
portion of this material was dissolved in pyridine (1 mL),
treated with acetic anhydride (0.4 mL) and DMAP (10 mg) in
CH2Cl2 (10 mL), stirred for 24 h, and concentrated. The residue
was subjected to flash chromatography on silica gel (elution
with 50% ethyl acetate in hexanes), the process yielding both
pure triacetates. Isomer 26 (197 mg) predominated over its
diastereomer (48 mg).
(4R*,5S*)-7-Ben zyl-4-(p h en ylselen o)-1-oxa -7-a za sp ir o-
[4.4]n on a n e-6,9-d ion e (23). A solution of 16 (4.20 g, 10.5
mmol) in dry benzene (35 mL) was treated with pyridinium
p-toluenesulfonate (200 mg, 0.79 mmol) and stirred at 80 °C
under N2 for 90 min. The cooled mixture was filtered and
concentrated to leave a solid. Recrystallization of this material
from ethyl acetate afforded isomerically pure 23 (3.67 g, 87%)
For 26: colorless crystals; mp 139-140 °C; IR (neat, cm-1
)
1751, 1702; 1H NMR (300 MHz, CDCl3) δ 7.31-7.21 (m, 3 H),
7.16-7.12 (m, 2 H), 5.86-5.80 (m, 1 H), 5.74 (d, J ) 4.8 Hz, 1
H), 5.22 (d, J ) 3.8 Hz, 1 H), 4.51 (d, J ) 14.9 Hz, 1 H), 4.38-
4.32 (m, 2 H), 3.81 (dd, J ) 8.2, 7.5 Hz, 1 H), 3.61 (dd, J )
11.5, 3.8 Hz, 1 H), 2.97 (d, J ) 11.5 Hz, 1 H), 2.02 (s, 3 H),
1.99 (s, 3 H), 1.90 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 169.6,
169.4, 169.2, 169.1, 135.0, 128.8, 127.9, 127.8, 87.4, 72.3, 71.6,
70.6, 69.8, 51.1, 46.4, 20.6, 20.4, 20.3; MS m/z (M+) calcd
405.1424, obsd 405.1436.
as a white amorphous solid: mp 121-123 °C; IR (neat, cm-1
)
1775, 1703; 1H NMR (300 MHz, CDCl3) δ 7.50-7.45 (m, 2 H),
7.35-7.24 (m, 6 H), 7.18-7.14 (m, 2H), 4.61 (d, J ) 14.8 Hz,
1 H), 4.34-4.18 (m, 2 H), 4.07-4.00 (m, 1 H), 4.01 (d, J )
14.8 Hz, 1 H), 3.67 (d, J ) 17.3 Hz, 1 H), 3.54 (d, J ) 17.3 Hz,
1 H), 2.63-2.53 (m, 1 H), 2.45-2.31 (m, 1 H); 13C NMR (75
MHz, CDCl3) δ 205.6, 169.6, 134.1, 132.7, 129.5, 128.9, 128.4,
128.1, 128.0, 83.1, 70.0, 53.9, 46.5, 42.7, 32.9 (1 C not observed);
MS m/z (M+) calcd 401.0530, obsd 401.0546.
Anal. Calcd for C20H23NO8: C, 59.25; H, 5.72. Found: C,
59.37; H, 5.75.
(1R*,2R*,4′R*,5R*)-1′-Ben zyl-4′-h yd r oxysp ir o[3,6-d i-
oxabicyclo[3.1.0]h exan e-2,3′-pyr r olidin ]-2′-on e (27). A mag-
netically stirred slurry of 25 (200 mg, 0.82 mmol) and finely
ground NaHCO3 (150 mg) in CH2Cl2 (5 mL) at 0 °C was treated
portionwise with m-chloroperbenzoic acid (300 mg of 70% puri-
ty, 1.5 equiv) and allowed to react at room temperature for 6
days. The reaction mixture was filtered and concentrated to
leave a residue that was chromatographed on silica gel (elution
with 50% ethyl acetate in hexanes). There was recovered 132
mg of unreacted 25 and 47 mg (85%) of 27 as a colorless gum:
1H NMR (300 MHz, CDCl3) δ 7.56-7.19 (m, 5H), 4.46 (s, 2 H),
4.46 (m, 1 H), 4.23 (d, J ) 10.0 Hz, 1 H), 4.17 (d, J ) 10.0 Hz,
1 H), 3.96 (dd, J ) 5.0, 16.2 Hz, 2 H), 3.57-3.51 (m, 1 H), 3.17
(dd, J ) 11, 3.5 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 170.8,
135.2, 128.8, 128.0, 127.9, 86.6, 70.1, 68.3, 56.6, 55.6, 51.2, 46.6;
MS m/z (M+) calcd 261.1001, obsd 261.1013.
Acid -Ca ta lyzed Isom er iza tion of 17a . A solution of 17a
(350 mg, 0.70 mmol) in benzene (20 mL) was treated with
pyridinium p-toluenesulfonate (350 mg), blanketed with ni-
trogen, and heated at 75-80 °C for 48 h. The cooled reaction
mixture was quenched with saturated NaHCO3 solution (1
mL), and the separated organic phase was dried and concen-
trated. Careful chromatography of the residual oil on silica
gel (elution with 10% ethyl acetate in hexanes) afforded the
faster eluting fraction 28 (105 mg, 1:1 mixture of two isomers),
the more polar fraction 29 (137 mg, 1:1 of two isomers), and a
mixed fraction (71 mg) for an overall yield of 89%.
For 28: IR (neat, cm-1) 1742, 1693; 1H NMR (300 MHz,
CDCl3) δ 7.38-7.06 (m, 10 H), 4.63-4.56 (m, 2 H), 4.32-4.23
(m, 1 H), 3.99-3.92 (m, 0.5 H), 3.89-3.83 (m, 1 H), 3.78-3.72
(m, 1 H), 3.80-3.70 (m, 0.5 H), 3.61 (d, J ) 17.2 Hz, 0.5 H),
3.49 (d, J ) 17.2 Hz, 0.5 H), 3.42 (d, J ) 17.7 Hz, 0.5 H), 2.97
(d, J ) 17.7 Hz, 0.5 H), 2.58-2.32 (m, 2 H), 0.93 (s, 4.5 H),
0.89 (s, 4.5 H), 0.12 (s, 1.5 H), 0.09 (s, 1.5 H), 0.08 (s, 1.5 H),
0.07 (s, 1.5 H); 13C NMR (75 MHz, CDCl3) δ 206.0, 169.2, 168.8,
134.5, 134.1, 133.7, 131.4, 130.9, 129.7, 129.3, 129.2, 129.1,
129.0, 128.92, 128.86, 128.4, 128.2, 128.1, 127.7, 127.2, 83.6,
83.4, 82.5, 81.1, 66.3, 65.8, 64.9, 53.9, 53.6, 53.4, 48.9, 46.6,
46.5, 36.4, 33.8, 26.1, 26.0, 25.94, 25.87, 25.84, 25.78, 18.4,
18.32, 18.27, 15.3, -5.2, -5.3, -5.5; MS m/z (M+) calcd
497.2056, obsd 497.2041; [R]2D5 +12.7 (c 1.2, CHCl3).
Anal. Calcd for C20H19NO3Se: C, 59.84; H, 4.77. Found: C,
59.74; H, 4.81.
(4R*,5S*,9R*)-7-Ben zyl-9-h yd r oxy-4-(p h en ylselen o)-1-
oxa -7-a za sp ir o[4.4]n on a n -6-on e (24). A vigorously stirred
solution of 23 (2.83 g, 7.06 mmol) in methanol (75 mL) was
treated with sodium borohydride (320 mg, 8.46 mmol) in one
portion, stirred for 15 min, and quenched with water (2 mL).
The mixture was concentrated in vacuo and subjected to
chromatography on silica gel (elution with 60% ethyl acetate
in hexanes) to give 24 (2.52 g, 89%) as a colorless, crystalline
1
solid: mp 131-132 °C; IR (neat, cm-1) 3474, 1694, 1478; H
NMR (300 MHz, CDCl3) δ 7.59-7.54 (m, 2 H), 7.34-7.21 (m,
8 H), 4.49 (d, J ) 15.0 Hz, 1 H), 4.41 (d, J ) 15.0 Hz, 1 H),
4.29 (dd, J ) 5.2, 5.2 Hz, 1 H), 4.16-4.03 (m, 2 H), 3.99 (dd,
J ) 6.5, 4.3 Hz, 1 H), 3.53 (dd, J ) 10.3, 5.2 Hz, 1 H), 3.23
(dd, J ) 10.3, 2.5 Hz, 1 H), 3.09-2.97 (m, 1 H), 2.38-2.30 (m,
1 H); 13C NMR (75 MHz, CDCl3) δ 171.7, 135.5, 133.8, 129.5,
128.7, 128.1, 127.8, 127.6, 99.6, 89.2, 72.5, 68.0, 51.6, 46.7, 45.6,
35.4; MS m/z (M+) calcd 403.0686, obsd 403.0671.
Anal. Calcd for C20H21NO3Se: C, 59.70; H, 5.26. Found: C,
59.59; H, 5.31.
(5R*,9S*)-7-Ben zyl-9-h ydr oxy-1-oxa-7-azaspir o[4.4]n on -
3-en -6-on e 25). A solution of sodium metaperiodate (2.44 g,
11.4 mmol) in distilled water (25 mL) was added dropwise to
a solution of 24 (2.30 g, 5.71 mmol) in methanol (100 mL).
The resulting slurry was stirred for 12 h prior to the addition
of Celite (5 g), filtration, and concentration to one-fourth of
the original volume in vacuo. The resulting sludge was
extracted with ethyl acetate (3 × 30 mL), and the combined
extracts were dried and concentrated to leave a residue that
was purified chromatographically (silica gel, elution with ethyl
acetate). There was isolated 1.07 g (77%) of 25 as an amor-
phous white powder: mp 119-120 °C); IR (neat, cm-1) 3400,
1
1698; H NMR (300 MHz, CDCl3) δ 7.33-7.18 (m, 5 H), 6.22
(m, 1 H), 5.78 (m, 1 H), 4.91 (dt, J ) 13.0, 2.2 Hz, 1 H), 4.73
(dt, J ) 13.0, 1.8 Hz, 1 H), 4.43 (s, 2 H), 4.29 (t, J ) 6.8 Hz, 1
H), 3.44 (dd, J ) 10.0, 7.3 Hz, 1 H), 3.04 (dd, J ) 10.0, 6.2 Hz,
1 H), 3.06-2.45 (br s, 1 H); 13C NMR (75 MHz, CDCl3) δ 171.6,
135.6, 131.7, 131.0, 128.8, 128.1, 127.7, 123.1, 96.1, 76.7, 72.1,
49.9, 46.8; MS m/z (M+) calcd 245.1052, obsd 245.0989.
Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16. Found: C,
68.25; H, 6.17.
Anal. Calcd for C27H35NO4SSi: C, 65.16; H, 7.09. Found:
C, 65.06; H, 7.13.
For 29: mp 69-76 °C; IR (neat, cm-1) 1742, 1693; 1H NMR
(300 MHz, CDCl3) δ 7.38-7.08 (m, 10 H), 4.64-4.55 (m, 2 H),
4.56-4.48 (m, 0.5 H), 4.31-4.26 (m, 0.5 H), 3.99-3.92 (m, 0.5
H), 3.87-3.45 (m, 4.5 H), 2.54-2.46 (m, 1 H), 2.19-2.03 (m, 1
H), 0.90 (s, 4.5 H), 0.89 (s, 4.5 H), 0.063 (s, 3 H), 0.061 (s, 1.5
H), 0.059 (s, 1.5 H); 13C NMR (75 MHz, CDCl3) δ 169.7, 169.6,
134.6, 133.7, 133.5, 131.1, 130.9, 129.8, 129.4, 129.1, 129.0,
128.92, 128.87, 128.8, 128.5, 128.2, 128.11, 128.05, 127.5,
127.4, 83.9, 83.1, 82.0, 81.4, 68.1, 65.8, 65.7, 65.1, 54.0, 53.7,
52.1, 50.6, 46.5, 46.4, 38.7, 35.7, 34.4, 28.9, 25.9, 25.8, 23.7,
18.4, 18.3, 15.3, 14.2, 11.0, -5.3, -5.4, -5.6; MS m/z (M+) calcd
497.2056, obsd 497.2049; [R]2D5 -29.3 (c 1.8, CHCl3).
(3R*,4R*,5R*,9R*)-7-Ben zyl-3,4,9-t r ih yd r oxy-1-oxa -7-
a za sp ir o[4.4]n on a n -6-on e 3,4,9-Tr ia ceta te (26). A vigor-
ously stirred solution of 25 (650 mg, 2.65 mmol) in pyridine
(2.0 mL) at 0 °C was treated with finely ground osmium
tetraoxide (675 mg, 2.66 mmol) and stirred for 12 h prior to
concentration in vacuo. The resulting dark brown glass was
redissolved in CH2Cl2 (10 × 10 mL), stirred with saturated
NaHSO3 solution (5 mL) for 2 h, filtered through a pad of
Celite, and exhaustively extracted with CH2Cl2 (10 × 10 mL).
The combined extracts were dried and evaporated to give the
triol (623 mg, 84%) as a viscous gum. A 210 mg (0.752 mmol)

2022 J . Org. Chem., Vol. 64, No. 6, 1999
Paquette et al.
Anal. Calcd for C24H35NO4SSi: C, 65.16; H, 7.09. Found:
C, 65.06; H, 7.13.
amine hydrochloride (300 mg, 4.3 mmol), and the mixture was
stirred at room temperature for 1 h prior to the addition of
pyridine (0.5 mL). After 12 additional hours, the solvent was
evaporated, and the residue was purified chromatographically
(silica gel, elution with ethyl acetate) to give 40 (79 mg, 96%)
as colorless crystals: mp 137-139 °C; 1H NMR (300 MHz,
CDCl3) δ 8.45 (br s, 1 H), 7.35-7.22 (m, 5 H), 4.55-4.45 (m, 1
H), 4.58 (d, J ) 14.5 Hz, 1 H), 4.51 (d, J ) 14.5 Hz, 1 H), 4.08-
3.87 (m, 3 H), 3.57 (dd, J ) 12.2, 2.0 Hz, 1 H), 2.51-2.28 (m,
2 H), 2.22-2.18 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 171.9,
157.2, 134.8, 128.9, 128.4, 128.1, 82.8, 82.1, 63.6, 46.9, 44.5,
36.3, 25.5; MS m/z (M+) calcd 290.1267, obsd 290.1268; [R]2D5
-20.2 (c 0.64, CHCl3).
Acid -Ca ta lyzed Isom er iza tion of 17b. Comparable treat-
ment of 17b (800 mg, 1.47 mmol) in benzene (25 mL) provided
327 mg of the less polar 34 (9:1 mixture of two isomers) and
364 mg of the slower eluting 35 (9:1 mixture of two isomers)
in an overall 86% yield. These fractions were individually
subjected to oxidative elimination.
(2S,5S)-7-Ben zyl-2-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-
1-oxa -7-a za sp ir o[4.4]n on -3-en e-6,9-d ion e (36). A solution
of 34 (500 mg, 0.92 mmol) in methanol (35 mL) was vigorously
agitated with a solution of sodium metaperiodate (0.59 g, 2.8
mmol) in water (5.9 mL) for 1 h, filtered, and concentrated in
vacuo. The residue was taken up in ethyl acetate (30 mL), and
the separated organic phase was allowed to stand at room
temperature for 2 h to complete the elimination. After solvent
evaporation, the residue was chromatographed on silica gel
(elution with 40% ethyl acetate in hexanes) to give 36 of 90%
isomeric purity as a colorless gum (292 mg, 82%): IR (neat,
cm-1) 1789, 1713; 1H NMR (300 MHz, CDCl3) δ 7.38-7.21 (m,
5 H), 6.31 (dd, J ) 1.5 6.1 Hz, 1 H), 5.65 (dd, J ) 2.1, 6.1 Hz,
1 H), 5.26 (m, 1 H), 4.65 (s, 2 H), 3.89-3.63 (m, 4 H), 0.89 (s,
9 H), 0.07 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 203.1, 168.9,
134.1, 128.7, 128.3, 127.7, 123.8, 90.1, 90.0, 87.9, 76.6, 67.0,
54.6, 52.9, 46.9, 46.8, 26.0, 25.9, 18.3, 14.2, -5.3, -5.4; MS
m/z (M+) calcd 383.1917, obsd 383.1936; [R]2D5 +2.3 (c 1.4,
CHCl3).
(2S,5R)-7-Ben zyl-2-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-
1-oxa -7-a za sp ir o[4.4]n on -3-en e-6,9-d ion e (37). Comparable
oxidation of 35 (100 mg) provided 37 in 82% yield as a single
diastereomer: IR (neat, cm-1) 1782, 1715; 1H NMR (300 MHz,
CDCl3) δ 7.40-7.25 (m, 5 H), 6.34 (dd, J ) 6.1, 1.5 Hz, 1 H),
5.65 (dd, J ) 6.1, 2.2 Hz, 1 H), 5.19 (m, 1 H), 4.67 (d, J ) 14.5
Hz, 1 H). 4.61 (d, J ) 14.5 Hz, 1 H), 3.96 (dd, J ) 10.0, 6.2 Hz,
1 H), 3.79 (d, J ) 17.5 Hz, 1 H), 3.74 (dd, J ) 10.0, 6.8 Hz,
1H), 3.67 (d, J ) 17.5 Hz, 1 H), 0.90 (s, 9 H), 0.090 (s, 3 H),
0.089 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 203.5, 168.7, 134.5,
134.2, 129.1, 128.5, 128.3, 123.7, 100.0, 90.2, 67.3, 52.9, 46.9,
25.9, 18.3, -5.3, -5.4; MS m/z (M+) calcd 383.1917, obsd
383.1870; [R]2D5 -82.9 (c 1.0, CHCl3).
Anal. Calcd for C15H18N2O4: C, 62.05; H, 6.25. Found: C,
61.78; H, 6.31.
(2S,5R)-7-Ben zyl-2-(h yd r oxym eth yl)-1-oxa -7-a za sp ir o-
[4.4]n on a n e-6,9-d ion e 9-Oxim e (42). A solution of 20b (109
mg, 0.28 mmol) in methanol (5 mL) was treated with finely
powdered hydroxylamine hydrochloride (300 mg, 4.3 mmol),
stirred for 1 h, treated with pyridine (0.5 mL), sealed in a high-
pressure reactor, and subjected to 10 000 Pa for 20 h. Workup
in the predescribed manner furnished 73 mg (90%) of 42: IR
1
(neat, cm-1) 3210, 1698, 1667; H NMR (300 MHz, CDCl3) δ
7.36-7.21 (m, 5 H), 4.59-4.49 (m, 1 H), 4.59 (d, J ) 14.6 Hz,
1 H), 4.49 (d, J ) 14.6 Hz, 1 H), 4.09 (d, J ) 16.4 Hz, 1 H),
4.00 (dd, J ) 12.2, 1.7 Hz, 1 H), 3.83 (d, J ) 16.4 Hz, 1 H),
3.55 (dd, J ) 12.2, 1.5 Hz, 1 H), 2.57-2.13 (m, 4 H), 1.25 (br
s, 1 H); 13C NMR (75 MHz, CDCl3) δ 171.9, 157.2, 134.8, 128.9,
128.4, 128.1, 82.8, 82.1, 62.6, 46.9, 44.5, 36.6, 25.6, 25.5.
Anal. Calcd for C15H18N2O4: C, 62.04; H, 6.25. Found: C,
61.78; H, 6.31.
(2S,5R)-7-Ben zyl-2-(h yd r oxym eth yl)-1-oxa -7-a za sp ir o-
[4.4]n on -3-en e-6,9-d ion e 9-Oxim e (44). A solution of 36 (70
mg, 0.18 mmol) and hydroxylamine hydrochloride (300 mg,
4.31 mmol) in methanol (5 mL) was stirred at room temper-
ature for 1 h prior to the addition of pyridine (0.5 mL). The
reaction was allowed to proceed for 12 h prior to solvent
evaporation and chromatographic purification (silica gel, elu-
tion with ethyl acetate). There was obtained 50 mg (96%) of
44 as a colorless glass that was directly hydrogenated.
(2S,5R)-7-Ben zyl-2-(h yd r oxym eth yl)-1-oxa -7-a za sp ir o-
[4.4]n on -3-en e-6,9-d ion e Oxim e (45). Reaction of 37 (50 mg,
0.13 mmol) with hydroxylamine hydrochloride (300 mg, 4.31
mmol) and pyridine (0.5 mL) in methanol (5 mL) in the manner
described above afforded 35 mg (94%) of 45 as a white solid
that was directly acetylated.
Anal. Calcd for C22H29NO3Si: C, 68.53; H, 8.11. Found: C,
68.37; H, 7.98.
(2S,5S)-7-Ben zyl-2-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-
9-m eth ylen e-1-oxa-7-azaspir o[4.4]n on -3-en -6-on e (38). Ole-
fination of 36 (30 mg, 78 µmol) with methylenetriphenylphos-
phorane in a manner analogous to that described above [from
430 mg (1.06 mmol) of the iodide salt] followed by chromatog-
raphy on silica gel (elution with 35% ethyl acetate in hexanes)
furnished 38 in quantitative yield (27 mg): 1H NMR (300 MHz,
CDCl3) δ 7.37-7.23 (m, 5 H), 6.26 (dd, J ) 1.5, 6.0 Hz, 1 H),
5.65 (dd, J ) 2.0-6.0 Hz, 1 H), 5.34 (t, J ) 2.3 Hz, 1 H), 5.24
(t, J ) 1.9 Hz, 1 H), 5.05 (m, 1 H), 4.56 (d, J ) 14.6 Hz, 1 H),
4.50 (d, J ) 14.6 Hz, 1 H), 3.99 (dd, J ) 9.8, 6.0 Hz, 1 H), 3.90
(dt, J ) 13.8, 2.1 Hz, 1 H), 3.82 (d, J ) 13.8, 2.1 Hz, 1 H), 3.75
(dd, J ) 9.8, 7.2 Hz, 1 H),0.91 (s, 9 H), 0.87 (s, 6 H); 13C NMR
(75 MHz, CDCl3) δ 171.5, 142.1, 135.5, 131.8, 128.8, 128.3,
127.8, 112.9, 100.0, 91.7, 88.4, 77.3, 77.21, 77.17, 67.8, 48.7,
47.0, 26.0, 18.4, -5.2, -5.3.
(2S,5R)-7-Ben zyl-2-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-
9-m eth ylen e-1-oxa -7-a za sp ir o[4.4]n on -3-en -6-on e (39). A
procedure identical to that used above was employed. From
430 mg (1.06 mmol) of methyltriphenylphosphonium iodide
and 27 mg (70 µmol) of 37 was isolated 27 mg (100%) of 39 as
a colorless gum: 1H NMR (300 MHz, CDCl3) δ 7.33-7.23 (m,
5 H), 6.19 (dd, J ) 1.3, 6.0 Hz, 1 H), 5.66 (dd, J ) 2.3, 6.0 Hz,
1 H), 5.47 (t, J ) 2.3 Hz, 1 H), 5.25 (t, J ) 1.9 Hz, 1 H), 5.21
(m, 1 H), 4.57 (d, J ) 14.6 Hz, 1 H), 4.51 (d, J ) 14.6 Hz, 1 H),
3.92-3.80 (m, 3 H), 3.68 (dd, J ) 10.6, 5.5 Hz, 1 H), 0.89 (s, 9
H), 0.061 (s, 3 H), 0.060 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
171.9, 142.1, 135.5, 131.7, 128.8, 128.5, 128.3, 127.8, 113.6,
88.1, 77.2, 66.1, 48.8, 46.9, 25.9, 18.4, -5.3.
(2S,5S)-7-Ben zyl-2-(h yd r oxym eth yl)-1-oxa -7-a za sp ir o-
[4.4]n on -3-en e-6,9-d ion e 9-Oxim e, Aceta te (46). In a typical
procedure, a solution of hydrogen chloride in glacial acetic acid
(no less than 0.1 g/mL) was prepared at 0 °C. The oxime (30-
120 mg) was treated with 2 mL of this solution and stirred at
room temperature for 8 h to 7 days (TLC analysis). The
solution was then concentrated, and the residue was purified
by column chromatography on silica gel (elution with ethyl
acetate). The yields varied from 69% for 43 to 77% for 41 to
83% in the present example.
For 46: colorless solid: mp 156-161 °C; IR (neat, cm-1
)
3571, 3500-3100, 1713; 1H NMR (300 MHz, CDCl3) δ 8.65 (br
s, 1 H), 7.37-7.23 (m, 5 H), 6.17 (dd, J ) 6.0, 1.5 Hz, 1 H),
5.76 (dd, J ) 6.0, 2.3 Hz, 1 H), 5.33 (m, 1 H), 4.60 (ABq, J )
11.0 Hz, 2 H), 4.27 (dd, J ) 11.5, 3.6 Hz, 1 H), 4.09 (dd, J )
11.5, 6.5 Hz, 1 H), 4.04 (d, J ) 16.4 Hz, 1 H), 3.97 (d, J ) 16.4
Hz, 1 H), 2.06 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 171.1,
169.8, 153.8, 134.7, 129.1, 128.9, 128.5, 128.4, 128.1, 127.8,
89.4, 86.1, 66.5, 47.1, 45.2, 20.9; MS m/z (M+) calcd 318.1341,
obsd 318.1311; [R]2D5 -26.3 (c 0.9, CHCl3).
(S)-N-Ben zyl-5-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-4,5-
d ih yd r o-2-fu r a m id e (48). A solution of 20b (803 mg, 2.06
mmol) in methanol (20 mL) was treated with pyridine (5 mL)
followed by hydroxylamine hydrochloride (500 mg, 7.2 mmol),
and the resulting mixture was pressurized at 10 000 Pa for
48 h. Workup in the predescribed manner gave amorphous
powdery 47a as a 1:1 mixture of diastereomers (786 mg, 97%).
A sample of this material (220 mg, 0.54 mmol) was dissolved
(2S,5S)-7-Ben zyl-2-(h yd r oxym eth yl)-1-oxa -7-a za sp ir o-
[4.4]n on a n e-6,9-d ion e 9-Oxim e (40). A solution of 19b (110
mg, 0.28 mmol) in methanol (5 mL) was treated with hydroxyl-

Enantioselective Ring Expansion Route
J . Org. Chem., Vol. 64, No. 6, 1999 2023
in cold (-20 °C) CH2Cl2 (8 mL) containing triethylamine (190
µL) and treated with methanesufonyl chloride (46 µL, 1.1
equiv). The reaction mixture was stirred at this temperature
for 2 h and concentrated. The residue was purified by chro-
matography on silica gel (elution with 20% ethyl acetate in
hexanes) to give 48 (132 mg, 70%): IR (neat, cm-1) 1647, 1435,
135.1, 128.9, 128.1, 128.0, 89.9, 82.0, 65.3, 49.8, 49.4, 35.8, 28.0,
25.7, 18.0, -5.5; MS m/z (M+) calcd 404.2131, obsd 404.2150.
Anal. Calcd for C21H32N2O4Si: C, 62.34; H, 7.98. Found: C,
62.41; H, 7.99.
For 53:42 colorless crystals; mp 107-108 °C; IR (neat, cm-1
)
3381, 1693; 1H NMR (300 MHz, CDCl3) δ 8.23 (br s, 1 H), 7.33-
7.22 (m, 5 H), 4.58 (s, 2 H), 4.23 (m, 1 H), 4.08 (d, J ) 17.6 Hz,
1 H), 3.68 (d, J ) 17.6 Hz, 1 H), 3.64 (dd, J ) 10.6, 5.6 Hz, 1
H), 3.56 (dd, J ) 10.6, 5.5 Hz, 1 H), 2.99-2.88 (m, 1 H), 2.18-
1.98 (m, 2 H), 1.86-1.82 (m, 1 H), 0.88 (s, 9 H), 0.044 (s, 3 H),
0.035 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 169.4, 164.8, 135.3,
128.9, 128.1, 128.0, 89.9, 81.3, 65.3, 49.6 (2 C), 34.3, 28.2, 25.9,
18.4, -5.3; MS m/z (M+) calcd 404.2131, obsd 404.2150;
[R]2D5 -19.4 (c 1.0, CHCl3).
1
1253; H NMR (300 MHz, CDCl3) δ 7.40-7.26 (m, 5 H), 5.78
(t, J ) 2.6 Hz, 1 H), 4.85-4.71 (m, 3 H), 4.14 (br s, 1 H), 3.70
(m, 2 H), 2.80 (ddd, J ) 16.8, 2.8, 10.4 Hz, 1 H), 2.63 (ddd, J
) 16.8, 7.6, 2.9 Hz, 1 H), 0.84 (s, 9 H), 0.02 (s, 6 H); 13C NMR
(75 MHz, CDCl3) δ 149.6, 134.9, 129.0, 128.3, 128.2, 109.5,
83.4, 64.7, 31.6, 25.7, 18.2, -5.5 (1 C not observed); MS m/z
(M+) calcd 347.1916, obsd 347.1904; [R]D25 +27.3 (c 1.4, CHCl3).
(2S,5S)-9-Ben zyl-2-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-
1,6-d ioxa -9-a za sp ir o[4.5]d eca n e-7,10-d ion e (49). A cold
(-5 °C) stirred solution of 19b (178 mg, 0.46 mmol) in CH2Cl2
(10 mL) was treated with finely ground NaHCO3 (230 mg, 3.0
mmol) and then m-chloroperbenzoic acid (200 mg, 0.82 mmol).
After 30 min at this temperature, saturated NaHSO3 solution
(5 mL) was introduced, and stirring was maintained for a
further 10 min prior to extraction with CH2Cl2 (3 × 10 mL).
The combined organic extracts were dried and concentrated
Anal. Calcd for C21H32N2O4Si: C, 62.34; H, 7.98. Found: C,
62.41; H, 7.99.
For 57: colorless crystalline solid; mp 142-148 °C; IR (neat,
1
cm-1) 3399, 3221, 1684; H NMR (300 MHz, CDCl3) δ 7.95-
7.83 (br s, 1 H), 7.37-7.20 (m, 5 H), 4.78 (d, J ) 14.8 Hz, 1
H), 4.43 (d, J ) 14.8 Hz, 1 H), 4.09 (d, J ) 17.2 Hz, 1 H), 3.83-
3.76 (m, 1 H), 3.71-3.63 (m, 2 H), 3.42 (dd, J ) 12.5, 10.0 Hz,
1 H), 2.56 (ddd, J ) 14.4, 4.7, 4.6 Hz, 1 H), 2.19-2.11 (m, 1
H), 1.83 (dt, J ) 14.4, 4.6 Hz, 1 H), 1.73-1.60 (m, 1 H), 0.87
(s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 169.1, 164.7, 135.2, 128.0, 127.90, 127.87, 80.7, 66.5, 65.2,
49.9, 49.7, 27.9, 27.8, 25.7, 18.0, -4.8; MS m/z (M+) calcd
404.2131, obsd 404.2150.
to leave 49 (169 mg, 96%) as a colorless oil: IR (neat, cm-1
)
1769, 1690; 1H NMR (300 MHz, CDCl3) δ 7.38-7.21 (m, 5 H),
4.74 (d, J ) 14.8 Hz, 1 H), 4.49 (d, J ) 14.8 Hz, 1 H), 4.48-
4.41 (m, 1 H), 4.26 (d, J ) 17.5 Hz, 1 H), 3.85 (d, J ) 17.5 Hz,
1 H), 3.63 (d, J ) 4.8 Hz, 2 H), 3.07-2.94 (m, 1 H), 2.30-2.17
(m, 2 H), 3.06-1.94 (m, 1 H), 0.89 (s, 9 H), 0.05 (s, 3 H), 0.03
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 166.4, 162.7, 134.7, 129.0,
128.2, 128.0, 108.4, 83.6, 64.5 49.6, 48.3, 32.7, 25.8, 25.6, 18.3,
-5.35, -5.44; MS m/z (M+) calcd 389.2022, obsd 389.1972;
[R]2D5 +11.9 (c 1.4, CHCl3).
Anal. Calcd for C21H32N2O4Si: C, 62.34; H, 7.98. Found: C,
62.42; H, 7.93.
(2S,5S)-9-Ben zyl-2-(h yd r oxym et h yl)-1-oxa -6,9-d ia za -
sp ir o[4.5]d eca n e-7,10-d ion e (58) a n d (2S,5R)-9-Ben zyl-2-
(h yd r oxym et h yl)-1-oxa -6,9-d ia za sp ir o[4.5]d eca n e-7,10-
d ion e (60). A solution of 52 (171 mg, 0.42 mmol) in THF (5.0
mL) was treated with tetra-n-butylammonium fluoride hydrate
(144 mg, 0.55 mmol) at 0 °C, stirred for 2 h, and concentrated
in vacuo. Chromatography of the residue (silica gel, elution
with ethyl acetate) furnished a 5:1 mixture of 58 and 60 as
evidenced by integration of the proton at C-2. Heating this
mixture with pyridinium p-toluenesulfonate (30 mg) in ben-
zene (5 mL) to 50 °C for 1 h altered the ratio to the 1:1 level.
For this mixture: IR (neat, cm-1)3379, 3600-3200, 3229, 1682;
1H NMR (300 MHz, CDCl3) δ 8.24 (br s, 0.5 H), 8.12 (br s, 0.5
H), 7.31-7.15 (m, 5 H), 4.61-4.51 (m, 2 H), 4.42-4.34 (m, 0.5
H), 4.34-4.32 (m, 0.5 H), 4.02-3.94 (m, 1 H), 3.76-3.68 (m, 2
H), 3.50-3.41 (m, 1 H), 2.87-2.76 (m, 1 H), 2.53 (br s, 1 H),
2.21-2.08 (m, 1 H), 2.06-1.84 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ 168.3, 165.9, 165.0, 164.9, 135.0, 134.7, 128.92,
128.86, 128.1, 128.0, 127.9, 90.0, 89.9, 82.13, 82.09, 64.9, 63.6,
50.1, 49.8, 49.31, 49.26, 35.9, 35.8, 27.1, 26.4; MS m/z (M+)
calcd 290.1266, obsd 290.1275; [R]2D5 +12.1 (c 1.7, CHCl3).
(2S,5S)-2-[(ter t-Bu tyldiph en ylsiloxy)m eth yl]-7-(p-m eth -
oxyben zyl)-1-oxa -7-a za sp ir o[4.4]n on -3-en e-6,9-d ion e (66)
a n d (2S,5R)-2-[(ter t-Bu t yld ip h en ylsiloxy)m et h yl]-7-(p -
m et h oxyb en zyl)-1-oxa -7-a za sp ir o[4.4]n on -3-en e-6,9-d i-
on e (67). A solution of 18 (8.90 g, 11.5 mmol) in dry benzene
(500 mL) was treated with freshly dried pyridinium p-
toluenesulfonate (1.0 g), heated to 80 °C for 4 h, cooled, washed
with 1 M NaHCO3 solution (100 mL), and concentrated. The
residue was subjected to flash chromatography on silica gel
(elution with 30% ethyl acetate in hexanes) to give two
separable fractions, each consisting of two isomeric selenides
(total 5.96 g, 75%).
Anal. Calcd for C21H31NO4Si: C, 62.19; H, 7.71. Found: C,
62.10; H, 7.66.
(2S,5R)-9-Ben zyl-2-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-
1,6-d ioxa -9-a za sp ir o[4.5]d eca n e-7,10-d ion e (50). Compa-
rable oxidation of 20b (280 mg, 0.72 mmol) with m-CPBA (320
mg, 1.3 mmol) in the presence of powdered NaHCO3 (360 mg,
4.3 mmol) afforded 272 mg (93%) of 50 as a colorless solid:
mp 54-56 °C; IR (neat, cm-1) 1767, 1692; 1H NMR (300 MHz,
CDCl3) δ 7.35-7.31 (m, 5 H), 4.72 (d, J ) 14.8 Hz, 1 H), 4.51
(d, J ) 14.8 Hz, 1 H), 4.49-4.37 (m, 1 H), 4.23 (d, J ) 17.5
Hz, 1 H), 3.85 (d, J ) 17.5 Hz, 1 H), 3.67 (d, J ) 5.3 Hz, 2 H),
2.99-2.91 (m, 1 H), 2.31-2.24 (m, 1 H), 2.22-2.12 (m, 1 H),
2.06-1.93 (m, 1 H), 0.87 (s, 9 H), 0.03 (s, 3 H), 0.02 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 166.0, 163.0, 134.6, 129.0, 128.2,
128.0, 107.7, 85.1, 65.8, 49.6, 48.2, 33.3, 26.0, 25.8, 18.3, -5.4,
-5.5; MS m/z (M+) calcd 404.2131, obsd 404.2072; [R]2D5 -14.8
(c 1.6, CHCl3).
Anal. Calcd for C21H31NO4Si: C, 62.19; H, 7.71. Found: C,
62.03; H, 7.62.
(2S,5S)-9-Ben zyl-2-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-
1-oxa-6,9-diazaspir o[4.5]decan e-7,10-dion e (52)an d (2S,5R)-
9-Ben zyl-2-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-1-oxa -6,9-
d ia za sp ir o[4.5]d eca n e-7,10-d ion e (53). A solution of either
49 or 50 (200 mg, 0.49 mmol) in distilled methanol (1.0 mL)
at 0 °C was treated with a saturated solution of ammonia in
methanol (9.0 mL, saturated at 0 °C for 30 min), stirred for
30 min, and concentrated in vacuo to give 51 as a viscous oil
(207 mg, 100%), which was used directly.
The above lactol (830 mg, 1.98 mmol) was dissolved in
benzene (15 mL) containing 4 Å molecular sieves (200 mg) and
pyridinium p-toluenesulfonate (30 mg) and heated at 90 °C
under N2 for 1 h. Chromatography of the product mixture on
silica gel (elution with ethyl acetate) afforded 280 mg (35%)
of 52, 279 mg (35%) of 53, and 230 mg (30%) of 57.
For A: IR (neat, cm-1) 1776, 1704; 1H NMR (300 MHz,
CDCl3) δ 7.68-7.63 (m, 4 H), 7.48-7.29 (m, 11 H), 7.08 (m, 2
H), 6.81 (m, 2 H), 4.59-4.52 (m, 2 H), 4.13-4.06 (m, 1 H), 3.93
(d, J ) 14.5 Hz, 1 H), 3.80-3.79 (m, 2 H), 3.77 (s, 3 H), 3.65
(d, J ) 17.3 Hz, 1 H), 3.52 (d, J ) 17.3 Hz, 1 H), 2.66-2.59
(m, 1 H), 2.51-2.43 (m, 1 H), 1.07 (s, 9 H); 13C NMR (75 MHz,
CDCl3) δ 206.2, 168.5, 159.4, 135.7, 135.5, 133.3, 133.1, 130.3,
129.8, 129.7, 129.2, 128.3, 127.74, 127.64, 127.6, 126.2, 114.2,
99.9, 84.0, 81.0, 65.2, 55.2, 53.7, 45.9, 45.8, 41.4, 34.1, 26.9,
19.2; FAB MS m/z (M+ + 1) calcd 700.19, obsd 700.33; [R]2D5
+13.0 (c 2.45, CHCl3).
For 52:42 colorless crystals; mp 127-129 °C; IR (neat, cm-1
)
3381, 1693; 1H NMR (300 MHz, CDCl3) δ 7.53 (br s, 1 H), 7.33-
7.21 (m, 5 H), 4.59 (s, 2 H), 4.35-4.25 (m, 1 H), 4.01 (d, J )
17.7 Hz, 1 H), 3.74 (d, J ) 17.7 Hz, 1 H), 3.71 (dd, J ) 10.9,
3.8 Hz, 1 H), 3.61 (dd, J ) 10.9, 3.5 Hz, 1 H), 2.93-2.83 (m, 1
H), 2.34-2.21 (m, 1 H), 2.08-1.90 (m, 2 H), 0.89 (s, 9 H), 0.07
(s, 3 H), 0.06 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 167.2, 165.1,

2024 J . Org. Chem., Vol. 64, No. 6, 1999
Paquette et al.
For B: IR (neat, cm-1) 1776, 1704; 1H NMR (300 MHz,
CDCl3) δ 7.68-7.63 (m, 4 H), 7.48-7.29 (m, 11 H), 7.08 (m, 2
H), 6.81 (m, 2 H), 4.57 (d, J ) 14.5 Hz, 1 H), 4.55-4.45 (m, 1
H), 4.13-4.06 (m, 1 H), 3.92 (d, J ) 14.5 Hz, 1 H), 3.94-3.74
(m, 2 H), 3.77 (s, 3 H), 3.64 (d, J ) 17.3 Hz, 1 H), 3.49 (d, J )
17.3 Hz, 1 H), 2.64-2.55 (m, 1 H), 2.22-2.10 (m, 1 H), 1.06 (s,
9 H); 13C NMR (75 MHz, CDCl3) δ 205.3, 169.5, 159.4, 135.6,
133.42, 133.40, 132.6, 129.6, 129.5, 128.2, 127.9, 127.7, 127.64,
127.60, 127.5, 126.2, 114.2, 83.5, 82.1, 66.2, 55.3, 53.8, 45.9,
42.9, 36.1, 28.5, 26.8, 19.2; FAB MS m/z (M+ + 1) calcd 700.19,
obsd 700.33; [R]2D5 -4.2 (c 1.35, CHCl3).
solution of 66 (1.01 g, 1.88 mmol) in THF (40 mL) and pyridine
(10 mL) was cooled to 0 °C, treated with a solution of osmium
tetraoxide (476 mg, 1.88 mmol) in the minimum amount of
pyridine, allowed to warm to room temperature during 4 h,
and concentrated in vacuo (bath temperature <50 °C). The
resulting dark brown foam was taken up in CH2Cl2 (100 mL),
treated with saturated NaHSO3 solution (1 mL), stirred
vigorously overnight, filtered through a pad of Celite, and
extracted repeatedly with CH2Cl2 (8 × 40 mL). The combined
extracts were dried and concentrated. The residual glass was
taken up in CH2Cl2 (50 mL), treated with acetic anhydride (3
mL), pyridine (6 mL), and DMAP (50 mg), stirred overnight,
and concentrated. The product was chromatographed on silica
gel (elution with 30% ethyl acetate in hexanes) to furnish 122
mg of 69 and 472 mg of 70 (48% total).
For 69: IR (neat, cm-1) 1782, 1681; 1H NMR (300 MHz,
CDCl3) δ 7.70-7.64 (m, 4 H), 7.44-7.43 (m, 6 H), 7.20-7.16
(m, 2 H), 6.88-6.84 (m, 2 H), 5.43 (t, J ) 6.4 Hz, 1 H), 5.20 (d,
J ) 6.3 Hz, 1 H), 4.69-4.64 (m, 1 H), 4.53 (d, J ) 14.4 Hz, 1
H), 4.48 (d, J ) 14.4 Hz, 1 H), 3.91-3.83 (m, 2 H), 3.87 (d, J
) 17.3 Hz, 1 H), 3.80 (s, 3 H), 3.57 (d, J ) 17.3 Hz, 1 H), 2.11
(s, 3 H), 2.05 (s, 3 H), 1.07 (s, 9 H); 13C NMR (75 MHz, CDCl3)
δ 202.1, 172.1, 170.5, 169.9, 166.8, 159.5, 135.6, 133.1, 132.9,
130.0, 129.74, 129.72, 127.4, 126.4, 114.3, 97.6, 83.3, 81.9, 73.8,
71.4 62.9, 55.3, 53.0, 46.0, 26.8, 26.7, 20.6, 20.4, 19.2; FAB MS
m/z (M+ + 1) calcd 659.26, obsd 659.28.
Anal. Calcd for C38H41NO5SeSi: C, 65.32; H, 5.91. Found:
C, 65.28; H, 5.91.
A solution of the A/B mixture (8.90 g, 12.8 mmol) in
methanol (350 mL) at 0 °C was treated with finely ground
NaHCO3 (10.0 g), and the resulting slurry was treated drop-
wise with a solution of sodium metaperiodate (8.20 g, 38.5
mmol) in distilled water (20 mL). After being stirred for 12 h,
the reaction mixture was filtered through a Celite pad, and
the filtrate was concentrated to approximately half-volume
prior to being partitioned between saturated NaHCO3 solution
and ethyl acetate. The separated aqueous phase was extracted
with ethyl acetate, and the combined organic layers were dried
and concentrated. Flash chromatography of the residue on
silica gel (elution with 30% ethyl acetate in hexanes) resulted
in the separation of 66 from 67 (5.69 g total, 82%).
1
For 66: IR (neat, cm-1) 1782, 1707, 1612, 1513; H NMR
Compound 70 was subjected directly to peracid oxidation.
(2R,3S,4R,5S)-2-[(ter t-Bu t yld ip h en ylsiloxy)m et h yl]-
3,4-d ih yd r oxy-9-(p-m eth oxyben zyl)-1,6-d ioxa -9-a za sp ir o-
[4.5]d eca n e Dia ceta te (Ester ) (73). A stirred slurry of 69
(300 mg, 4.6 mmol) and finely ground NaHCO3 (150 mg) in
CH2Cl2 (20 mL) was treated with m-CPBA (225 mg of 70%
purity, 2 equiv) and stirred for 20 in prior to dilution with more
CH2Cl2 (10 mL) and NaHSO3 solution (5 mL). The predescribed
workup led to the isolation of 282 mg (92%) of 73 after
chromatography on silica gel (elution with 30% ethyl acetate
in hexanes): white foam; IR (neat, cm-1) 1756, 1695, 1514;
1H NMR (300 MHz, CDCl3) δ 7.68-7.63 (m, 4 H), 7.49-7.33
(m, 6 H), 7.19-7.15 (m, 2 H), 6.89-6.85 (m, 2 H), 5.62 (d, J )
5.2 Hz, 1 H), 5.47 (dd, J ) 5.2, 7.4 Hz, 1 H), 4.69 (d, J ) 14.5
Hz, 1 H), 4.64-4.60 (m, 1 H), 4.25 (d, J ) 14.5 Hz, 1 H), 4.12
(d, J ) 17.8 Hz, 1 H), 3.96 (d, J ) 17.8 Hz, 1 H), 3.92 (dd, J )
11.5, 4.5 Hz, 1 H), 3.84 (dd, J ) 11.4, 4.4 Hz, 1 H), 3.80 (s, 3
H), 2.10 (s, 3 H), 2.06 (s, 3 H), 1.07 (s, 9 H); 13C NMR (75 MHz,
CDCl3) δ 169.9, 169.6, 162.6, 160.5, 159.7, 135.6, 132.98, 132.8,
130.0, 129.8, 127.8, 126.1, 114.4, 104.3, 83.8, 75.0, 70.5, 63.2,
55.3, 49.1, 47.2, 26.7, 20.6, 20.4, 19.2; FAB MS m/z (M+ + 1)
calcd 676.25, obsd 676.34; [R]2D5 +40.2 (c 0.9, CHCl3).
(2R,3R,4S,5S)-2-[(ter t-Bu t yld ip h en ylsiloxy)m et h yl]-
3,4-d ih yd r oxy-9-(p-m eth oxyben zyl)-1,6-d ioxa -9-a za sp ir o-
[4.5]d eca n e Dia ceta te (Ester ) (74). Comparable oxidation
of 70 (122 mg, 1.87 mmol) delivered 107 mg (86%) of 74 as a
white foam: 1H NMR (300 MHz, CDCl3) δ 77.71-7.60 (m, 4
H), 7.45-7.32 (m, 6 H), 7.25-7.15 (m, 2 H), 6.89-6.83 (m, 2
H), 6.09 (d, J ) 6.3 Hz, 1 H), 5.62 (t, J ) 6.3 Hz, 1 H), 4.67 (d,
J ) 14.6 Hz, 1 H), 4.43 (d, J ) 14.6 Hz, 1 H), 4.32-4.28 (m, 1
H), 4.02 (d, J ) 18.0 Hz, 1 H), 3.84 (d, J ) 18.0 Hz, 1 H), 3.86-
3.78 (m, 2 H), 3.79 (s, 3 H), 2.08 (s, 3 H), 2.07 (s, 3 H), 1.05 (s,
9 H); 13C NMR (75 MHz, CDCl3) δ 169.9, 169.8, 163.3, 160.8,
159.7, 135.7, 132.9, 132.8, 130.0, 129.6, 127.71, 127.68, 126.0,
114.5, 102.4, 83.1, 74.7, 63.8, 55.3, 49.1, 46.9, 26.7, 20.7, 20.4,
19.2; FAB MS m/z (M+ + 1) calcd 676.25, obsd 676.34; [R]2D5
+13.1 (c 1.0 CHCl3).
(300 MHz, CDCl3) δ 7.71-7.25 (m, 10 H), 7.19 (d, J ) 8.6 Hz,
2 H), 6.88 (d, J ) 8.6 Hz, 2 H), 6.37 (dd, J ) 6.1, 4.1 Hz, 1 H),
5.65 (dd, J ) 6.1, 2.1 Hz, 1 H), 5.26 (m, 1 H), 4.59 (d, J ) 14.5
Hz, 1 H), 4.53 (d, J ) 14.5 Hz, 1 H), 4.05 (dd, J ) 10.0, 5.9 Hz,
1 H), 3.83 (dd, J ) 10.0, 7.2 Hz, 1 H), 3.80 (s, 3 H), 3.76 (d, J
) 17.5 Hz, 1 H), 3.65 (d, J ) 17.5 Hz, 1 H), 1.09 (s, 9 H); 13C
NMR (75 MHz, CDCl3) δ 203.7, 168.4. 159.5, 135.54, 135.49,
134.2, 133.4, 133.3, 129.8, 129.6, 127.7, 126.4, 123.8, 114.4,
90.1, 89.8, 67.7, 55.2, 52.7, 46.2, 26.8, 19.2; MS m/z (M+ - 1)
calcd 541.2285, obsd 541.2313; [R]2D5 -102 (c 1.8, CHCl3).
Anal. Calcd for C32H35NO5Si: C, 70.95; H, 6.51. Found: C,
70.83; H, 6.47.
1
For 67: IR (neat, cm-1) 1783, 1703, 1611, 1513; H NMR
(300 MHz, CDCl3) δ 7.69-7.25 (m, 10 H), 7.19 (d, J ) 8.6 Hz,
2 H), 6.88 (d, J ) 8.6 Hz, 2 H), 6.33 (dd, J ) 6.0, 1.5 Hz, 1 H),
5.63 (dd, J ) 6.0, 2.1 Hz, 1 H), 5.38-5.33 (m, 1 H), 4.58 (s, 2
H), 3.92 (dd, J ) 10.2, 5.9 Hz, 1 H), 3.78 (dd, J ) 10.2, 7.0 Hz,
1 H), 3.80 (s, 3 H), 3.71 (d, J ) 17.2 Hz, 1 H), 3.64 (d, J ) 17.2
Hz, 1 H), 1.06 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 202.9,
168.8, 159.6, 135.61, 135.55, 134.0, 133.4, 133.2, 129.9, 129.68,
129.66, 127.7, 126.4, 123.9, 114.4, 90.1, 89.9, 67.5, 55.3, 52.7,
46.3, 26.8, 19.2; MS m/z (M+ - 1) calcd 541.2285, obsd
541.2288; [R]2D5 -12.7 (c 1.8, CHCl3).
(2S,5S)-2-[(ter t-Bu tyldiph en ylsiloxy)m eth yl]-7-(p-m eth -
oxyb en zyl)-9-m et h ylen e-1-oxa -7-a za sp ir o[4.4]n on a n -6-
on e (68). Reaction of 66 (50 mg, 0.093 mmol) with the ylide
prepared from methyltriphenylphosphonium iodide (400 mg)
and n-butyllithium (0.4 mL) in THF (13 mL) according to the
predescribed procedure gave, after chromatography on silica
gel (elution with 40% ethyl acetate in hexanes), 42 mg (84%)
1
of 68 as a colorless oil: IR (neat, cm-1) 1702, 1513; H NMR
(300 MHz, CDCl3) δ 7.71-7.25 (m, 10 H), 7.19 (d, J ) 8.5 Hz,
2 H), 6.88 (d, J ) 8.6 Hz, 2 H), 6.34 (dd, J ) 6.0, 1.5 Hz, 1 H),
5.66 (dd, J ) 6.0, 2.0 Hz, 1 H), 5.34 (m, 1 H), 5.24 (t, J ) 2.3
Hz, 1 H), 5.14-5.08 (m, 1 H), 4.49 (d, J ) 24.5 Hz, 1 H), 4.43
(d, J ) 14.5 Hz, 1 H), 4.07 (dd, J ) 9.7, 5.7 Hz, 1 H), 3.89-
3.72 (m, 3 H), 3.79 (s, 3 H), 1.09 (s, 9 H); 13C NMR (75 MHz,
CDCl3) δ 171.2, 159.2, 142.2, 135.58, 135.56, 133.7, 133.6,
132.0, 129.6, 128.2, 127.8, 127.6, 114.1, 112.8, 91.8, 88.0, 68.5,
55.3, 48.5, 46.4, 27.0, 26.0, 19.3; MS m/z (M+) calcd 541.2648,
obsd 541.2670; [R]2D5 +27.1 (c 2.1, CHCl3).
(2R,3S,4R,5S)-2-[(ter t-Bu t yld ip h en ylsiloxy)m et h yl]-
3,4-d ih yd r oxy-7-(p-m eth oxyben zyl)-1-oxa -7-a za sp ir o[4.4]-
n on an e-6,9-dion e, Diacetate (Ester ) (69) an d (2R,3R,4S,5S)-
2-[(ter t-Bu tyld ip h en ylsiloxy)m eth yl]-3,4-d ih yd r oxy-7-(p-
m et h oxyben zyl)-1-oxa-7-a za sp ir o[4.4]n on a n e-6,9-d ion e,
Dia ceta te (Ester ) (70). P r ototyp ica l P r oced u r e. A stirred
(2R,3S,4R,5R)-2-[(ter t-Bu t yld ip h en ylsiloxy)m et h yl]-
3,4-d ih yd r oxy-7-(p-m eth oxyben zyl)-1-oxa -7-a za sp ir o[4.4]-
n on an e-6,9-dion e,Diacetate (Ester )(71)an d (2R,3R,4S,5R)-
2-[(ter t-Bu tyld ip h en ylsiloxy)m eth yl]-3,4-d ih yd r oxy-7-(p-
m et h oxyben zyl)-1-oxa-7-a za sp ir o[4.4]n on a n e-6,9-d ion e,
Dia ceta te (Ester ) (72). A 1.02 g (1.92 mmol) sample of 67
was osmylated and acetylated in a manner directly paralleling
that described above for 66. There was isolated 132 mg of 71
and 395 mg of 72 (43% total).
For 71: IR (neat, cm-1) 1750, 1697; 1H NMR (300 MHz,
CDCl3) δ 7.67-7.63 (m, 4 H), 7.39-7.26 (m, 6 H), 7.14 (d, J )

Enantioselective Ring Expansion Route
J . Org. Chem., Vol. 64, No. 6, 1999 2025
8.5 Hz, 2 H), 6.83 (d, J ) 8.5 Hz, 2 H), 5.69 (t, J ) 5.2 Hz, 1
H), 5.55 (d, J ) 6.7 Hz, 1 H), 4.67 (dd, J ) 5.2, 4.5 Hz, 1 H),
4.52 (d, J ) 14.5 Hz, 1 H), 4.43 (d, J ) 14.5 Hz, 1 H), 3.99-
3.92 (m, 4 H), 3.78 (s, 3 H), 2.04 (s, 3 H), 1.98 (s, 3 H), 1.03 (s,
9 H); 13C NMR (75 MHz, CDCl3) δ 169.9, 169.8, 163.4, 159.7,
159.4, 135.6, 135.5, 133.1, 132.9, 127.8, 126.1, 114.4, 103,6,
80.7, 77.3, 70.3, 61.3, 55.3, 49.0, 47.3, 26.6, 20.5, 20.4, 19.2;
FAB MS m/z (M+ + 1) calcd 676.25, obsd 676.38.
Compound 72 was subjected directly to peracid oxidation.
(2R,3R,4S,5R)-2-[(ter t-Bu t yld ip h en ylsiloxy)m et h yl]-
3,4-d ih yd r oxy-9-(p-m eth oxyben zyl)-1,6-d ioxa -9-a za sp ir o-
[4.5]d eca n e-7,10-d ion e, Dia ceta te (Ester ) (76). Oxidation
of 72 (66 mg, 0.14 mmol) with buffered m-CPBA according to
the general procedure afforded 47 mg (68%) of 76: IR (neat,
cm-1) 1750, 1697; 1H NMR (300 MHz, CDCl3) δ 7.67-7.63 (m,
4 H), 7.46-7.36 (m, 6 H), 7.14 (d, J ) 8.7 Hz, 2 H), 6.83 (d, J
) 8.7 Hz, 2 H), 5.69 (t, J ) 5.2 Hz, 1 H), 5.54 (dd, J ) 0.6, 5.2
Hz, 1 H), 4.71-4.65 (m, 1 H), 4.52 (d, J ) 14.5 Hz, 1 H), 4.43
(d, J ) 14.5 Hz, 1 H), 3.98-3.95 (m, 4 H), 3.78 (s, 3 H), 2.04
(s, 3 H), 1.98 (s, 3 H), 1.03 (s, 9 H); 13C NMR (75 MHz, CDCl3)
δ 169.8, 163.4, 159.7, 159.4, 135.6, 135.5, 133.1, 132.9, 129.8,
127.8, 126.2, 114.4, 103.6, 80.7, 77.2, 76.7, 70.3, 61.3, 55.3, 49.0,
47.3, 26.7, 20.5, 19.2; FAB MS m/z (M+ + 1) calcd 676.25, obsd
676.34; [R]2D5 +4.2 (c 0.1, CHCl3).
[4.5]d eca n e-7,10-d ion e, Dia ceta te (Ester ) (78). Comparable
ammonolysis of 74 or 76 afforded 78 in 71% and 77% yield,
respectively: white foam; 1H NMR (300 MHz, CDCl3) δ 7.67-
7.57 (m, 4 H), 7.46-7.33 (m, 6 H), 7.15 (m, 2 H), 6.86 (m, 2
H), 6.08 (d, J ) 5.0 Hz, 1 H), 5.80 (dd, J ) 4.2, 5.0 Hz, 1 H),
4.68 (d, J ) 14.5 Hz, 1 H), 4.59-4.52 (m, 1 H), 4.41 (d, J )
14.5 Hz, 1 H), 4.00 (d, J ) 17.9 Hz, 1 H), 3.85 (d, J ) 17.9 Hz,
1 H), 3.93-3.80 (m, 2 H), 3.79 (s, 3 H), 2.05 (s, 3 H), 2.04 (s, 3
H), 1.01 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 169.8, 169.1,
161.3, 159.7, 135.5, 135.4, 130.0, 129.9, 129.7, 127.83, 127.78,
114.5, 101.9, 82.0, 61.4, 55.3, 49.2, 47.0, 26.7, 20.5, 20.3, 19.1;
FAB MS m/z (M+ + 2) calcd 676.27, obsd 676.33.
(2R,3S,4R,5S)-2-[(ter t-Bu t yld ip h en ylsiloxy)m et h yl]-
3,4-d ih yd r oxy-1-oxa -6,9-d ia za sp ir o[4.5]d eca n e-7,10-d i-
on e, Dia ceta te (Ester ) (79). A solution of 77 (105 mg, 0.16
mmol) in water (0.25 mL) and acetonitrile (3.5 mL) was treated
with ceric ammonium nitrate (500 mg, ca. 6 equiv) and stirred
for 6 h before being partitioned between saturated NaHCO3
solution (5 mL) and ethyl acetate (10 mL). The resulting
emulsion was filtered and extracted repeatedly with ethyl
acetate. The combined organic phases were dried and concen-
trated to leave a residue that was chromatographed on silica
gel (gradient elution with 30-100% ethyl acetate in hexanes)
to give anisaldehyde (7 mg), unreacted 77 (61 mg, 58%), and
79 (19 mg, 53%) as a white foam: IR (neat, cm-1) 1748, 1725,
1603; 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 4 H), 7.43-
7.33 (m, 6 H), 6.00 (d, J ) 6.6 Hz, 1 H), 5.61 (dd, J ) 2.4, 6.6
Hz, 1 H), 4.46-4.45 (m, 1 H), 4.24 (dd, J ) 17.8, 9.7 Hz, 1 H),
4.05 (dd, J ) 17.8, 4.3 Hz, 1 H), 3.89-3.79 (m, 2 H), 2.13 (s, 3
H), 2.12 (s, 3 H), 1.09 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ
170.3, 169.0, 164.6, 162.3, 135.7, 132.7, 132.6, 129.9, 129.8,
127.8, 127.7, 103.5, 87.4, 77.2, 71.5, 69.9, 63.0, 43.9, 26.8,
26.7, 20.7, 19.1; FAB MS m/z (M+ + 2) calcd 556.21, obsd
556.31.
(2R,3S,4R,5S)-2-[(ter t-Bu t yld ip h en ylsiloxy)m et h yl]-
3,4-d ih yd r oxy-9-(p-m eth oxyben zyl)-1-oxa -6,9-d ia za sp ir o-
[4.5]d eca n e-7,10-d ion e, Dia ceta te (Ester ) (77). A solution
of 73 (262 mg, 3.79 mmol) in CHCl3 (25 mL) was cooled to
-20 °C prior to the addition of a saturated solution of ammonia
in methanol (4 mL). The progress of reaction was monitored
periodically by TLC until complete disappearance of starting
material (spot to spot). The mixture was concentrated in vacuo
to remove all traces of methanol. The residual foam was taken
up in benzene (20 mL), admixed with 4 Å molecular sieves
(500 mg) and pyridinium p-toluenesulfonate (50 mg), and
stirred at room temperature for 24 h. Filtration, concentration,
and chromatography on silica gel (elution with 50% ethyl
acetate in hexanes) followed to give 77 (201 mg, 79%) as a
Ack n ow led gm en t. This work was supported in part
by a grant from the National Institutes of Health, with
additional allocations of funds from the Eli Lilly Co. The
authors thank Prof. Robin Rogers (University of Ala-
bama) for the X-ray crystallographic analyses and Dr.
Kurt Loening for assistance with nomenclature.
1
white foam: IR (neat, cm-1) 1748, 1698; H NMR (300 MHz,
CDCl3) δ 7.71-7.65 (m, 4 H), 7.44-7.33 (m, 6 H), 7.19-7.16
(m, 2 H), 6.87-6.84 (m, 2 H), 6.10 (d, J ) 6.7 Hz, 1 H), 5.61
(dd, J ) 2.7, 6.7 Hz, 1 H), 4.82 (d, J ) 17.8 Hz, 1 H), 4.44-
4.40 (m, 1 H), 4.38 (d, J ) 14.6 Hz, 1 H), 4.17 (d, J ) 17.8 Hz,
1 H), 3.91 (d, J ) 17.8 Hz, 1 H), 3.80 (s, 3 H), 3.94-3.75 (m,
2 H), 2.13 (s, 3 H), 2.12 (s, 3 H), 1.11 (s, 9 H); 13C NMR (75
MHz, CDCl3) δ 170.3, 169.7, 169.0, 164.8, 160.3, 159.7, 135.7,
135.6, 132.7, 129.8, 129.71, 129.65, 127.8, 127.7, 126.3, 114.5,
103.7, 87.1, 62.9, 55.3, 49.3, 47.5, 26.6, 20.7, 20.3, 19.1; FAB
MS m/z (M+ + 2) calcd 676.27, obsd 676.33; [R]2D5 +4.2 (c 1.7,
CHCl3).
Su p p or tin g In for m a tion Ava ila ble: High-field 1H and
13C NMR spectra of key compounds lacking elemental analysis,
along with tables giving the crystal data and structure
refinement information, bond lengths and bond angles, atomic
and hydrogen coordinates, and isotropic and anisotropic
displacement coordinates for 26 and 44. This material is
available free of charge via the Internet at http://pubs.acs.org.
(2R,3R,4S,5S)-2-[(ter t-Bu t yld ip h en ylsiloxy)m et h yl]-
3,4-d ih yd r oxy-9-(p-m eth oxyben zyl)-1-oxa -6,9-d ia za sp ir o-
J O982259U