Synthesis of functionalized 1-azaspirocyclic cyclopentanones using bronsted acid or N-bromosuccinimide promoted ring expansions

Article abstract of DOI:10.1021/jo0493572

Azaspirocyclic ring systems are present in a variety of alkaloids. Functionalized 1-azaspirocyclopentanones (6, 7, 11, 12) can be efficiently constructed through semipinacol ring expansion reactions of 2-(1- hydroxycyclobutyl)-p-toluenesulfonylenamides (4

Full text of DOI:10.1021/jo0493572

Syn th esis of F u n ction a lized 1-Aza sp ir ocyclic Cyclop en ta n on es
Usin g Br on sted Acid or N-Br om osu ccin im id e P r om oted Rin g
Exp a n sion s
Gregory R. Dake,* Michae¨l D. B. Fenster, Paul B. Hurley, and Brian O. Patrick†
Department of Chemistry, 2036 Main Mall, University of British Columbia,
Vancouver, British Columbia, Canada V6T 1Z1
gdake@chem.ubc.ca
Received April 16, 2004
Azaspirocyclic ring systems are present in a variety of alkaloids. Functionalized 1-azaspirocyclo-
pentanones (6, 7, 11, 12) can be efficiently constructed through semipinacol ring expansion reactions
of 2-(1-hydroxycyclobutyl)-p-toluenesulfonylenamides (4) promoted by either a Bronsted acid ((S)-
(+)-10-camphorsulfonic acid or HCl) or N-bromosuccinimide, an electrophilic bromine source.
Reactions promoted by N-bromosuccinimide tend to proceed in higher yields (80-95%) and with
greater diastereoselectivity (3:1-1:0) compared to those reactions promoted by a Bronsted acid. In
addition, N-bromosuccinimide promoted reactions can produce a complementary stereochemical
outcome compared to the reactions using Bronsted acid.
In tr od u ction
The presence of interesting structural motifs within
natural products motivates the synthetic organic chem-
istry community. As an example, a number of alkaloids
such as lepadiformine, cephalotaxine, fasicularin, and
halichlorine all share a 1-azaspirocyclic ring system as
a common architectural feature (Figure 1). That these
alkaloids have triggered significant attention from a
number of research groups is not surprising.1-4 Methods
to construct these azaspirocyclic ring systems are con-
tinually being invented and developed.5
† Manager, UBC X-ray Structural Facility; to whom inquiries
regarding crystal structures should be addressed.
(1) Lepidiformine. Isolation: (a) Biard, J . F.; Goyut, S.; Roussakis,
C.; Verbist, J . F.; Vercauteren, J .; Weber, J . F.; Boukef, K. Tetrahedron
Lett. 1994, 35, 2691. Synthetic work: (b) For a nice summary, see:
Weinreb, S. M. Acc. Chem. Res. 2003, 36, 59. (c) Abe, H.; Aoyagi, S.;
Kibayashi, C. Angew. Chem., Int. Ed. 2002, 41, 3017. (d) Sun, P.; Sun,
C.; Weinreb, S. M. J . Org. Chem. 2002, 67, 4337. (e) Sun, P.; Sun, C.;
Weinreb, S. M. Org. Lett. 2001, 3, 3507. (f) Greshock, T. J .; Funk, R.
L. Org. Lett. 2001, 3, 3511. (g) Reference 3b. (h) Abe, H.; Aoyogi, S.;
Kibayashi, C. Tetrahedron Lett. 2000, 41, 1205. (i) Werner, K. M.; De
los Santos, J . M.; Weinreb, S. M.; Shang, M. J . Org. Chem. 1999, 64,
4865. (j) Pearson, W. H.; Ren, Y. J . Org. Chem. 1999, 64, 688. (k)
Werner, K. M.; De los Santos, J . M.; Weinreb, S. M.; Shang, M. J . Org.
Chem. 1999, 64, 686. (l) Pearson, W. H.; Barta, N. S.; Kampf, J . W.
Tetrahedron Lett. 1997, 38, 3369.
(2) Cephalotaxine. For recent total syntheses, see: (a) Li, W.-D. Z.;
Wang, Y.-Q. Org. Lett. 2003, 4, 2931. (b) Suga, S.; Watanabe, M.;
Yoshida, J . J . Am. Chem. Soc. 2002, 124, 14824. (c) Koseki, Y.; Sato,
H.; Watanabe, Y.; Nagasaka, T. Org. Lett. 2002, 4, 885. (d) Tietze, L.
F.; Schirok, H. J . Am. Chem. Soc. 1999, 121, 10264. (e) Planas, L.;
Perard-Viret, J .; Royer, J . J . Org. Chem. 2004, 69, 3087. For a review,
see: (e) J alil Miah, M. A.; Hudlicky, T.; Reed, J . W. In The Alkaloids;
Brossi, A., Ed.; Academic Press: New York, 1998; Vol. 51, pp 199-
269.
F IGUR E 1. Representative alkaloids with 1-azaspirocyclic
ring systems.
In developing a conceptually different approach to
1-azaspirocyclic ring systems, we became intrigued with
the idea of using a semipinacol rearrangement as a key
step.6 The concept is outlined in Scheme 1. The reaction
of an appropriate electrophile with a 2-(hydroxycyclo-
butyl)-substituted enamine derivative such as a should
produce a transient azacarbenium ion intermediate b.
Migration of one of the adjacent cyclobutane carbon-
carbon bonds with concomitant CdO π-bond formation
would generate protonated azaspirocyclic ketone c. Pro-
ton loss from c generates the desired azaspirocyclic ring
system d .
Pinacol and semipinacol reactions have become popular
methods for structural reorganization and have been
utilized in the construction of both natural and unnatural
products.7 An advantage to these methods is the sub-
stantial increase in molecular complexity that can result
even though the reactions are relatively “low-tech”sfor
(3) Fasicularin. Isolation papers: (a) Patil. A. D.; Freyer, A. J .;
Reichwein, R.; Carte, B.; Killmer, L. B.; Faucette, L.; J ohnson, R. K.;
Faulkner, D. J . Tetrahedron Lett. 1997, 38, 363. Synthetic work: (b)
Abe, H.; Aoyogi, S.; Kobayashi, C. J . Am. Chem. Soc. 2000, 122, 4583.
(c) Maeng, J .-H.; Funk, R. L. Org. Lett. 2002, 4, 331. (d) Fenster, M.
D. B.; Dake, G. R. Org. Lett. 2003, 5, 4313.
10.1021/jo0493572 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/21/2004
5668
J . Org. Chem. 2004, 69, 5668-5675

Functionalized Spirocyclic Cyclopentanones
SCHEME 1. Sem ip in a col-Ba sed Ap p r oa ch to
1-Aza sp ir ocycles
Aware of these reports and that nitrogen is less electro-
negative than oxygen, we selected cyclobutanols as initial
substrates. Cyclobutanols have been demonstrated to
undergo facile ring expansion reactions, presumably due
to both the relief of ring strain upon the formation of a
five-membered ring from a four-membered ring as well
as the formation of a carbon-oxygen π bond.10a,11 This
report will document the successful formation of func-
tionalized azaspirocyclic cyclopentanones, initiated by
either Bronsted acids or N-bromosuccinimide (NBS), an
electrophilic bromine source.
Resu lts a n d Discu ssion
Con str u ction of Su bstr a tes. The reaction between
a “2-metallo-N-protected-2-piperidene” and cyclobutanone
appeared to be the most straightforward method of
generating structures such as A (eq 1). The p-toluene-
sulfonyl group was selected to be the protecting group
on nitrogen because of its perceived compatibility with
organometallic compounds, Bronsted acids and Lewis
acids. Our attempts to form the desired organometallic
species using either direct lithiation or metal-halide
exchange reaction were unsuccessful. Following the work
of Hiemstra and Speckamp, we considered forming these
nucleophilic organometallic compounds by transmetala-
tion of an appropriate vinylstannane.12
example, simple Bronsted acids can be used to promote
these reactions.
Examples of hydroxy-imine rearrangements are
present in the chemical literature; despite their synthetic
potential, the promise of these processes has yet to be
fully realized.8 A marked exception is the transformations
of 3-hydroxyindolines to spiroindoxyl ring systems as in
the construction of austamide and brevianamide A.8i,9
However, we could uncover no examples of this type of
process used to form spirocyclic ring systems such as
those present in the natural products described in Figure
1. Relevant studies on “hydroxy-oxonium” semipinacol
reactions forming oxaspirocycles had been initiated and
examined by the Paquette group throughout the 1990s.10
A key finding in their assorted examinations was that
the efficiency of the semipinacol process was affected by
the substituents (either inductively withdrawing or
donating) on the ring bearing the oxacarbenium ion.
The vinylstannanes were generated using a Pd(0)
catalyzed coupling of a lactam-derived enol triflate and
hexamethyldistannane.12,13 The lactams14 (1a -g) were
(4) Halichlorine. Isolation papers: (a) Kuramoto, M.; Tong, C.;
Yamada, K.; Chiba, T.; Hayashi, Y.; Uemura, D. Tetrahedron Lett.
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3871. (d) Arimoto, H.; Asano, S.; Uemura, D. Tetrahedron Lett. 1999,
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D.; Churchill, D. G.; Danishefsky, S. J . Helv. Chim. Acta 2000, 83,
2344. (l) Wright, D. L.; Shulte, J . P.; Page, M. Org. Lett. 2000, 2, 1847.
(m) White, J . D.; Blakemore, P. R.; Korf, E. A.; Yokochi, A. F. T. Org.
Lett. 2001, 3, 313. (n) Shindo. M.; Fukuda, Y.; Shishido, K. Tetrahedron
Lett. 2000, 41, 929. (o) Itoh, M.; Kuwahara, J .; Itoh, K.; Fukuda, Y.;
Kohya, M.; Shindo, M.; Shishido, K. Bioorg. Med. Chem. Lett. 2002,
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Int. Ed. 2001, 40, 4453. (q) Carson, M. W.; Kim, G.; Hentemann, M.
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59, 441. (s) Takasu, K.; Ohsato, H.; Ihara, M. Org. Lett. 2003, 5, 3017.
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systems, see: (a) Wardrop, D. J .; Burge, M. S.; Zhang, W.; Ortiz, J . A.
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J .; Selkti, M.; Thomas, A. Synlett 2002, 1629. (c) Kibayashi, C.;
Yamazaki, N.; Ito, T. Synlett 2001, 1506. (d) Braun, N. A.; Ousmer,
M.; Bray, J . D.; Bouchu, D.; Peters, K.; Peters, E.-M.; Ciufolini, M. A.
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J . Org. Chem, Vol. 69, No. 17, 2004 5669

Dake et al.
SCHEME 2. F or m a tion of Cyclobu ta n ols 4a -g
typically was best performed using hexamethyldistan-
nane in the presence of a catalytic amount of tris-
(bisdibenzylideneacetone)dipalladium(0) (Pd2(dba)3) with
triphenylarsine in tetrahydrofuran (THF) at room tem-
perature for 7-9 h.13 Longer reaction times appeared to
lead to the decomposition of the vinylstannane product.
The use of hexabutyldistannane in place of hexameth-
ylstannane resulted in no reaction. Yields for the conver-
sion of 2 to 3 ranged from 42 to 71%. The transmetalation
of the vinylstannane function in 3 to a vinyllithium
species required at least 2 equiv of methyllithium in THF
at -78 °C. The addition of anhydrous magnesium bro-
mide etherate (or magnesium bromide)16 prior to addition
of cyclobutanone was necessary in most cases to obtain
satisfactory yields of the isolated carbonyl addition
product. The yields for this reaction varied from 55 to
89%.17
F IGURE 2. Structures of the enol triflates 2a -g.
converted into their respective enol triflates (2a -g) under
standard conditions (eq 2 and Figure 2).15 In certain cases
the enol triflates converted back to the starting lactams
within a few hours (2a ,e) and so were immediately
carried onto subsequent reactions.
In addition to the substrates made in this manner, two
further cyclobutanols were constructed (Scheme 3). After
removal of the silyl ether in 4b, the hydroxyl function
was converted to its corresponding benzyl ether or
p-nitrobenzoyl ester to produce both 4h and 4i, respec-
tively.
Br on sted Acid P r om oter s. In itia l Stu d ies. The first
attempts to initiate a semipinacol ring expansion were
performed using Bronsted acids. Because of its solubility
in organic solvents, (S)-(+)-10-camphorsulfonic acid (CSA)
was selected for preliminary reactions. Treating cyclo-
The conversion of the enol triflates of common struc-
ture 2 to cyclobutanols of type 4 is described in general
in Scheme 2. The details for specific substrates are
presented in the Supporting Information. The conversion
of an enol triflate 2 to its corresponding vinylstannane 3
(11) For examples, see: (a) Hirst, G. C.; J ohnson, T. O., J r.;
Overman, L. E. J . Am. Chem. Soc. 1993, 115, 2992. (b) Trost, B. M.;
Chen, D. W. C. J . Am. Chem. Soc. 1996, 118, 1254. (c) Eastieu, K.;
Ollivier, J .; Salau¨n, J . Tetrahedron 1998, 54, 8075. For reviews of the
chemistry of cyclobutane ring containing compounds: (d) Lee-Ruff, E.;
Mladenova, G. Chem. Rev. 2003, 103, 1449. (e) Namyslo, J . C.;
Kaufmann, D. E. Chem. Rev. 2003, 103, 1485.
(12) Luker, T.; Hiemstra, H.; Speckamp, W. N. J . Org. Chem. 1997,
62, 8131.
(13) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron,
K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J .
Org. Chem. 1986, 51, 279.
(15) Use of lactam-derived enol triflates in metal catalyzed or
promoted reactions: (a) Foti, C. J .; Comins, D. L. J . Org Chem. 1995,
60, 2656. (b) Okita, T.; Isobe, M. Synlett 1994, 589. (c) Okita, T.; Isobe,
M. Tetrahedron 1995, 51, 3737. (d) Reference 12. (e) Reference 14c. (f)
Ha, J . D.; Cha, J . K. J . Org. Chem. 1997, 62, 4550. (g) Ha, J . D.; Lee,
D.; Cha, J . K. J . Am. Chem. Soc. 1999, 121, 10012. (h) Toyooka, N.;
Okumura, M.; Takahata, H.; Nemoto, H. Tetrahedron 1999, 55, 10673.
(i) Toyooka, N.; Okumura, M.; Takahata., H. J . Org. Chem. 1999, 64,
2182. (j) Coe, J . W. Org. Lett. 2000, 2, 4205. (k) Lindstro¨m, S.; Ripa,
L.; Hallberg, A. Org. Lett. 2000, 2, 2291. (l) Li, X.; Xu, Z.; DiMauro, E.
F.; Kozlowski, M. C. Tetrahedon Lett. 2000, 43, 3747. (m) Occhiato, E.
G.; Trabocchi, A.; Guarna, A. Org. Lett. 2000, 2, 1241. (n) Occhiato, E.
G.; Trabocchi, A.; Guarna, A. J . Org. Chem. 2001, 66, 2459. (o)
Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A.; Deagostino, A.;
Venturello, P. J . Org. Chem. 2002, 67, 7144. (p) Toyooka, N.; Fuku-
tome, A.; Nemoto, H.; Daly, J . W.; Spande, T. F.; Garraffo, Kaneko, T.
Org. Lett. 2002, 4, 1715. (q) Easton, L. P.; Dake, G. R. Can. J . Chem.
2004, 82, 139. For a review, see: (r) Occhiato, E. G. Mini-Rev. Org.
Chem. 2004, 1, 149.
(16) Initial experiments were conducted with magnesium bromide
etherate purchased from Aldrich. Later experiments gave varying
results, perhaps because of the inconsistent quality of this reagent.
The use of anhydrous magnesium bromide purchased from Strem
alleviated this problem.
(17) The significant byproduct from this reaction seemed to result
from enolization of the cyclobutanone rather than carbonyl addition.
For a study of the enolization of cyclobutanone, see: Cantlin, R. J .;
Drake, J .; Nagorski, R. W. Org. Lett. 2002, 4, 2433.
(14) The N-p-toluenesulfonylated lactams were typically made by
treating the “parent” lactams with n-BuLi and TsCl. (a) Lactam 1b:
Herdeis, C. Synthesis 1986, 232. (b) Lactams 1c-1e were made using
a
copper-catalyzed conjugate addition reaction of an appropriate
Grignard reagent to ∆3,4-N-p-toluenesulfonyl-2-oxopiperidene: Na-
gashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K. Tetrahedron Lett.
1985, 26, 657. (c) Lactam 1f: Luker, T.; Heimstra, H.; Speckamp, W.
N. Tetrahedron Lett. 1996, 37, 8257. Luker, T.; Hiemstra, H.; Speck-
amp, W. N. J . Org. Chem. 1997, 62, 3592. (d) Lactam 1g was made by
reacting N-(tert-butoxycarbonyl)-p-toluenesulfonamide with (5R)-5-
hydroxyoct-7-enoate (Ramachandran, P. V.; Krzeminski, M. P.; Reddy,
M. V. R.; Brown, H. C. Tetrahedron: Asymmetry 1999, 10, 11) under
Mitsunobu conditions as described by Weinreb (Henry, J . R.; Marcin,
L. R.; McIntosh, M. C.; Scola, P. M.; Harris, G. D.; Weinreb, S. M.
Tetrahedron Lett. 1989, 30, 5709) followed by thermal deprotection of
the Boc group and trimethylaluminum promoted lactamization. Please
refer to the Supporting Information for details.
5670 J . Org. Chem., Vol. 69, No. 17, 2004

Functionalized Spirocyclic Cyclopentanones
SCHEME 3. F or m a tion of 4h a n d 4i
cleaved under these reaction conditions, resulting in an
intractable mixture of compounds.
Dia ster eoselectivity. What would be the intrinsic
effect of a substituent on the ring containing the N-p-
toluenesulfonylazacarbenium ion on the stereoselectivity
of the cyclobutanone ring expansion? The ring expansion
reactions of 4b-4d , 4h , and 4i were attempted to probe
this question (eq 5 and Table 1). Only modest diastereo-
selectivities were observed in reactions using CSA at 45
°C. As examples, 4b generates a 2.7:1 mixture of dia-
stereomeric cyclopentanones 6b and 7b in 81% yield
(entry 1), while the 4-phenyl derivative 4c produces a
4.5:1 ratio of inseparable ring expansion products 6c and
7c in 89% yield (entry 2).18 Interestingly, while 4b only
required 13 h for reaction, 4c was stirred for 144 h to
ensure complete conversion. In the limited number of
cases attempted, substrates with inductively electron-
withdrawing groups on the ring bearing the azacarbe-
nium ion appeared to be more reactive. To examine the
effect of the tert-butyldimethylsiloxy group on the chem-
istry of 4b, substrates with alternative protecting groups
were examined. Cyclobutanol 4h , which bears a benzyl
ether substituent, decomposed when it was subjected to
acid (entry 3). Compound 4i sluggishly underwent a ring
expansion reaction, producing cyclopentanones 6i and 7i
in 51% combined yield after 13 h in refluxing dichlo-
romethane. Unreacted 4i was also recovered in 31% yield
(entry 4). Although the diastereoselectivity is still quite
poor (1.8:1), this reaction predominantly produces the
alternative diastereomer compared to the reaction of 4b.19
butanol 4a with 1.2 equiv of CSA in dichloromethane at
room temperature gave largely no reaction after 24 h (eq
3). Fortunately, it was discovered that the desired ring
expansion occurred quite smoothly when the reaction
mixture was warmed to 45 °C for 13 h. The spirocyclic
cyclopentanone 5 was isolated as a white solid (mp 103-
104 °C) in 73% yield after purification.
That a reaction involving the alkene had taken place
was clearly indicated by the absence of a signal corre-
sponding to the vinyl proton in 4a (δ 5.66 ppm, t, J ) 4
1
Hz) in the H NMR spectrum. A ketone functional group
was clearly present in 5 (IR: ν ) 1746 cm-1 13C NMR:
;
δ 216.4 ppm). An APT spectrum was used to establish
the presence of the spirocyclic carbon atom adjacent to
nitrogen (13C NMR: δ 66.7 ppm) that had zero attached
protons.
Similar results were observed using 4b (eq 4). Experi-
mental conditions that involved either ambient temper-
ature or short reaction times resulted in poor conversions
to product. The protocol adopted for 4a (45 °C, 13 h) led
to the formation of a mixture of diastereomeric ketones
6b and 7b (vide infra) in 81% isolated yield.
Because 4c did not contain any extraneous acid-
sensitive functional groups, attempts to promote ring
expansion were made using hydrochloric acid to try to
improve the overall diastereoselectivity (entries 5 and 6).
The reaction temperature could be lowered substantially
when a stronger acid was used to catalyze the reaction.
Consequently, much better stereoselectivities in this
process were observed at the expense of reaction time.
The most selective conditions were 1.1 equiv of hydro-
chloric acid at 0 °C, which resulted in the formation of
6c and 7c in 93% yield as a 14:1 mixture of diastereo-
mers. Unfortunately, the reactions of 4d or 4e proved to
be very sluggish using these conditions (entries 7 and
8).20 Several days were required for these reactions, and
in the case of 4d warming the reaction to room temper-
Because the starting materials (4a or 4b) coeluted with
their respective products (5 or 6b/7b) using a variety of
solvent systems for thin-layer chromatography, no ex-
tensive efforts to optimize the Bronsted acid promoter
(18) The relative stereochemistry of 6b and 7b was established
through chemical correlation with products derived from R-siloxy
epoxide rearrangement reactions. The relative stereochemistry of 7c
was confirmed by converting 11c, a product of the NBS promoted
reaction, to 7c ((1) Super-Hydride; (2) Bu3SnH, AIBN; (3) TPAP, NMO).
Please see the Supporting Information for details.
(19) This result was confirmed as 6b could be converted to 6i. For
a study on the electrostatic stabilization of pseudoaxial conformers on
oxacarbenium ions by heteroatom substituents and its resulting
stereochemical consequences, see: Ayala, L.; Lucero, C. G.; Romero,
J . A. C.; Tabacco, S. A.; Woerpel, K. A. J . Am. Chem. Soc. 2003, 125,
15521.
1
were undertaken. By following these reactions using H
NMR spectroscopy, it was discovered that a much stron-
ger acid such as hydrochloric acid could also be used at
lower reaction temperatures for shorter reaction times.
Under unoptimized conditions, cyclobutanol 4a , when
treated with 1.1 equiv of hydrochloric acid at 25 °C for 2
h, gave 5 in 67% yield. The silyl ether in 4b was partially
J . Org. Chem, Vol. 69, No. 17, 2004 5671

Dake et al.
ratioe
TABLE 1. Acid P r om oted Rea ction s of Su bstr a tes of Str u ctu r e 4
entry
substrate
R1
R2
acida
T (°C)
t (h)
pdts
% yieldb
1
2
3
4
5
6
7
8
4b
4c
4h
4i
4c
4c
4d
4e
OTBS
H
OBn
OPNB
H
H
H
H
H
Ph
H
CSA
CSA
CSA
CSA
HCl
HCl
HCl
HCl
45
45
45
45
25
0
13
144
13
13
11
48
50
67
6b:7b
6c:7c
see text
6i:7i
6c:7c
6c:7c
6d :7d
6e:7e
81
89
2.7:1
4.5:1
H
51c
93
1:1.8
11:1
14:1
4.7:1
3.7:1
Ph
Ph
iPr
CH3
93
25
0
71d
68
a
b
CSA ) (+)-camphorsulfonic acid (1.2 equiv) in dichloromethane; HCl ) hydrochloric acid (1.1 equiv) in dichloromethane. Isolated
yield. c Unreacted 4i was recovered in 31% yield. A more polar byproduct was isolated in 23% yield. e Ratios are determined by 1H NMR
d
integration and/or GC analysis of the product mixture.
SCHEME 4. Retr osyn th esis of th e Sp ir ocyclic Cor es of Ha lich lor in e a n d P in n a ic Acid
SCHEME 5. Rea ction s of 6-Eth oxy Am in a l 4f
ature was necessary for good conversion of the starting
material. The diastereoselectivity for each reaction was
modest.
Ch em oselectivity P r oblem s: Use of a N-Br om o-
su ccin im id e P r om oted Rea ction . With these early
results in hand, a synthetic route toward the spirocyclic
cores of halichlorine and pinnaic acid was planned
(Scheme 4). In essence, an azaspirocyclic ketone with a
functional group at the 6-position of the piperidine ring
was required. The vinylstannane 3f was known in the
literature as we began our studies.12 It was believed that
the 6-ethoxy aminal, despite its possible sensitivity
toward acid, could serve as a chemical handle for the
installation of appropriate side chains at the 6-position
of the heterocycle. In principle, these transformations of
the heterocycle could be executed prior to the proposed
semipinacol rearrangement reaction or after the forma-
tion of the azaspirocycle.
as solvent, we were surprised to observe the formation
of a new product that apparently did not undergo ring
expansion (Scheme 5, path b). The structure is consistent
with compound 8, although the relative stereochemistry
was not established.
We then opted to try to chemoselectively functionalize
the 6-position.21 When 4f was treated with 2 equiv of
allyltrimethylsilane in the presence of magnesium bro-
mide etherate for 15 min, the bis-allylated product 9 was
isolated in 89% yield as a single diastereomer (tentatively
assigned as shown). When only 1 equiv of allyltrimeth-
ylsilane was used, 9 and unreacted 4f was recovered.
Clearly, 4f was unstable to Bronsted or Lewis acids.
We then opted to attempt to functionalize the 6-position
of the heterocycle after a projected semipinacol rear-
In the event, attempts to promote the ring expansion
of 4f (CSA, CH2Cl2) led to decomposition (Scheme 5, path
a). The formation of a N-toluenesulfonylazacarbenium ion
at the 6-position of 4f was believed to be the major
complication. It was postulated that if this reaction was
performed in ethanol, a simple “exchange” reaction would
take place in the event that an azacarbenium ion was
formed at the 6-position of 4f. After switching to ethanol
(20) The relative stereochemistries of 6e and 7e were established
by chemical correlation with the products resulting from the NBS
promoted ring expansions. The minor constituent of the NBS promoted
reaction, 12e, was converted to 6e ((1) Super-Hydride; (2) Bu3SnH,
AIBN; (3) TPAP, NMO). Similarly, 11e was converted to 7e.
(21) A° hman, J .; Somfai, P. Tetrahedron 1992, 48, 9537. For a review
of N-acyl(sulfonyl)iminium ion chemistry, see: Speckamp, W. N.;
Moolenaar, M. J . Tetrahedron 2000, 56, 3817.
5672 J . Org. Chem., Vol. 69, No. 17, 2004

Functionalized Spirocyclic Cyclopentanones
TABLE 2. Rin g Exp a n sion s P r om oted by NBSa
entry
substrate
R1
R2
R3
pdts
11a
11b:12b
11c
11d :12d
11e:12e
11gd
% yieldb
ratioc
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4gd
4h
H
H
Ph
iPr
CH3
H
H
H
H
H
H
H
allyl
H
85
95
80
85
79
98
90
single isomer
3.5:1
single isomer
3.5:1
1.9:1
single isomer
5:1
OTBS
H
H
H
H
H
OBn
11h :12h
a
b
Standard conditions: NBS (1.2 equiv) in a 1:1 mixture of 2-propanol and propylene oxide at -78 °C. Isolated yields. c Ratio was
determined by integration of the 1H NMR spectrum of the crude reaction mixture and typically confirmed by isolation of each of the
diastereomeric products. For consistency throughout eq 7 and Table 2, the enantiomer of 4g and 11g is shown.
d
rangement. A nonacidic method for triggering the ring
expansion was required. We believed that activation of
the alkene through the formation of a bromonium ion
could conceivably coerce the cyclobutanol to ring ex-
pand.22
Thus, we were quite pleased when the reaction be-
tween 4f and 1.2 equiv of NBS in a 1:1 mixture of
ducing products 11b and 12b in a 3.5:1 ratio, while the
2-propanol and propylene oxide (as an acid scavenger)
5-benzyloxy derivative 4h produced a 5:1 mixture of
at -78 °C produced the cyclopentanone 10 in 96% yield
diastereomers. In each case, the ether substituent in the
as a single diastereomer (eq 6).23 The structure of 10 was
major diastereomeric product was trans to the bromine
tentatively determined using NMR spectroscopy and was
ultimately assigned using X-ray analysis.
substituent.24
Ster eoch em ica l Assign m en ts. Because the assign-
ment of the configuration of the products was quite
challenging using NMR spectroscopy, X-ray analysis of
single crystals of the products was used whenever
feasible. The structures of 10, 11c, and 11g were verified
in this way.25 In each case the methylene group of the
cyclopentanone was trans to the bromine substituent.
NBS P r om oted Rea ction s: Dia ster eoselectivity.
As the NBS protocol seemed to be both higher yielding
and more stereoselective than the use of a Bronsted acid
for the ring expansion, a number of substrates were
subjected to these reaction conditions (eq 7 and Table 2).
The yields of isolated and purified cyclopentanone prod-
ucts were uniformly high (80-98%). The diastereoselec-
tivities of the ring expansions ranged from little selec-
tivity (entries 4 and 5) to complete selectivity (entries 3
and entry 6). Similar to the reaction of 4f, the reaction
of 4c and 4g each resulted in the formation of a single
diastereomeric product, 11c and 11g, respectively (en-
tries 3 and 6). Modifying the substituent at the 4-position
from phenyl to isopropyl to methyl lowered the stereo-
selectivity of the process considerably, although the major
diastereomer (where the bromine is trans to the sub-
stituent at the 4-position) was the same in each case
(entries 3-5). Substrates having oxygen substituents at
the 5-position reacted much less selectively overall, the
5-tert-butyldimethylsiloxy substituted compound 4b pro-
F IGURE 3. NMR data used to establish the structures of 11b
and 12b.
The spirocyclic carbon centers in the other products were
assigned (methylene group trans to the bromine sub-
stituent) by analogy. The relative stereochemistry of 11b
and 12b was established by examining coupling con-
stants of specific protons in conjunction with NOE studies
(Figure 3). For each of the compounds 11b and 12b, the
protons on the carbon bearing the bromine substituent
(Ha and Hc) were assigned to be pseudoaxial on the basis
of a large coupling constant for each (Ha: δ 4.21 ppm,
dd, J ) 9.9, 4.0 Hz; Hc: δ 4.21 ppm, dd, J ) 12.8, 4.6
Hz). The proton on the carbon bearing the siloxy group
in either 11b or 12b (Hb or Hd) could not be as trivially
assigned as axial or equatorial. A significant NOE
enhancement was present between Hc and Hd in 12b,
while no NOE enhancement could be observed between
(22) Examples of the use of NBS and other electrophilic bromine
sources to promote migration reactions: (a) Trost, B. M.; Mao, M. K.-
T.; Balkovec, J . M.; Buhlmayer, P. J . Am. Chem. Soc. 1986, 108, 4965.
(b) Trost, B. M.; Mao, M. K.-T. J . Am. Chem. Soc. 1983, 105, 6753. (c)
Wasserman, H. H.; Hearn, M. J . J . Org. Chem. 1980, 45, 2874. (d)
Paquette, L. A.; Owen, D. R.; Bibart, R. T.; Seekamp, C. K.; Kahane,
A. L.; Lanter, J . C.; Corral, M. A. J . Org. Chem. 2001, 66, 2828. (e)
Maroto, B. L.; Cerero, S. de la M.; Martinez, A. G.; Fraile, A. G.; Vilar,
E. T. Tetrahedron: Asymmetry 2000, 11, 3059. (f) Martinez, A. G.;
Vilar, E. T.; Fraile, A. G.; Cerero, S. de la M.; Maroto, B. L. Tetrahedron
Lett. 2001, 42, 6539.
(24) For some examples of electrophilic addition to an alkene in
which nonbonding interactions play a crucial stereochemical role: (a)
Crimmins, M. T.; Lever, J . G. Tetrahedron Lett. 1986, 27, 291. (b)
Tanner, D.; Somfai, P. Tetrahedron 1986, 42, 5657. (c) Tanner, D.;
Selle´n, M.; Ba¨ckvall, J . E. J . Org. Chem. 1989, 54, 3374. (d) Murray,
R. W.; Singh, M.; Williams, B. L.; Moncrieff, H. M. J . Org. Chem. 1996,
61, 1830.
(23) The reaction of 4f with PhSeCl generated a complex mixture
of products. Studies using other potential electrophilic promoters are
ongoing at the present time.
(25) Please refer to the Supporting Information for details.
J . Org. Chem, Vol. 69, No. 17, 2004 5673

Dake et al.
SCHEME 7. Attem p ted Rea ction s of An a logou s
Cyclop en ta n ol 14
F IGURE 4. NMR data used to establish the structures of
11c-e and 12d -e.
Ha and Hb in 11b. The major diastereomer in this
reaction, 11b, was converted to benzyl ether 11h ((1) HCl,
EtOH; (2) PhCH2N2) in order to assign the stereochemical
configurations of 11h and 12h .
bromide 16 in 75% yield. Elimination to form a vinyl
bromide is apparently faster than the ring expansion
process.
Interestingly, the 3-phenyl-substituted compound 4c
reacted to form 11c as a single diastereomer. The
4-phenyl and 3-bromo substituents were assigned to be
trans to each other due to the coupling constant (J ) 11.6
Hz) between the protons attached at C-3 and C-4 (Figure
4). Cyclopentanones 11d (isopropyl substituent) and 11e
(methyl substituent), which were the major diastereo-
mers formed in their respective reactions, also had
similar coupling constants between the attached protons
at C-3 and C-4 (J ) 10.6 Hz for 11d ; J ) 11.0 Hz for
11e). The coupling constants between the corresponding
protons in the minor diastereomers were much smaller
(J ) 1.8 Hz for 12d ; no coupling observed in 12e).
Syn th etic Ela bor a tion of 10. As described in Scheme
3, the initial interest in a compound such as 10 was
derived from its potential as a synthetic intermediate in
the synthesis of azaspirocyclic alkaloids such as halichlo-
rine and pinnaic acid. To test the feasibility of 10 as an
intermediate, further functionalization of the ethyl ami-
nal function in 10 was attempted (Scheme 6). Attempts
to substitute the ethyl aminal function in 10 with an allyl
group using trimethylallylsilane and Lewis acid gener-
ated alkene 13. This reaction took place within minutes
at -78 °C. Interestingly, an allyl group could be installed
at the 6-position of the heterocycle via 13. Reacting 13
with allyltrimethylsilane and trifluoroacetic acid gener-
ated 11g as a single diastereomer.26
Ra tion a liza tion of Dia ster eoselectivity. Br on sted
Acid . The results using Bronsted acid appear to be
consistent with previous work on ring expansions of
cyclobutanols to oxacarbenium ions.10a The major di-
astereomer results from an alkyl migration toward the
azacarbenium ion that takes place through “chairlike”
transition state I with pseudoequatorial substituents
(Scheme 8). The minor diastereomer could be formed
from either (a) a “chairlike” transition state with pseudo-
axial substituents or (b) a “twist-boat-like” transition
state II with pseudoequatorial substituents. The latter
possibility is probably lower in energy relative to the
former.
NBS P r om ot ed E xp a n sion s. (a ) Su b st it u t ion a t
th e 6-P osition . The diastereoselectivity of the NBS
promoted ring expansion was complete on substrates
with substitution at the 6-position (4f and 4g). The
substituent at the 6-position probably resides in a
pseudoaxial orientation to reduce A1,3 interactions with
the p-toluenesulfonyl group on nitrogen.27 This inference
1
is supported by the small coupling constants for the H
NMR signal corresponding to the pseudoequatorial
methine proton at the 6-position (5.2 and 3.7 Hz) of 4f.
The results are consistent with axial attack of the
electrophilic brominating reagent on the less sterically
hindered face of the more stable half-chair conformer of
4f or 4g (Scheme 9). Formation of a “bromonium ion” or
bromine alkene π-complex triggers an alkyl shift that
forms the cyclopentanone products. The relative stereo-
chemistry of the spiro carbon and the bromine-bearing
carbon appear to be the results of antiperiplanar alkyl
migration, where the migrating methylene group ends
up on the face opposite the bromine atom (a SN2-like
process).
SCHEME 6. Ela bor a tion of 10
(b) Su bstitu en t a t th e 5-P osition . Because the
electrophilic bromine atom can reasonably react on either
face of the alkene in substrates such as 4b or 4h , only
modest diastereoselectivities are obtained. A slight ste-
reoelectronic bias could be present for “(pseudo)-axial”
approach of the NBS to these substrates.
Attem p ts To Exp a n d Cyclop en ta n ols. Attempts to
promote the expansion reactions of cyclopentanols to
cyclohexanones using either Bronsted acid or NBS initia-
tion have not met with success (Scheme 7). For example,
the reaction of 14 with CSA produced enone 15 in 42%
yield. Following this reaction by 1H NMR, this compound
results from elimination of the tertiary allylic alcohol
with concomitant hydrolytic ring opening of the ene-
sulfonamide. Mixing 14 with NBS produces the vinyl
(27) A similar effect has been noted in conjugate addition reactions
of 2- or 6-substituted 2H-pyridinones: (a) Harris, J . M.; Padwa, A. J .
Org. Chem. 2003, 68, 4371. For reviews on the effect of the A1,3 strain
on conformational analysis and its applications to stereoselective
reactions: (b) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841. (c)
Hoffmann, R. W. Angew. Chem., Int. Ed. Eng. 1992, 31, 1124. (d)
Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054.
(26) Greshock, T. J .; Funk, R. L. Org. Lett. 2001, 3, 3511.
5674 J . Org. Chem., Vol. 69, No. 17, 2004

Functionalized Spirocyclic Cyclopentanones
SCHEME 8. Ra tion a liza tion for Dia ster eoselectivity in Acid P r om oted Rea ction
SCHEME 9. Dia ster eoselective Rea ction s of 4f a n d 4g
SCHEME 10. Rea ction s of 4-Su bstitu ted
Su bstr a tes
tivity than reactions involving Bronsted acid promotion.
Interestingly, the expansions of 4-substituted substrates
using acid or NBS produce complementary diastereomers
with respect to the newly formed spirocyclic carbon and
the substituent at the 4-position. Separating and estab-
lishing the relative stereochemistry of brominated aza-
spirocyclopentanones is also somewhat easier than in the
products lacking the 3-bromo substituents. In accord with
Paquette’s work, electron-donating substituents on the
ring bearing the azacarbenium ion typically retard the
reaction rate. As yet, we have been unable to induce
cyclopentanols to ring-expand using either of these
methods. By careful design of the substrates, however,
these reactions are capable of generating structurally
intricate molecules in excellent yields and diastereo-
selectivities. We are currently exploring versions of these
processes using more structurally complex substrates to
produce azaspirocyclic cyclopentanones that will be useful
intermediates in the total synthesis of alkaloids.
(c) Su bstitu en t a t th e 4-P osition . In this case, the
electrophilic bromine may approach from the less hin-
dered face of the alkene (Scheme 10).28 Axial attack of
the bromine results in the R group residing in a pseudo-
axial orientation during the reaction as well. Ring
expansion once again occurs wherein the migrating alkyl
group is oriented trans to the bromine atom on the
piperidine ring.
Ack n ow led gm en t. The authors thank the Univer-
sity of British Columbia and the Natural Sciences and
Engineering Research Council (NSERC) of Canada for
the financial support of our programs. M.D.B.F. and
P.B.H. each individually thank the Gladys Estella Laird
Foundation for Laird Fellowships.
Con clu sion
We have demonstrated that substrates of general
structure 4 can be induced to undergo ring expansion
reactions to form highly functionalized 1-azaspirocyclo-
pentanones. Our experience suggests that, given an
option, the reaction protocol using NBS is faster, higher
yielding, and exhibits typically greater diastereoselec-
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization data, copies of spectra, and CIF files
for previously unreported compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(28) Similar trends are observed during the epoxidation of 3-sub-
stituted cyclohexenes: Inglis, D. B. Chem. Ind. 1971, 1268. See also:
Shimizu, M.; Morita, O.; Itoh, S.; Fujisawa, T. Tetrahedron Lett. 1992,
33, 7003.
J O0493572
J . Org. Chem, Vol. 69, No. 17, 2004 5675