Synthesis and characterization of novel spirooxazacamphorsultam derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.10.105

Derivatives of camphorsultam which contain novel spirooxazolidine and spirooxazine structures have been prepared in high yield and purity. Though it was expected that the ketone moiety would undergo acetal formation, the imine instead underwent reaction and was proven by X-ray crystallography and 2D NMR techniques. The initial ketone-containing derivatives were then reduced to produce exo-hydroxy analogs that have potential as a new family of chiral auxiliaries.

Full text of DOI:10.1016/j.tetlet.2010.10.105

Tetrahedron Letters 51 (2010) 6871–6873
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and characterization of novel spirooxazacamphorsultam derivatives
Burkhardt I. Wilke, Angela K. Goodenough, Cory C. Bausch, Erika N. Cline, M. Leigh Abrams,
⇑
Effrat L. Fayer, Diana M. Cermak
Department of Chemistry, Knox College, 2 E. South Street, Galesburg, IL 61401, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Derivatives of camphorsultam which contain novel spirooxazolidine and spirooxazine structures have
been prepared in high yield and purity. Though it was expected that the ketone moiety would undergo
acetal formation, the imine instead underwent reaction and was proven by X-ray crystallography and
Received 5 October 2010
Accepted 21 October 2010
Available online 28 October 2010
2
D NMR techniques. The initial ketone-containing derivatives were then reduced to produce exo-hydroxy
analogs that have potential as a new family of chiral auxiliaries.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Camphor
Acetal formation
Strained ring systems
1
. Introduction
and attempted to produce a cyclic acetal version of oxaziridine 3c.
Although we anticipated difficulty in the incorporation of another
ring into an already rigid multicyclic ring system, the formation of
a cyclic acetal at the C-3 position (as in dioxolane 5a and dioxane
5b, Scheme 2) seemed a natural extension of dimethyl acetal 3c
published by Davis and co-workers. Our initial target was the for-
mation of acetal imines 6a and 6b.
Synthesis of the desired acetal derivatives was begun with
(1S)-(+)-10-camphorsulfonic acid (1b) following the literature
Camphor (1a, Scheme 1) has long been utilized as a source of
chirality in asymmetric synthesis. Well known for its synthetic
utility as a compound found in the chiral pool, camphor has been
functionalized in a number of positions on its bornane skeleton
to form a number of synthetically-diverse derivatives. A few exam-
ples of camphor derivatives that have found wide use in organic
synthesis are (1S)-(+)-10-camphorsulfonic acid (1b), which has
been widely used as a resolving agent;1 Oppolzer’s sultam (2), a
versatile chiral auxiliary found throughout the literature;
Davis’ oxaziridines (3
tion as chiral reagents.
2
0
,2
3
–10
and
1
1,12
13
and 4 ), which have found wide applica-
X
X
X
NH
N
O
O
N
SO2
2
. Results and discussion
We have long been interested in N-sulfonyloxaziridines as chi-
X
SO2
S
O
O
2
1a X = H
b X = SO H
2
3a X = H
b X = Cl
4a X = H
b X = Cl
ral, aprotic oxidizing agents. The synthetic utility that these com-
pounds have contributed to the field of asymmetric organic
synthesis is well documented in the literature, as these compounds
3
c X = OCH3
Scheme 1.
have found a number of uses in the synthesis of a wide variety of
natural and synthetic products.1
4–18
The structural diversity of this
family of compounds and the enantioselectivity displayed by the
derivatives, in particular dichloro derivative 3b and acetal 3c,
sparked our interest in expanding on these structures. It is well
known that the rigidity, steric demands, and electronic interactions
of the oxaziridines play a large role in the enantioselectivity they
O
O
O
N
O
n
n
N
S
O
S
O
O
2
2
1
1,19
exhibit.
We envisioned expansion of Davis’ acetal oxaziridines,
5
a n = 1
b n = 2
6a n = 1
b n = 2
⇑
Corresponding author. Tel.: +1 309 341 7434; fax: +1 309 341 7829.
E-mail address: dcermak@knox.edu (D.M. Cermak).
Scheme 2.
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.105

6
872
B. I. Wilke et al. / Tetrahedron Letters 51 (2010) 6871–6873
OH
O
N
O
SeO2
AcOH
Δ
O
a
b
H
Ref. 20-22
1
b
8
N
N
N
n
O
n
S
S
SO2
SO2
O2
O2
9
a n = 1, 86%
10 a n = 1, 60%
b n = 2, 71%
7
8
b n = 2, 61%
Scheme 3.
2 2 2 2 2
Scheme 5. Reagents and conditions: (a) BrCH CH OH (9a) or BrCH CH CH OH (9b),
DBU, CH Cl , reflux; (b) LiAlH , THF, 0 °C to reflux.
2
2
4
methods20–22 (Scheme 3). The oxidation of imine 7 using SeO
to -ketoimine 8 as a mixture with an over-oxidation product.
led
2
a
Allowing this mixture to sit overnight led to pronounced over-
oxidation of the desired ketone 8 and drastically lowered yields
of the desired product. Simple vacuum filtration through silica
gel afforded the removal of oxidant that remained after vacuum
filtration through Celite, as well as the oxidation byproduct, and
led to a 90% yield of
extended shelf life.
a-ketoimine 8 in sufficient purity with an
2
3
Table 1 shows a number of methods of acetal formation
attempted which ultimately led to successful formation of a
crystalline product. Standard acetal formation conditions (acid-
catalyzed, Dean–Stark trap, entry 1) and use of a ‘bulky proton’
2
4–26
source of ethylene glycol
(entry 2) showed no signs of reac-
tion. It was found that use of 2-chloroethanol2 led to the forma-
tion of product (entry 3), but the yield was limited by
polymerization of 2-chloroethanol under basic conditions; lower
reaction temperatures in a non-polar solvent showed no signs of
the desired product (entries 4 and 5). The yield of the desired prod-
uct was improved using 2-bromoethanol28 (entry 6) with lessened
observation of polymerization; the reaction was optimized at a
lower temperature (entry 7) to produce compound 9a in an 86%
7
2
9
yield.
Initial data, primarily H and 13C NMR, led us to believe that we
1
had formed desired acetal imine 6a (Scheme 4); upon X-ray crys-
3
0
tallography and 2D NMR techniques (DEPT, COSY, and HETCOR),
it was discovered that the imine functionality had actually under-
gone reaction instead of the ketone to produce spirooxazoline
Figure 1. ORTEP of alcohol 10a.
derivative 9a. The novelty of these compounds and their potential
as a new category of camphor-based chiral auxiliaries redirected
our attention toward the synthetic utility of these spirooxazolines.
To expand the scope and utility of this novel camphor-derived
spirooxazoline and explore its potential as a chiral auxiliary, we
Table 1
Methods of acetal formation for acetal 9a
Entry
1
Conditions
Yield (%)
Ethylene glycol, pTsOH, toluene, reflux
0
0
54
0
0
60
86
2
2
4–26
7
2
3
4
5
6
7
TMSOCH
2
CH
2
OTMS, TMSOTf, CH
Cl
2 2
, À78 to 0 °C
29
not only produced the dioxolane-type oxazolidine 9a, but also
2-Chloroethanol, Li
2-Chloroethanol, Li
2-Chloroethanol, Li
2-Bromoethanol, DBU, toluene, reflux
2 2
2-Bromoethanol, DBU, CH Cl , reflux
2
CO
2
CO
2
CO
3
3
3
, 130 °C
, toluene, reflux
, xylenes, reflux
its dioxane counterpart oxazine 9b through a similar procedure
3
1
(
4
Scheme 5). Both ketones were then reduced with LiAlH in rea-
2
2
8
9
32
33
sonable yields to produce the exo alcohols 10a and 10b. The
structure and orientation of the reduction products were again
proven by X-ray crystallography, as seen in the ORTEP of alcohol
1
0a (Fig. 1). The ketone and/or alcohol functionalities may provide
a useful attachment point for the application of these compounds
as chiral auxiliaries.
O
O
N
O
N
S
S
3. Conclusions
O2
O2
We have produced a new family of chiral, non-racemic com-
pounds which contain a novel multicyclic ring system. Produced
by reaction of the imine functionality instead of the ketone, the
structures of keto spirooxazolidine 9a and spirooxazine 9b were
confirmed by X-ray diffraction, which subsequently underwent
reduction to produce the exo-hydroxy analogs 10a and 10b as con-
firmed by X-ray diffraction as well. We are continuing to study
these compounds for their potential as chiral auxiliaries, as well
as investigating methods of acetal formation in order to produce
sulfonylimines 6.
8
6
a
X
O
OH
N
O
base, Δ
X = Cl, Br
S
3
0
O2
9
a
Scheme 4.

B. I. Wilke et al. / Tetrahedron Letters 51 (2010) 6871–6873
6873
2
2
6. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357–1358.
7. Newkome, G. R.; Sauer, J. D.; McClure, G. L. Tetrahedron Lett. 1973, 18, 1599–
Acknowledgments
1
602.
The authors would like to thank Professor David F. Wiemer
from The University of Iowa for meaningful discussions of this pro-
ject and Dr. Dale C. Swenson from The University of Iowa for his
assistance with the single crystal diffraction analysis. We would
also like to thank Drs. Steven C. Cermak and Karl Vermillion from
USDA-NCAUR for their help with the 500 MHz NMR spectra. This
research was supported by the Knox College Richter Memorial
Scholars Program, the Knox College Ford Foundation Research Fel-
lows Program, and the Knox College Ronald E. McNair Early Entry
Fellowship Program.
28. Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.; Merritt, A.; Vicker, N.
J. Am. Chem. Soc. 1992, 114, 4403–4405.
2
9. General procedure for the preparation of derivatives 9: To a solution of (À)-(3-
oxocamphorsulfonyl)imine (8; 7.00 g, 30.7 mmol) in CH Cl (105 mL) was
2
2
added 1,8-diazabicyclo[5.4.0]undec-7-ene (23.0 mL, 153 mmol, 5 equiv), and
2-bromoethanol (11.0 mL, 153 mmol, 5 equiv). The mixture was heated to
reflux and stirred for 1 h. The mixture was allowed to cool to rt and
dichloromethane (100 mL) was added. The reaction mixture was washed
with satd aq NH
4
Cl (2 Â 100 mL) and the organic layer was dried over MgSO
4
,
filtered, and concentrated in vacuo to yield the crude product as a mix of
yellow and orange solids. The solid was crystallized from 100% ethanol to yield
spirooxazolidine 9a as long, white needle-like crystals (7.23 g, 86%). Mp 234–
, c 1.0); 1H NMR (500 MHz, CDCl
D 3 3
a] +34.1 (CHCl ) d 4.05–4.12 (m,
2
35 °C; [
2H), 3.99 (dd, J = 8.55, 15.96 Hz, 1H), 3.65–3.72 (m, 1H), 3.43 (AB quartet,
J = 13.81 Hz, 2H), 2.38 (d, J = 5.70 Hz, 1H), 2.31 (ddd, J = 3.25, 9.13, 12.29 Hz,
References and notes
1
1
H), 2.11 (dddd, J = 3.26, 5.70, 11.70, 13.90 Hz, 1H), 1.96 (ddd, J = 5.23, 11.70,
1.70 Hz, 1H), 1.82 (ddd, J = 5.33, 9.13, 13.90 Hz, 1H), 1.29 (s, 3H), 1.12 (s, 3H);
1.
2.
3.
4.
5.
6.
7.
Rohloff, J. C.; Dyson, N. H.; Gardner, J. O.; Alfredson, T. V.; Sparacino, M. L.;
Robinson, J., III J.Org. Chem. 1993, 58, 1935–1938.
Reider, P. J.; Davis, P.; Hughes, D. L.; Grabowski, E. J. J. J. Org. Chem. 1987, 52,
13
C NMR (125 MHz, CDCl
2.9, 22.2, 18.5; DEPT (125 MHz, 135°, CDCl
À), 26.1 (À), 22.9 (À), 22.2 (+), 18.5 (+). Anal. Calcd for C12
H, 6.32; N, 5.16. Found: C, 53.20; H, 6.28; N, 5.24.
3
) d 208.6, 100.5, 65.1, 58.9, 52.2, 49.8, 46.3, 44.0, 26.1,
) d 65.1 (À), 58.9 (+), 49.8 (À), 46.3
17NO S: C, 53.12;
2
(
3
H
4
9
55–957.
Cao, X.; Liu, F.; Lu, W.; Chen, G.; Yu, G.-A.; Liu, S. H. Tetrahedron 2008, 64, 5629–
636.
Pham, T. Q.; Pyne, S. G.; Skelton, B. W.; White, A. H. J. Org. Chem. 2005, 70,
369–6377.
3
3
0. Details of X-ray diffraction analysis for compounds 9a, 9b, 10a, and 10b will be
published elsewhere: Wilke, B.I.; Goodenough, A.K.; Bausch, C.C.; Cline, E.N.;
Abrams, M.L.; Fayer, E.L.; Swenson, D.C.; Cermak, D.M. Acta Cryst. 2010, C66,
o600–o605.
5
6
Lee, J.; Lee, Y.-I.; Kang, M. J.; Lee, Y.-J.; Jeong, B.-S.; Lee, J.-H.; Kim, M.-J.; Choi, J.;
Ku, J.-M.; Park, H.-G.; Jew, S.-S. J. Org. Chem. 2005, 70, 4158–4161.
Feroci, M.; Orsini, M.; Palombi, L.; Sotgiu, G.; Colapietro, M.; Inesi, A. J. Org.
Chem. 2004, 69, 487–494.
Garner, P.; Dogan, O.; Youngs, W. J.; Kennedy, V. O.; Protasiewicz, J.; Zaniewski,
R. Tetrahedron 2001, 57, 71–85.
1. Compound 9b: The solid was crystallized from 100% ethanol to yield
spirooxazine 9b as a white crystalline solid (61%). Mp 184–185 °C; [
(
a
]
D
À5.5
, c 1.0); 1H NMR (500 MHz, CDCl
3 3
CHCl ) d 4.51 (ddd, J = 2.67, 11.65, 13.20 Hz,
1
1
2
3
2
4
C
H), 3.99–4.02 (m, 1H), 3.78 (ddd, J = 3.56, 13.06, 14.72 Hz, 1H), 3.64–3.68 (m,
H), 3.34 (s, 2H), 2.37–2.47 (m, 1H), 2.34 (d, J = 5.70 Hz, 1H), 2.29–2.33 (m, 1H),
.00–2.07 (m, 1H), 1.77–1.85 (m, 2H), 1.34–1.38 (m, 1H), 1.19 (s, 3H), 1.08 (s,
8
9
.
.
Garner, P.; Dogan, O.; Pillai, S. Tetrahedron Lett. 1994, 35, 1653–1656.
Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 293–318.
13
H); C NMR (125 MHz, CDCl
3
) d 206.3, 87.5, 63.2, 59.3, 54.5, 48.2, 44.0, 38.0,
) d 63.1 (À), 59.3 (+),
8.2 (À), 38.0 (À), 24.6 (À), 23.1 (À), 22.0 (+), 22.0 (À), 19.1 (+). Anal. Calcd for
19NO S: C, 54.72; H, 6.71; N, 4.91. Found: C, 54.69; H, 6.70; N, 4.88.
4.6, 23.1, 22.0 (2C), 19.1; DEPT (125 MHz, 135°, CDCl
3
1
1
0. Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241–1250.
1. Davis, F. A.; Weismiller, M. C.; Murphy, C. K.; Reddy, R. T.; Chen, B.-C. J. Org.
Chem. 1992, 57, 7274–7285.
13
H
4
3
2. General procedure for the preparation of exo-hydroxy derivatives 10: To a
1
1
2. Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919–934.
3. Davis, F. A.; Reddy, R. E.; Kasu, P. V. N.; Portonovo, P. S.; Carroll, P. J. J. Org. Chem.
mixture of LiAlH (1.21 g, 31.8 mmol, 1.2 equiv) in THF (450 mL) at 0 °C was
4
added spirooxazolidine 9a (7.24 g, 26.7 mmol) in portions. The mixture was
heated to reflux while stirring for 12 h. The mixture was cooled to 0 °C and
methanol (250 mL) was added dropwise. Solvent was removed from the
mixture in vacuo until a white solid/gray residue remained. The solid was
dissolved in 20% KOH (150 mL). The resulting mixture was continuously
extracted with CH Cl . The organic layer was dried over MgSO , filtered, and
2 2 4
concentrated in vacuo to yield a mix of white and yellow solids. The solid was
crystallized from 100% ethanol to yield exo-hydroxy spirooxazolidine 10a as
1
997, 62, 3625–3630.
14. Cermak, D. M.; Du, Y.; Wiemer, D. F. J. Org. Chem. 1999, 64, 388–393.
15. Pogatchnik, D. M.; Wiemer, D. F. Tetrahedron Lett. 1997, 38, 3495–3498.
16. Davis, F. A.; Reddy, G. V.; Chen, B.-C.; Kumar, A.; Haque, M. S. J. Org. Chem. 1995,
60, 6148–6153.
17. Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434–9453.
18. Chen, B.-C.; Weismiller, M. C.; Davis, F. A. Tetrahedron 1991, 47, 173–182.
19. Bach, R. D.; Andres, J. L.; Davis, F. A. J. Org. Chem. 1992, 57, 613–618.
20. Chen, B.-C.; Murphy, C. K.; Kumar, A.; Reddy, R. T.; Clark, C.; Zhou, P.; Lewis, B.
M.; Gala, D.; Mergelsberg, I.; Scherer, D.; Buckley, J.; DiBenedetto, D.; Davis, F.
A. Org. Synth. 1996, 73, 159–173.
white needle-like crystals (4.34 g, 60%). Mp 201–205 °C; [
a
]
D
À6.2 (CHCl
3
, c
.0); 1H NMR (500 MHz, CDCl
1
3
) d 4.11 (ddd, J = 4.80, 8.07, 12.57 Hz, 1H), 3.97
(
dd, J = 7.77, 14.68 Hz, 1H), 3.81 (ddd, J = 4.80, 7.77, 8.43 Hz, 1H), 3.68 (d,
J = 4.68 Hz, 1H), 3.44 (ddd, J = 6.84, 8.72, 12.25 Hz, 1H), 3.38 (AB quartet,
2
2
1. Bartlett, P. D.; Knox, L. H. Org. Synth. 1973, Coll. Vol. V, 196–198.
2. Towson, J. C.; Weismiller, M. C.; Lai, G. S.; Sheppard, A. C.; Davis, F. A. Org. Synth.
J = 13.60 Hz, 2H), 2.07 (ddd, J = 2.98. 9.17, 12.25 Hz, 1H), 1.89–2.01 (m, 3H),
13
1
.68–1.76 (m, 1H), 1.46 (s, 3H), 1.29–1.39 (m, 1H), 1.01 (s, 3H); C NMR
1
990, 69, 158–168.
(
3
125 MHz, CDCl ) d 110.0, 83.1, 63.0, 53.2, 52.1, 50.6, 48.6, 46.4, 25.7, 24.6,
2
3. Synthesis of (À)-(3-oxocamphorsulfonyl)imine (8) was accomplished
2
4
5
2.6, 21.6; DEPT (125 MHz, 135°, CDCl ) d 83.1 (+), 63.0 (À), 52.1 (+), 50.6 (À),
3
20
following the procedure delineated by B.-C. Chen et al. (Ref. ) with the
following additions: The reaction mixture was vacuum filtered through a pad
6.4 (À), 25.7 (À), 24.6 (À), 22.6 (+), 21.6 (+). Anal. Calcd for C12
4
H19NO S: C,
2.73; H, 7.01; N, 5.12. Found: C, 52.97; H, 6.76; N, 5.08.
of Celite and rinsed with CH
concentrated in vacuo and the resulting yellow and orange solids were
dissolved in minimal CH
gel and rinsed with CH
concentrated in vacuo to yield (À)-(3-oxocamphorsulfonyl)imine (8) as a
yellow crystalline solid (90%). This product has spectroscopic data identical to
Chen et al. and was used in a timely manner to avoid decomposition. We have
also shelved the purified imine for over three months and have seen no signs of
decomposition.
2 2
Cl until the filtrate was colorless. The filtrate was
3
3. Compound 10b: Purification by flash column chromatography (5:95 acetone/
chloroform) gave exo-hydroxy spirooxazine 10b as a white crystalline solid
2
Cl
Cl
2
. The solution was vacuum filtered through silica
until the filtrate was colorless. The filtrate was
, c 1.0); 1H NMR (500 MHz, CDCl
3 3
) d
.03–4.06 (m, 3H), 3.65–3.76 (m, 2H), 3.27 (AB quartet, J = 13.54 Hz, 2H), 2.37–
.49 (m, 1H), 2.00–2.06 (m, 2H), 1.83–1.91 (m, 2H), 1.49–1.56 (m, 1H), 1.42 (s,
3
H), 1.22–1.31 (m, 2H), 0.97 (s, 3H); C NMR (125 MHz, CDCl ) d 97.7, 81.9,
(
71%). Mp 186–188 °C; [
a
]
D
À27.0 °C (CHCl
2
2
4
2
3
6
1
2
13
2.9, 55.6, 52.6, 48.9, 48.7, 39.5, 25.0, 23.9, 22.3, 22.0, 21.9; DEPT (125 MHz,
35°, CDCl ) d 81.9 (+), 62.9 (À), 52.6 (+), 48.9 (À), 39.5 (À), 25.0 (À), 23.9 (À),
2.3 (+), 22.0 (+), 21.9 Anal. Calcd for C13 21NO S: C, 54.33; H, 7.37; N, 4.87.
3
H
4
2
2
4. Hwu, J. R.; Leu, L.-C.; Robl, J. A.; Anderson, D. A.; Wetzel, J. M. J. Org. Chem. 1987,
Found: C, 54.40; H, 7.46; N, 4.90.
52, 188–191.
5. Hwu, J. R.; Wetzel, J. M. J. Org. Chem. 1985, 50, 3946–3948.