Unexpected exo selectivity for an intramolecular Diels-Alder reaction involving a doubly-activated δ-pentenolide dienophile

Article abstract of DOI:10.1016/j.tetasy.2010.12.018

The intramolecular Diels-Alder cyclization of a homochiral doubly-activated δ-pentenolide system is described, proceeding predominantly via an exo transition state to provide an advanced precursor toward unique stereochemical analogs of (+)-symbioimine.

Full text of DOI:10.1016/j.tetasy.2010.12.018

Tetrahedron: Asymmetry 22 (2011) 31–35
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Unexpected exo selectivity for an intramolecular Diels–Alder reaction
involving a doubly-activated d-pentenolide dienophile
Jason P. Burke a, Michal Sabat a, William H. Myers b, Jason J. Chruma a,
⇑
a Department of Chemistry, University of Virginia, McCormick Road, PO Box 400319, Charlottesville, VA 22903-4319, USA
b Department of Chemistry, University of Richmond, 28 Westhampton Way, Richmond, VA 23173, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The intramolecular Diels–Alder cyclization of a homochiral doubly-activated d-pentenolide system is
described, proceeding predominantly via an exo transition state to provide an advanced precursor toward
unique stereochemical analogs of (+)-symbioimine.
Received 2 November 2010
Accepted 17 December 2010
Available online 25 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
products, ( )-5a, (+)-5b and 5c, are doubly epimeric to (+)-1 at the
C-3 and C-4 stereocenters.
The intramolecular Diels–Alder (IMDA) reaction is a powerful
tool in organic synthesis, allowing for the controlled formation of
two new rings and up to four new stereocenters in a single trans-
formation.1 Accordingly, the IMDA reaction has played a promi-
nent role in the total synthesis of biologically active natural
products.2 Indeed, the remarkable efficiency of the unimolecular
[4 + 2] cycloaddition has inspired several groups to propose IMDA
reactions as part of the biosyntheses of a host of diverse polycyclic
natural products.3 For example, Uemura et al. suggested that the
biosynthesis of the anti-osteoclastogenic iminium alkaloid (+)-
symbioimine 1 could involve either an exo-selective IMDA cycload-
dition of (E)-enone 24a or an endo-selective cyclization of dihydro-
pyridinium 34b followed by epimerization of the enolizable C-4
stereocenter (Scheme 1). Strong experimental support exists for
the latter process,5 but efforts by both Kobayashi6 and ourselves7
suggest that the originally proposed exo-selective IMDA cyclization
of 2 runs counter to the inherent reactivity of the (E,E,E)-1,7,9-
decatrien-3-one framework. For example, the Lewis acid-catalyzed
IMDA cyclization of triene ( )-4a exclusively provided the endo
product ( )-5a in 88% isolated yield (Table 1).7 The freely rotating
2. Results and discussion
In view of these observations, we sought an alternative toward
the trans-decalin framework of (+)-1.8 Accordingly, we proposed
that the desired stereochemical configuration could be obtained
via an endo-selective IMDA cyclization of
a-acyl-d-pentenolide 8
(Scheme 2). In order to remain consistent with the precedents of
Thomas9 and Jauch,10 and in contrast to our previous studies,7
the term ‘endo’ in this circumstance (and throughout the remain-
der of the paper) refers to the overlap between the diene p-system
and the lactone carbonyl (not the ketone carbonyl) in the transition
state. Saponification and concomitant decarboxylation of the
expectant lactone product 7 would provide the complete carbon
framework of (+)-1 in the correct stereoisomeric configuration.
The requisite acyclic triene precursor 8 could be obtained by cou-
pling the known homochiral
c
-methyl-d-pentenolide (ꢀ)-911 and
an assortment of carbonyl-based electrophiles, for example, 10 or
11.7 Examples involving
a-linked-a,b-unsaturated lactones as
dienophiles for IMDA reactions are surprisingly sparse.10 In all
previous examples, the participating dienophile is a five-mem-
exocyclic C-2 stereogenic center completely dictates the
p-facial
selectively of the cycloaddition. Attempts to affect a similar endo
selective Lewis acid-catalyzed IMDA reaction of the corresponding
(Z)-enone analog of ( )-4a once again led to the exclusive forma-
tion of cis-decalin ( )-5a, indicating that enone isomerization
occurs significantly faster than cycloaddition. Exchanging the
N-Boc amine moiety in ( )-4a for a silyl ether (+)-4b or pivalate
bered
c-butenolide and the major products typically arise from
an endo transition state.
To date, only a single example exists for an IMDA cyclization
involving
dienophile.12 Specifically, Jauch et al. demonstrated that the
-acyl- -butenolide generated by the oxidation of alcohol 12
a doubly-activated a-acyl-a,b-unsaturated lactone
a
c
ester (+)-4c resulted in diminished
p-facial selectivity without
spontaneously cyclized upon formation at rt to afford a ꢁ5.7:1
ratio of endo:exo products 13 and 14, respectively (Scheme 3). With
regards to the less reactive six-membered d-pentenolides, Taguchi
and co-workers recently described the Lewis acid-catalyzed inter-
molecular Diels–Alder condensation of ( )-9 with cyclopentadiene,
which afforded a 13:1 endo:exo ratio.13 The resulting endo product
deterioration of the exclusive endo selectivity. The resulting major
⇑
Corresponding author. Tel.: +1 434 243 2131; fax: +1 434 924 3710.
E-mail address: jjc5p@virginia.edu (J.J. Chruma).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.12.018

32
J. P. Burke et al. / Tetrahedron: Asymmetry 22 (2011) 31–35
Me
–
NH3 OSO3
exo-IMDA reaction;
imine formation
OH
O
–
OSO3
2
2
H
Me
H
N
H
H
OH
4
H
–
OSO3
(+)-symbioimine 1
H
Me
N
endo-IMDA reaction;
C-4 epimerization
OH
3
Scheme 1. Uemura’s two proposed biosyntheses of (+)-symbioimine.
Table 1
Lewis acid-catalyzed IMDA reaction of (E)-enones7
R
R
Me
R
2
Me
Me
O
O
Me2AlCl,
CH2Cl2,
H
H
H
3
+
Ar
H
Ar
H
Ar
4
H
H
O
–78 °C
–20 °C
Ar = 3,5-(MeO)2Ph–
H
4
5
6
Triene
R
Yielda (%)
dr (5:6)b
( )-4a
(+)-4b
(+)-4c
NHBoc
OSiPh2t-Bu
OPiv
88
76
52
P20:1
3:1
4.5:1
a
Isolated yield after chromatography.
b
Determined by 1H NMR spectroscopic analysis of the unpurified reaction mixture.
was isolated as a 2.4:1 mixture of
p-facial stereoisomers favoring
the product arising from the diene approaching opposite the dieno-
phile d-methyl substituent. Based on these precedents, we felt it
reasonable to propose that the IMDA cyclization of triene 8 would
favor the desired endo product 7. Accordingly, we set out to rapidly
construct the requisite IMDA precursor triene.
Me
O
H
O
O
O
Me
H
R
H
H
(+)-1
O
O
R
Toward this end, homochiral d-pentenolide (ꢀ)-9 was readily
obtained from ethyl acetate and (+)-(S)-Roche ester following an
adapted literature protocol.14 Homochiral lactone (ꢀ)-9 appeared
to be an attractive general chiral feedstock in organic synthesis.
Examples toward this end are essentially absent in the literature,
7
8
O
O
OMe
however.13,15 While enone (ꢀ)-9 was readily converted into
a-bro-
O
R
+
R =
mo,
a-iodo, or a-stannane congeners, all of these d-pentenolides
X
proved remarkably uncooperative as nucleophilic precursors. For
example, formation of the corresponding Grignard or vinylzinc
species at low temperature following Knochel’s protocols16,17 was
feasible, but the resulting organometallic species failed to react
even with relatively potent ‘soft’ electrophiles such as iodine or
bis-(4-chlorophenyl)di-sulfide. Various attempts at Pd-catalyzed
cross-couplings, either under Stille18 or Negishi coupling
OMe
Me
10: X = H
11: X = N(OMe)Me
9
(–)-
Scheme 2. Retrosynthetic analysis of (+)-1.

J. P. Burke et al. / Tetrahedron: Asymmetry 22 (2011) 31–35
33
OH
OR
H
OR
H
O
O
O
O
O
O
OR
R'
R'
R'
DMP,
+
O
H
2,6-lutidine,
CH2Cl2
H
O
H
H
23 °C
R = (+)-menthyl,
endo-13
exo-14
12
R' = CH2OTBDPS
(79-81%)
(~14%)
trans-decalin
cis-decalin
Scheme 3. Jauch’s doubly-activated d-butenolide IMDA reaction.12
conditions were unsuccessful. Moreover, in accordance with re-
lated reports,19 the DABCO-mediated Baylis–Hillman condensation
of 9 with phenylacetaldehyde did not proceed. The lithium phenyl-
selenide-mediated Baylis–Hillman tactic introduced by Jauch20
successfully coupled d-pentenolide (ꢀ)-9 with aldehyde 10, albeit
in low yield (Scheme 4). The unreacted lactone 9 could be recov-
ered from the reaction mixture, but the remaining aldehyde 10
decomposed under the reaction conditions.
Attempts to initiate an IMDA cyclization of the mixture of
epimeric alcohols 15 thermally (140 °C, PhCH3) were not success-
ful.21 Oxidation to the corresponding ketone 8 was accomplished
in high yield using Dess–Martin periodinane (DMP, Scheme 5).23
Unlike the doubly-activated d-butenolide 12,12 ketone 8 did not
spontaneously undergo IMDA cyclization at ambient tempera-
ture.22 Heating the resulting doubly-activated dienophile with
toluene in a sealed tube to 140 °C, gave complete conversion to
two products in a ꢁ4:1 ratio.24 Extensive 2D NMR spectroscopic
analysis and X-ray crystallography25 confirmed that the major
product was the unexpected exo isomer (ꢀ)-16.26,27 Resubjection
of purified (ꢀ)-16 to the reaction conditions (140 °C, PhCH3, 18 h)
resulted in the quantitative recovery of the tricyclic lactone, indi-
cating that the initial product mixture does not represent a ther-
modynamic equilibrium ratio. The cis-decalin (ꢀ)-16 is epimeric
to (+)-1 at C-9 and C-12. Attempts to induce an intermolecular
Diels–Alder condensation between d-pentenolide (ꢀ)-9 and diene
11 either thermally (120 °C, PhCH3) or with a Lewis acid (1.5 equiv
Me2AlCl, CH2Cl2, ꢀ78 °C?ꢀ20 °C) in the hopes of procuring the
endo isomer were not productive.
Me
O
OMe
10, PhSeLi,
O
(–)-9
THF
(18%, dr~1.5:1)
OH
OMe
15
Scheme 4. Synthesis of triene alcohol 15.
O
O
Me
DMP,
CH2Cl2
(91%)
140 °C
8
15
PhCH3
(49%)
~4:1 dr
H
O
Ar
Re-face, exo TS
OMe
Me
O
O
O
H
OMe
12
H
9
H
(–)-16 (major)
mp = 42-45 °C
Scheme 5. Formation and IMDA reaction of
transition state and Re-facial selectivity.25
a-acyl-d-pentenolide 8. Inset: ORTEP diagram (50% probability ellipsoids) for the major IMDA product (ꢀ)-16, confirming the exo-

34
J. P. Burke et al. / Tetrahedron: Asymmetry 22 (2011) 31–35
OH
CO2Me
O
MeO2C
MeO2C
OAc
DMP,
O
CH2Cl2
(60%)
H
OAc
18
OAc
17
exo-19
Scheme 6. Formation and exo-selective IMDA reaction of acrylate 18.27
ꢁ1.5:1 mixture of diastereomers (69 mg, 18%). The resulting dia-
stereomeric mixture of alcohols (56 mg, 0.15 mmol) was allowed
to stir with Dess–Martin periodinane23 (96 mg, 0.23 mmol) in
CH2Cl2 (2 mL) at rt for 4 h. The reaction was diluted with CH2Cl2
(3 mL) and washed sequentially with satd NaHCO3 (5 mL), satd
Na2S2O3 (5 mL), and brine (5 ml) before drying (MgSO4) and con-
centrating to a yellow oil (50 mg, 91%). A solution of the crude tri-
ene 822 (50 mg, 0.13 mmol) in toluene (2 mL, 0.07 M) was heated
at 140 °C in a sealed tube for 15 h. 1H NMR analysis of the crude
reaction showed two products in a ꢁ4:1 ratio (d, 0.77 and
0.44 ppm). The residue was purified by flash column chromatogra-
phy (30% EtOAc/Hex) to afford lactone (ꢀ)-16 as an ivory solid
(19 mg, 38%): Rf (30% EtOAc/hexanes) = 0.31; 1H NMR (500 MHz,
CDCl3) d 6.37 (s, 3H), 5.84 (ddd, J = 9.9, 5.1, 2.5 Hz, 1H), 5.49 (dd,
J = 10.0, 1.7 Hz, 1H), 4.41 (dd, J = 12.0, 9.1 Hz, 1H), 3.94 (dd,
J = 12.0, 10.5 Hz, 1H), 3.81 (s, 6H), 3.17–3.05 (m, 2H), 2.71 (dt,
J = 12.5, 5.5 Hz, 1H), 2.64 (dd, J = 9.4, 1.8 Hz, 1H), 2.53 (ddd,
J = 13.2, 5.2, 3.8 Hz, 1H), 2.37–2.28 (m, 1H), 2.18–2.09 (m, 2H,),
1.85–1.67 (m, 2H), 0.78 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
125 MHz) d 210.6, 171.8, 161.0, 144.7, 129.0, 128.2, 106.9, 98.0,
69.9, 62.5, 55.3, 48.7, 42.8, 40.9, 39.8, 30.0, 29.9, 26.2, 18.5; IR
(cmꢀ1) 3054, 2918, 2848, 1749, 1699, 1595, 1460, 1315, 1265,
3. Conclusion
In conclusion while the stereoconfiguration of tricycle (ꢀ)-16
does not match that of (+)-1, it does correlate to the absolute
stereoconfiguration of the minor IMDA products (ꢀ)-6b and 6c
obtained in our previous studies.7 Therefore, constraining the C-2
stereogenic center within the lactone affords a complete reversal
of
p-facial selectivity without obviating the overlap between the
ketone carbonyl and diene in the transition state. Accordingly,
we now have two alternative strategies to directly access stereo-
chemical analogs of (+)-symbioimine. We intend to employ these
valuable molecular tools to explore the structure–activity relation-
ship of the unique anti-osteoclastogenic alkaloid.
4. Experimental
4.1. (R)-5-Methyl-5,6-dihydro-2H-pyran-2-one (ꢀ)-9
At first, n-BuLi (1.6 M in hexanes, 6.2 mL, 9.97 mmol) was added
dropwise to distilled diisopropylamine (1.01 g, 9.97 mmol) in THF
(10 mL) at ꢀ30 °C and let stir 15 min before cooling to ꢀ78 °C and
adding dry EtOAc (0.97 mL, 9.97 mmol) dropwise. After stirring for
1 h at ꢀ78 °C, (2S)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)-
propan-al14 (1.56 g, 9.05 mmol) in THF (10 mL) was added drop-
wise. The reaction mixture was stirred 30 min at ꢀ78 °C and then
quenched with satd NH4Cl (20 mL) before extracting with CH2Cl2
(2 ꢂ 20 mL), drying (MgSO4), and concentrating to a partially solid-
ified oil (1.95 g, 83%). Benzene and p-TsOHꢃH2O (1.71 g, 8.99 mmol)
were then added to the crude product and the mixture was heated
at reflux (Dean–Stark) for 7 h. The reaction mixture was diluted
with satd NaHCO3 (20 mL) and the resulting organic layer was
washed sequentially with H2O (20 mL) and brine (20 mL), dried
(MgSO4), and concentrated to a black residue before distillation
using a Kugelrohr apparatus (1 torr, 90–110 °C) to collect a clear
colorless oil (0.78 g, 92%): Rf = 0.27 (30% EtOAc/hexanes); 1H
NMR (300 MHz, CDCl3) d 6.78 (ddd, J = 9.8, 3.5, 0.7 Hz, 1H), 5.93
(dd, J = 9.8, 2.0 Hz, 1H), 4.37 (ddd, J = 11.0, 5.0, 1.1 Hz, 1H), 4.03
(dd, J = 11.0, 8.3 Hz, 1H), 2.72–2.59 (m, 1H), 1.11 (d, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 75 MHz) d 163.6, 151.5, 120.0, 72.0, 28.7,
1158; ½a 2D3
¼ ꢀ119:8 (c 0.40, CHCl3); HRMS (ES+) m/z 393.1666
ꢄ
[(M+Na)+; calculated for C22H26O5Na+: 393.1673]. A crystal suit-
able for X-ray analysis was obtained by slow evaporation from
EtOAc/Hex; mp = 42–45 °C.25,26
Acknowledgments
Partial financial support provided by the UVA Institute on Aging
(UVA) and the NSF [CHE-0320669 (UR)]. J.P.B. was supported by a
Presidential Fellowship from the UVA GSA&S.
References
1. Roush, W. R. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: Oxford, 1992; Vol. 5, p 513.
2. Recent examples: (a) Spangler, J. E.; Sorensen, E. J. Tetrahedron 2009, 65, 6739;
(b) Miller, K. A.; Tsukamoto, S.; Williams, R. M. Nat. Chem. 2009, 1, 63; (c)
Nicolaou, K. C.; Toh, Q. Y.; Chen, D. Y. K. J. Am. Chem. Soc. 2008, 130, 11292; (d)
Miller, K. A.; Welch, T. R.; Greshock, T. J.; Ding, Y. S.; Sherman, D. H.; Williams,
R. M. J. Org. Chem. 2008, 73, 3116.
3. For recent examples and reviews see: (a) Tantillo, D. J. Org. Lett. 2010, 12, 1164;
(b) Kelly, W. L. Org. Biomol. Chem. 2008, 6, 4483; (c) Miller, K. A.; Williams, R. M.
Chem. Soc. Rev. 2009, 38, 3160; (d) Williams, R. M. Chem. Pharm. Bull. 2002, 50,
711; (e) Tsukamoto, S.; Kawabata, T.; Kato, H.; Greshock, T. J.; Hirota, H.; Ohta,
T.; Williams, R. M. Org. Lett. 2009, 11, 1297.
15.3; ½a 2D3
¼ ꢀ42:0 (c 1.0, CHCl3); HRMS (ES+) m/z 135.0425
ꢄ
[(M+Na)+; calcd for C6H8NaO2þ: 135.0417].
4.2. Tricyclic lactone (ꢀ)-16
4. (a) Kita, M.; Konda, M.; Koyama, T.; Yamada, K.; Matsumoto, T.; Lee, K.; Woo, J.;
Uemura, D. J. Am. Chem. Soc. 2004, 125, 4794; (b) Kita, M.; Ohishi, N.; Washida,
K.; Kondo, M.; Koyama, T.; Yamada, K.; Uemura, D. Bioorg. Med. Chem. 2005, 13,
5253.
5. (a) Zou, Y.; Che, Q.; Snider, B. B. Org. Lett. 2006, 8, 5605; (b) Snider, B. B.; Che, Q.
Angew. Chem., Int. Ed. 2006, 45, 932; (c) Kim, J.; Thomson, R. J. Angew. Chem., Int.
Ed. 2007, 46, 3104.
6. Born, S.; Bacani, G.; Olson, E. E.; Kobayashi, Y. Synlett 2008, 2877.
7. Burke, J. P.; Sabat, M.; Iovan, D.; Myers, W. H.; Chruma, J. J. Org. Lett. 2010, 12,
3192.
8. For previous total syntheses of 1, see Refs. 5a, 5c and: Varseev, G. N.; Maier, M.
E. Angew. Chem., Int. Ed. 2006, 45, 4767.
At first, n-BuLi (1.6 M in hexane, 1.0 mL, 1.58 mmol) was added
dropwise to a solution of diphenyldiselenide (492 mg, 1.58 mmol)
in THF (3 mL) at ꢀ20 °C. After 20 min, the solution was cooled to
ꢀ78 °C and a solution of aldehyde 10 (273 mg, 1.05 mmol) and d-
pentenolide (ꢀ)-9 (118 mg, 1.05 mmol) in THF (3 mL) was added.
The reaction mixture was kept at ꢀ78 °C for 3 h followed by 16 h
at ꢀ20 °C. The reaction was then quenched with satd NH4Cl
(10 mL), extracted with EtOAc (3 ꢂ 10 mL), and dried (MgSO4).
The concentrated residue was passed through a silica gel column
(50% EtOAc/Hex) to give 15 as a yellow oil and as an inseparable
9. In his studies toward the cytochalasins, E. J. Thomas regularly employed IMDA
reactions involving a-acyl-a,b-unsaturated-c-lactams as dienophiles. The endo

J. P. Burke et al. / Tetrahedron: Asymmetry 22 (2011) 31–35
35
products were preferred for connecting chains of 69 carbons; larger chains
provided essentially no selectivity (ꢁ1:1 endo:exo): (a) Harkin, S. A.; Jones, R.
H.; Tapolczay, D. J.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1989, 489; (b)
Thomas, E. J.; Watts, J. P. J. Chem. Soc., Chem. Commun. 1990, 467. and references
therein.
20. Jauch, J. J. Org. Chem. 2001, 66, 609.
21. Similarly, the corresponding TBS ethers of 15 did not undergo IMDA reaction
with heat (140 °C).
22. Ketone 8 proved to be an unstable intermediate, decomposing to a complex
mixture within ꢁ1 week upon storage at –20 °C. Accordingly, this intermediate
was directly converted to the significantly more stable (ꢀ)-16 upon formation
without purification.
10. (a) Jauch, J. Eur. J. Org. Chem. 2001, 473; (b) Jauch, J. Angew. Chem., Int. Ed. 2000,
39, 2764; (c) Jauch, J. Synlett 1999, 1325; (d) Jauch, J. Synlett 2001, 87.
11. (a) Esteban, J.; Costa, A. M.; Gómez, A.; Vilarrasa, J. Org. Lett. 2008, 10, 65; (b)
Dieter, R. K.; Guo, F. Org. Lett. 2006, 8, 4779.
23. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
24. Attempts to accelerate the IMDA cyclization of triene
8 with a variety
12. Reiser, U.; Jauch, J.; Herdtweck, E. Tetrahedron: Asymmetry 2000, 11, 3345.
13. Yanai, H.; Takahashi, A.; Taguchi, T. Tetrahedron 2007, 63, 12149.
14. Andrus, M. B.; Li, W.; Keyes, R. F. J. Org. Chem. 1997, 62, 5542.
15. For examples of ( )-9 as a Michael acceptor see: (a) Lim, S. H.; Beak, P. Org. Lett.
2002, 4, 2657; (b) Fleming, I.; Reddy, N. L.; Takaki, K.; Ware, A. C. J. Chem. Soc.,
Chem. Commun. 1987, 1472.
16. Krasovskiy, A.; Staub, B. F.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 159.
17. Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 6040.
18. (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1; (b) Wang,
Y.; Burton, D. J. Org. Lett. 2006, 8, 1109; (c) Farina, V.; Krishnan, B. J. Am. Chem.
Soc. 1991, 113, 9585; (d) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Angew. Chem., Int.
Ed. 2004, 43, 1132.
standard catalysts, including Lewis acids MgBr2 and Sc(OTf)3, led to
complete degradation of the starting material. This could be attributed to
the known sensitivity of related unsaturated cyclic b-dicarbonyl
compounds: Ref. 9a and Thomas, E. J.; Whitehead, J. W. F. J. Chem. Soc.,
Perkin Trans. 1. 1989, 499.
25. Crystallographic data for (ꢀ)-16 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
778906. Copies of data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223-336033 or email:
deposit@ccdc.cam.as.uk].
26. The minor diastereomer could not be isolated in sufficient purity for
characterization.
27. The observed exo selectivity is similar to that observed by Mix and Blechert for
19. Ciganek, E. In Organic Reactions; Paquette, L. A., Ed.; Wiley: New York, 1997;
Vol. 51, p 201.
the spontaneous IMDA reaction of
Blechert, S. Org. Lett. 2005, 7, 2015.
a-acylmethacrylate 18 (Scheme 6): Mix, S.;