Complete facial selectivity in the Diels-Alder reaction of a 5-amino-5-carboxycyclopentadiene derivative

Article abstract of DOI:10.1021/ol201236j

5-tert-Butoxycarbonylamino-5-carbethoxy-2-tert-butyldimethylsilyloxy- cyclopentadiene undergoes a Diels-Alder reaction exclusively from the face syn to the nitrogen functionality. Complete reversal of facial bias may be achieved, but at the cost of dimini

Full text of DOI:10.1021/ol201236j

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3274–3277
Complete Facial Selectivity in the
DielsÀAlder Reaction of a 5-Amino-5-
carboxycyclopentadiene Derivative
Simon Kim and Marco A. Ciufolini*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver,
BC V6T 1Z1, Canada
ciufi@chem.ubc.ca
Received May 10, 2011
ABSTRACT
5-tert-Butoxycarbonylamino-5-carbethoxy-2-tert-butyldimethylsilyloxy-cyclopentadiene undergoes a DielsÀAlder reaction exclusively from the
face syn to the nitrogen functionality. Complete reversal of facial bias may be achieved, but at the cost of diminished reactivity, through steric
shielding of the N-syn face.
Synthetic efforts underway in our group have unveiled
the desirability of a facially selective DielsÀAlder reaction
of a cyclopentadiene such as 1 (Figure 1). Compounds of
this type are special cases of siloxy dienes1 but were
undocumented at the onset of our investigations. Indeed,
most known 5-substituted cyclopentadienes carry a single
substituent at that position.2 If this substituent is an alkyl
Figure 1. Cyclopentadienes of interest in this study.
group, then the diene tends to engage dienophiles from the
face opposite the C-5 substituent, i.e., with C-5 alkyl-anti
facial bias: a preference attributed to steric effects. Known
monosubstituted cyclopentadienes carrying a heteroa-
tomic group at C-5 differ from 1 in that they lack the
literature exists on the behavior of 5,5-disubstituted cyclo-
activating siloxy unit, and none incorporate nitrogen at
Namely, 4a3 and 4c4 display complete halogen-syn facial-
ity, but for reasons that remain unclear, 4b reacts with a
modest 2:1 = Cl-syn bias (Table 1).4 Considerably less
pentadienes, perhaps because these species tend to react
with poor facial selectivity. Thus, the DielsÀAlder reaction
C-5. The facial selectivity of the DielsÀAlder reactions of
such dienes is sensitive to subtle structural differences.
of 55 and 6a6 occurs with no facial bias, while 6b exhibits
weak R-anti preference.7 However, diene 7a8 exhibits
(1) Reviews: (a) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400. (b)
moderate COOEt-syn faciality (5: 1), a preference that is
greatly enhanced in 7b (complete N-syn selectivity).9 If
Danishefsky, S. J.; DeNinno, M. P. Angew. Chem., Int. Ed. Engl. 1987,
26, 15. (c) Danishefsky, S.; Kitahara, T.; Schuda, P. F. Org. Synth., Coll.
Vol. VII 1990, 312.
(2) Representative siloxy cyclopentadienes and their chemistry: (a)
Snowden, R. L. Tetrahedron Lett. 1981, 22, 97. (b) Trost, B. M.; Curran,
D. P. J. Am. Chem. Soc. 1981, 103, 7380. (c) Kodpinid, M.; Siwapinyoyos,
T.; Thebtaranonth, Y. J. Am. Chem. Soc. 1984, 106, 4862. (d) Forsyth,
C. J.; Clardy, J. J. Am. Chem. Soc. 1988, 110, 5911. (e) Forsyth, C. J.;
Clardy, J. J. Am. Chem. Soc. 1990, 112, 3497. (f) Corey, E. J.; Wood, H. B.,
Jr. J. Am. Chem. Soc. 1996, 118, 11982. (g) Lalic, G.; Petrowski, Z.;
Galonic, D.; Matovic, R.; Saicic, R. N. Tetrahedron 2001, 57, 583. (h)
Ashenhurst, J. A.; Gleason, J. L. Tetrahedron Lett. 2008, 49, 504. (i)
Hudon, J.; Cernak, T. A.; Ashenhurst, J. A.; Gleason, J. L. Angew. Chem.,
Int. Ed. 2008, 47, 8885. (j) Ashenhurst, J. A.; Isakovic, L.; Gleason, J. L.
Tetrahedron 2010, 66, 368.
(3) McClinton, M. A.; Sik, V. J. Chem. Soc., Perkin Trans. 1 1992, 1891.
(4) Franck-Neumann, M.; Sedrati, M. Tetrahedron Lett. 1983, 24,
1391.
ꢀ
(5) Schule, A.; Liang, H.; Vors, J.-P.; Ciufolini, M. A. J. Org. Chem.
2009, 74, 1587.
(6) (a) Starr, J. T.; Koch, G.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 8793. Compound 6a is a variant of the Corey cyclopentadiene:(b)
Corey, E. J.; Shiner, C. S.; Volante, R. P.; Cyr, C. R. Tetrahedron Lett.
1975, 16, 1161.
(7) Reynaud, C.; Giorgi, M.; Doucet, H.; Santelli, M. Synthesis 2011,
674.
r
10.1021/ol201236j
Published on Web 05/26/2011
2011 American Chemical Society

Table 1. Facial Selectivity in the DielsÀAlder Reaction of Some
Scheme 1. Preparation and Enol Silylation of Enone 15
Cyclopentadienes Known Prior to the Present Study
CdO and N groups are both syn-directing, the simulta-
neous presence of such functionalities at the C-5 position
of 1 made it unclear whether this diene would exhibit facial
selectivity, and in which sense. Experimentation was
needed to address this issue.
A suitable diene was made by enol silylation of enone 15
(Scheme 1). Enantioselective routes to 15 are known,10,11
but optically enriched substrates were irrelevant to the
objective of the present study, which aimed to address the
question of facial selectivity. All work was thus conducted
with racemic materials. The synthesis of (()-1510À12
started with alkylation of imine 9 with cis-1,4-dichloro-2-
butene.
Subsequent imine cleavage (aq 1 N HCl) resulted in
partial hydrolysis of the ester, necessitating subjection of
thecrudeproducttoFisheresterification toeffectcomplete
conversion into 11. BOC-protection of the amine gener-
ated 12, which reacted with MCPBA to afford a 5:1
(1H NMR) mixture of unassigneddiastereomers of epoxide
13.13 Smooth rearrangement toallylic alcohols14occurred
upon reaction of the epoxide mixture with LDA. An
ensuing DessÀMartin oxidation furnished 15 in 69% yield
over two steps on a scale of 0.5 mmol.14 The conversion of
enone 15intodiene 16was bestcarried out byreaction with
TBSOTf and base.15 However, the desired 16 was accom-
panied by variable quantities of byproducts 17 and 18. The
genesisof17is attributable toa Michael-type cyclization of
the carbamate into the enone and concomitant exchangeof
the tert-butyl with a silyl group. The use of 1.5 equiv or less
of TBS-OTf resulted in formation of a 1:1:1 mixture of 16,
17, and 18. Reaction of 15 with 2 equiv of TBS-OTf and
2,6-lutidine generated only 18, while replacement of luti-
dine with Hunig’s base afforded only the bicyclic product
17. Optimal results were obtained by treatment of 15 with 2
equiv of TBSOTf in the presence of Et3N, whereupon a
1À1.2:1 mixture of 16 and 17 was obtained in 81% yield
after chromatography on neutral alumina.16 Unacceptable
losses occurred upon attempted separation of the two
components. Subsequent DielsÀAlder experiments thus
employed the mixture of 16 and 17, since only the former
can undergo cycloaddition. Diene 16 underwent a DielsÀ
Alder reaction with maleic anhydride at room temperature
(8) (a) Ishida, M.; Tomohiro, S.; Shimizu, M.; Inagaki, S. Chem. Lett.
1995, 24, 739. (b) Ishida, M.; Hirasawa, S.; Inagaki, S. Tetrahedron Lett.
2003, 44, 2187. These authors also report that DielsÀAlder reactions of
an analogue of 7a wherein a CN group replaces the COOEt unit proceed
with complete CN-syn facial selectivity.
(9) Macaulay, J. B.; Fallis, A. G. J. Am. Chem. Soc. 1990, 112, 1136.
(10) Hodgson, D. M.; Thompson, A. J.; Wadman, S.; Keats, C. J.
Tetrahedron 1999, 55, 10815.
(11) Varie, D. L.; Beck, C.; Borders, S. K.; Brady, M. D.; Cronin,
J. S.; Ditsworth, T. K.; Hay, D. A.; Hoard, D. W.; Hoying, R. C.;
Linder, R. J.; Miller, R. D.; Moher, E. D.; Remacle, J. R.; Rieck, J. A.;
Anderson, D. D.; Dodson, P. N.; Forst, M. B.; Pierson, D. A.; Turpin,
J. A. Org. Process Res. Dev. 2007, 11, 546.
(12) (a) Park, K.-H.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem.
1998, 63, 113. (b) Park, K.-H.; Olmstead, M. M.; Kurth, M. J. J. Org.
Chem. 1998, 63, 6579.
(14) The rearrangement step did not scale up well: the yield dropped
to 27% when the same reaction was run with 6.5 mmol of epoxide. This is
consistent with the results of Varie (ref 11). In the interest of time, the
optimization of large-scale reaction conditions was postponed to a more
favorable juncture.
(15) The formation of 16 by deprotonation (LDA) and silylation
(TBS-Cl) proceeded cleanly, but in lower yield. Furthermore, our choice
of a TBS enol ether was motivated by results obtained with other dienes
related to 5 (ref 5). Briefly, a TBS group provides an ideal balance
between chemical stability and reactivity. Moreover, the action of
TESOTf and TIPSOTf on 15 afforded virtually only the cyclic product
17 and none of the desired 16.
(13) The major isomer was obtained in pure form upon chromato-
graphy; however, no stereochemical characterization was carried out at
this stage. The work Hodgson (ref 10) suggests that the major epoxide is
likely to have the syn relationship between oxiranyl and nitrogen
functions.
(16) Contact with silica induced considerable desilylation of the
sensitive diene.
Org. Lett., Vol. 13, No. 12, 2011
3275

Scheme 2. Facially Selective DielsÀAlder Reactions of Diene 16
Scheme 3. Anticipated Facial Selectivity in the DielsÀAlder
Reaction of Diene 22
N-anti face is readily accessible, seemed a good substrate
for an N-anti facially selective DielsÀAlder reaction.
The preparation of 22 commenced with LiBH4 reduc-
tion of 12, cyclization (NaH) of the resulting alcohol 24,
and in situ N-tosylation of the transient oxazolidinone
anion (Scheme 4). Compound 25 emerged in 47% isolated
yield over two steps.19 Epoxidation produced 26 as a single
diastereomer.17 We presume, on steric grounds, that the
epoxide was formed anti to the nitrogen functionality;
however, the configuration of 26 was not ascertained.
Contrary to the case of 13, the rearrangement of 26 to an
allylic alcohol was best carried out under Noyori
conditions.20 The resultant 27 was directly exposed to the
action of PCC, the acidic nature of which induced both
cleavage of the TMS ether and oxidation of the liberated
alcohol21 to afford 28 in 68% yield from 26.
to yield cycloadduct 19 as a single diastereomer17 (Scheme
2). The yield of purified (silica gel chromatography) 19 from
15 was 26% (62% from 16 as determined by 1H NMR). The
detection of strong dipolar coupling (2D-NOESY NMR)
between the BOC group hydrogens and the exo H’s, as well
as between the ethyl ester methylene H’s and the TBS group
hydrogens, implied that the reaction had occurred in an
endo mode and with complete N-syn facial selectivity.17 The
moderate yield of 19 proved to be a consequence of the
sensitivity of the anhydride unit to silica gel.18 Indeed, the
product obtained from the reaction of 16 with N-methyl-
maleimide, also formed as a single diastereomer,17 was
considerably more stable than 19, and it was isolated in
41% yield from 15 (92% from the 1:1 mixture of 16 and 17
as calculated by 1H NMR). Again, the structure of 20 was
assigned on the basis of NOESY spectroscopy, which
confirmed that the product had originated from an N-syn
facially selective endo-cycloaddition. The reaction of 16 with
diethyl acetylenedicarboxylate also afforded a single dia-
stereomer of the adduct17 (39% yield from 15 after silica gel
chromatography; 86% from the mixture of 16 and 17 by 1H
NMR). While an unequivocal stereochemical elucidation
was not carried out, it seems unlikely that the new dieno-
phile should have reacted with a faciality opposite that of
the others. Therefore, we presume that the product of
this reaction was 21: the resultant of an N-syn selective
cycloaddition.
Scheme 4. Preparation of Diene 22 and Facially Selective
DielsÀAlder Reaction Thereof
Having determined that 16 exhibits N-syn facial bias, we
sought to reverse such a preference. This could be done by
increasing the steric demand of the nitrogen functionality
while decreasing that of the ester group. Diene 22 (Scheme
3), wherein the arylsulfonyl residue bars approach of the
dienophile from the N-syn face of the molecule, while the
(19) The yield of 28 was substantially higher when cyclization and
tosyl protection were carried out in one pot, rather than as two distinct
steps (47% vs 25%).
(20) Murata, S.; Suzuki, M.; Noyori, R. J. Am. Chem. Soc. 1979, 101,
2738.
(21) Muzart, J. Synthesis 1993, 11.
(22) Enone 28 is only slightly soluble in organic solvents suitable for
the conduct of this step (CH2Cl2, THF, ether, EtOAc), which therefore
was carried out in dilute solution (ca. 0.02 M; some of 28 remained in
suspension even after sonication). Importantly, diene 22 required no
purification before use.
(17) Within the limits of 300 MHz 1H NMR spectroscopy.
(18) Chromatography on supports such as alumina or florisil af-
forded unacceptable levels of purification.
3276
Org. Lett., Vol. 13, No. 12, 2011

The subsequent enol silylation of 26 proceeded unevent-
fully,22 but diene 22displayed poor DielsÀAlder reactivity,
failing to combine even with freshly sublimed maleic
anhydride.23 Fortunately, acetylenedicarboxylic ester did
react with 22 (60 °C, neat)24 to give adduct 29 as a single
diastereomer17 (46% yield). Extensive NOESY-2D NMR
experiments confirmed 29 to be the product of an N-anti
facially selective DielsÀAlder reaction.
All the results presented herein are consistent with a
Cieplak-type25 rationale.26 A C-5 σCÀR bond (R = alkyl
or H) provides more efficient electron donation into the
incipient σ* orbitals associated with developing σCÀC bonds
relative to a C-5 σCÀZ bond (Z = COOMe, NH2, halogen;
Figure 2). This translates into a more efficient stabilization of
the transition state for a Z-syn DielsÀAlder reaction and
preferential formation of products arising from such a
topology with dienes 4 and 7. The lower electronegativity
of C relative to N makes a CÀC bond a more efficient
electron donor than a CÀN bond. Diene 16 thus favors
reaction through transition state 30, leading to products of
N-syn facially selective cycloaddition. Finally, steric effects force
diene 22 to react with N-anti faciality, a mode of reactivity
that is disfavored on Cieplak grounds. Moreover, as the
reaction proceeds, a decrease in the dihedral angle between
NÀC5ÀC1ÀC2 and NÀC5ÀC4ÀC3 engenders compres-
sion of the Ts group against the remainder of the cyclopen-
Figure 2. A Cieplak rationale for the observed results.
(23) Only silyl group release occurred during several such attempts,
regardless of temperature (rt to 60 °C), solvent (CH2Cl2 or benzene),
nature of the silyl ether (TMS, TES, TIPS), or whether a Lewis acid
(Me2AlCl) was utilized to promote the DielsÀAlder reaction, or a mild
base (K2CO3; destruction of adventitious acid) was introduced to
preserve the diene.
tadiene ring. Transition state 32 is thus destabilized both on
electronic and on steric grounds, resulting in a slow overall
rate. While it is indeed possible to override the inherent
stereoelectronic preferences of the diene through sterics, the
price for N-anti selectivity is a diminished reaction rate.
Knowledge of the inherent facial bias of the dienes described
herein is essential to the progress of research currently under-
way in our laboratory, and it could be of value in charting the
synthesis of diverse nitrogenous substances.
(24) No significant reaction occurred at room temperature (1H
NMR).
(25) Cieplak, A. S. Chem. Rev. 1999, 99, 1265.
(26) Review: (a) Mehta, G.; Uma, R. Acc. Chem. Res. 2000, 33, 278.
We note that despite the successful predictions that arise from a Cieplak
analysis, controversy exists in the literature concerning the origin of
facial selectivity in such DielsÀAlder reactions: (b) Anh, N. T. Tetra-
hedron 1973, 29, 3227. (c) Coxon, J. M.; McDonald, D. Q. Tetrahedron
Lett. 1992, 33, 651. (d) Inagaki, S.; Fujimoto, H.; Fukui, K. J. Am.
Chem. Soc. 1976, 98, 4054. (e) Ishida, M.; Aoyama, T.; Beniya, Y.;
Yamabe, S.; Kato, S.; Inagaki, S. Bull. Chem. Soc. Jpn. 1993, 66, 3430. (f)
Ishida, M.; Beniya, Y.; Inagaki, S.; Kato, S. J. Am. Chem. Soc. 1990, 112,
8980. (g) Kiri, S.; Odo, Y.; Omar, H. I.; Shimo, T.; Somekawa, K. Bull.
Chem. Soc. Jpn. 2004, 77, 1499. (h) Kolakowski, R. V.; Williams, L. J.
Nat. Chem. 2010, 2, 303. (i) Poirier, R. A.; Pye, C. C.; Xidos, J. D.;
Burnell, D. J. J. Org. Chem. 1995, 60, 2328. (j) Pye, C. C.; Xidos, J. D.;
Burnell, D. J.; Poirier, R. A. Can. J. Chem. 2003, 81, 14. (k) Xidos, J. D.;
Poirier, R. A.; Pye, C. C.; Burnell, D. J. J. Org. Chem. 1998, 63, 105. See
also refs 8 and 9.
Acknowledgment. We thank the University of British
Columbia, the Canada Research Chair Program, BCKDF,
CFI, NSERC, and CIHR for financial support.
Supporting Information Available. Experimental proce-
dures, characterization data, and NMR spectra (1H and
13C) of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 12, 2011
3277