Using nucleophilic substitution reactions to understand how a remote alkyl or alkoxy substituent influences the conformation of eight-membered ring oxocarbenium ions

Article abstract of DOI:10.1021/ol047998d

(Chemical Equation Presented) A remote alkoxy substituent strongly stabilizes one particular conformer of an eight-membered ring oxocarbenium ion by a through-space electrostatic effect. X-ray crystallographic analysis of a crystalline derivative proves t

Full text of DOI:10.1021/ol047998d

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4739-4741
Using Nucleophilic Substitution
Reactions to Understand How a Remote
Alkyl or Alkoxy Substituent Influences
the Conformation of Eight-Membered
Ring Oxocarbenium Ions
Stephen Chamberland and K. A. Woerpel*
Department of Chemistry, UniVersity of California-IrVine,
IrVine, California 92697-2025
kwoerpel@uci.edu
Received September 30, 2004
ABSTRACT
A remote alkoxy substituent strongly stabilizes one particular conformer of an eight-membered ring oxocarbenium ion by a through-space
electrostatic effect. X-ray crystallographic analysis of a crystalline derivative proves that kinetically controlled nucleophilic substitution favors
the 1,4-trans product. Nucleophilic substitution of the corresponding alkyl-substituted acetate, however, is unselective. A computational model
has been developed and experimentally validated to predict the low-energy conformers of C3-, C4-, or C5-alkyl- or alkoxy-substituted eight-
membered ring oxocarbenium ions.
Many of the methods employed to synthesize the substituted
medium-ring ethers contained within cytotoxic natural
products such as the ladder ether toxins1 and Laurencia
metabolites2 rely on establishing stereochemistry prior to or
during cyclization. Selective introduction of a substituent to
a medium-ring oxocarbenium ion represents another powerful
method for preparing this class of compounds.2d The
stereoselectivities resulting from nucleophilic attack on
medium-ring oxocarbenium ions, however, are largely
undocumented,1a,2d in contrast to reactions of the more
common five- and six-membered ring systems.3 In this
communication, we provide a systematic study of the
influence of substituents on the selectivity of nucleophilic
additions to eight-membered ring oxocarbenium ions. We
demonstrate that steric effects alone are insufficient to obtain
high selectivity. In contrast, electronic effects exhibited by
remote alkoxy substituents in eight-membered rings can be
powerful forces for the control of ring conformation, and
therefore selectivity, mirroring results observed for five- and
six-membered rings.3
Selective nucleophilic addition to monosubstituted eight-
membered ring oxocarbenium ions4 can be complicated by
the presence of many accessible low-energy conformations
of these intermediates. Furthermore, the distribution of
(1) (a) Nicloaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am. Chem. Soc.
1989, 111, 4136-4137. (b) Crimmins, M. T.; Cleary, P. A. Heterocycles
2003, 61, 87-92 and references cited therein.
(2) (a) Paquette, L. A.; Sweeney, T. J. J. Org. Chem. 1990, 55, 1703-
1704. (b) Blumenkopf, T. A.; Bratz, M.; Castan˜eda, A.; Look, G. C.;
Overman, L. E.; Rodriguez, D.; Thompson, A. S. J. Am. Chem. Soc. 1990,
112, 4386-4399. (c) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.;
Bendall, J. G.; Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483-7498.
(d) For an example of nucleophilic addition to a C7-alkyl-substituted eight-
membered ring oxocarbenium ion, see: Rychnovsky, S. D.; Dahanukar,
V. H. J. Org. Chem. 1996, 61, 7648-7649. (e) Crimmins, M. T.; Choy, A.
L. J. Am. Chem. Soc. 1999, 121, 5653-5660 and references cited therein.
(3) (a) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.;
Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521-15528 and references
cited therein. (b) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K.
A. J. Am. Chem. Soc. 1999, 121, 12208-12209.
(4) Reactions of acetals with carbon nucleophiles likely proceed via
oxocarbenium ion intermediates: Sammakia, T.; Smith, R. S. J. Am. Chem.
Soc. 1994, 116, 7915-7916.
10.1021/ol047998d CCC: $27.50
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conformers cannot be predicted easily. Preference among the
conformers is crucial for achieving highly selective reactions
because nucleophilic attack should be slow relative to
conformer interconversion.2b,5,6 The unsubstituted intermedi-
ate exists as two low-energy conformations, boat-chair-2 (1)
and boat-chair-3 (2), which are comparable in energy
(Scheme 1).7-10 When a remote substituent is appended to
Scheme 2
Scheme 1
the ring, conformational control becomes even more com-
plex. Selectivity upon nucleophilic attack depends not only
on the preferred substituent orientation but also on the relative
contribution of 1, 2, and other possible conformers to the
overall energy profile.7b Each of these conformers should
undergo attack by nucleophiles from the periphery as
observed for electrophilic approach to medium- and large-
ring olefins.11
To elucidate the influence of remote substitution on
selectivity, we compared nucleophilic substitution reactions
of eight-membered ring oxocarbenium ion precursors bearing
a C3-, C4-, or C5-alkyl or alkoxy substituent.12,13 Nucleo-
philic addition to a C4-methyl-substituted eight-membered
ring oxocarbenium ion, generated upon treatment of acetate
3a with a Lewis acid, is unselective (Scheme 2).14-16 The
lowest energy conformers of this intermediate, 6 and 7, bear
a strong resemblance to the unsubstituted cations shown in
Scheme 1. Although the steric preference for a methyl
substituent to adopt a pseudoequatorial orientation seems to
dominate, conformers 6 and 7 should be similar in energy.10
As a consequence, selectivity is low because both di-
astereomeric faces of the oxocarbenium ion are presented
to the nucleophile.
A C4-alkoxy substituent, however, does control the
conformation of the charged intermediate.10 The C4-benzyl-
oxy-substituted acetate 3b afforded high 1,4-trans di-
astereoselectivity upon nucleophilic substitution (Scheme
2).14-16 This selectivity can be explained by a through-space
electrostatic attraction17,18 between the remote electronegative
substituent and C-19a that stabilizes conformer 8 (Scheme
(14) Mixtures of diastereomeric acetates (the syntheses of acetates are
contained in Supporting Information) were used in these reactions. Control
experiments indicate that diastereomeric acetates give the same product with
largely the same degree of selectivity. These control experiments strongly
suggest that the reaction operates by a dissociative mechanism. If direct
displacement occurred, the selectivity should reflect the initial acetate ratio.
(15) In all cases, diastereoselectivities were determined by GC or single-
scan 1H NMR spectra of unpurified reaction mixtures. The relative
stereochemistry of the major product was not proven for unselective
reactions (C4- and C5-methyl) but was postulated to be cis on the basis of
computational results (ref 10). For nitrile 4b, the relative stereochemistry
was proven by X-ray crystallography.
(16) Control experiments indicate that cyanide addition is irreversible,
so these reactions are kinetically controlled. These reactions require the
presence of Lewis acid, and the selectivity of product formation is
independent of the solvent (CH2Cl2, toluene, or Et2O) and Lewis acid
(EtAlCl2 or TiCl4) employed. A table of comparative selectivities appears
in Supporting Information.
(5) Cremer, D.; Gauss, J.; Childs, R. F.; Blackburn, C. J. Am. Chem.
Soc. 1985, 107, 2435-2441.
(6) Under certain conditions, solvent cage effects can exert strong
influences on the selective reactions of oxocarbenium ions: Zhang, Y.;
Reynolds, N. T.; Manju, K.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 9720-
9721.
(7) (a) Anet, F. A. L. In Conformational Analysis of Medium-Sized
Heterocycles; Glass, R. S., Ed.; VCH: New York, 1988, Chapter 2. (b)
Meyer, W. L.; Taylor, P. W.; Reed, S. A.; Leister, M. C.; Schneider, H.-J.;
Schmidt, G.; Evans, F. E.; Levine, R. A. J. Org. Chem. 1992, 57, 291-
298. (c) Yavari, I.; Tahmassebi, D.; Nori-Shargh, D.; Heydari, M. Monatsh.
Chem. 1996, 127, 1021-1025.
(8) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; pp 765-771.
(9) (a) Dudley, T. J.; Smoliakova, I. P.; Hoffmann, M. R. J. Org. Chem.
1999, 64, 1247-1253. (b) Liang, G.; Sorensen, J. B.; Whitmire, D.; Bowen,
J. P. J. Comput. Chem. 2000, 21, 329-339.
(17) (a) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc.
1992, 114, 859-864. (b) Miljkovic´, M.; Yeagley, D.; Deslongchamps, P.;
Dory, Y. L. J. Org. Chem. 1997, 62, 7597-7604. (c) Jensen, H.; Bols, M.
Org. Lett. 2003, 5, 3419-3421.
(10) Details of calculations are provided as Supporting Information.
(11) Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981-3996.
(12) Numbering in this paper considers the carbocationic carbon as C-1.
(13) For these reactions, a small nucleophile, trimethylsilyl cyanide
(Evans, D. A.; Carroll, G. L.; Truesdale, L. K. J. Org. Chem. 1974, 39,
914-917), was chosen to minimize steric effects in the transition state that
might perturb the inherent conformational preferences of the charged
intermediates. Lewis acid-mediated nucleophilic substitution of 10a and
15a with another small nucleophile, diethyl-2-phenylethynylalane, gave
selectivities comparable to those reactions using trimethylsilyl cyanide as
the nucleophile.
(18) The border between anchimeric assistance and electrostatics is not
a clear one. On the basis of B3LYP/6-31G* calculations, the oxygen of the
benzyloxy group and the carbocationic carbon are approximately 2.6 Å apart
in the optimized geometry of 8. Although this separation is less than the
van der Waals contact distance (3.2 Å, as found in: Bondi, A. J. Phys.
Chem. 1964, 68, 441-451), it is considerably greater than a standard
carbon-oxygen bond (1.4 Å) and longer than the bond distance in a trivalent
oxonium ion such as the Et3O cation (1.5 Å, as found in: Watkins, M. I.;
Ip, W. M.; Olah, G. A.; Bau, R. J. Am. Chem. Soc. 1982, 104, 2365-
2372). In addition, the C4-OBn bond and the C1dO+ bond are of standard
lengths (1.4 and 1.27 Å, respectively, ref 9b).
4740
Org. Lett., Vol. 6, No. 25, 2004

2).19,20 This counterintuitive interaction occurs despite the
inherent preference for substituents at this position to reside
outside the ring, avoiding transannular strain.11 Conformer
9 is higher in energy than 8 because the benzyloxy substituent
is too far away from the cationic carbon9a to stabilize this
conformer effectively. It is likely that nucleophilic addition
to 9 provides the minor 1,4-cis product 5b.
Scheme 4
The conformational preferences with substitution at C-5
resemble those observed when a C-4 substituent is present.
For example, nucleophilic substitution of acetate 10a afforded
a nearly equal ratio of diastereomeric products 11a and 12a
(Scheme 3). The presence of two low-energy conformers (13,
Scheme 3
distribution of conformers with alkyl substitution at C-3. The
1,3-cis isomer 17a is the major product of nucleophilic
substitution of acetate 15a, arising primarily from addition
to low-energy conformer 18 (Scheme 4). While a pseudoaxial
benzyloxy substituent at the 3-position likely stabilizes the
carbocation in conformers 19 and the pseudoaxial C3-alkoxy
analogue of conformer 2, the electrostatic attraction is
attenuated by the less than optimal geometry of the inter-
action.10 Nucleophilic addition to these conformers affords
the major 1,3-trans isomer 16b. Other low-energy conformers
of the charged intermediate contain a pseudoequatorial C-3
alkoxy substituent and provide the minor 1,3-cis isomer 17b
upon nucleophilic addition.
In conclusion, the strong electrostatic (alkoxy) or more
subtle steric (alkyl) effects exerted by remote substituents
in monosubstituted eight-membered ring oxocarbenium ions
govern the distributions of conformers in solution. These
distributions were predicted on the basis of a computational10
assessment of the low-energy conformers of these intermedi-
ates. Nucleophilic addition to these oxocarbenium ions
affords disubstituted oxocanes. Highly selective reactions
occur when a remote electronegative substituent can stabilize
one oxocarbenium ion conformer over all others prior to
nucleophilic attack.
and the C5-pseudoequatorial analogue of 6) again leads to
an unselective nucleophilic substitution reaction.10,18,19 A C5-
alkoxy-substituted eight-membered ring oxocarbenium ion
also exists as a mixture of conformers in which the remote
alkoxy group stabilizes the charged intermediate. Nucleo-
philic substitution reactions of C5-benzyloxy acetate 10b
mainly provided 1,5-trans product 11b (Scheme 3). Because
the energy difference among the three low-energy conformers
of the intermediate (only the lowest, 14, is shown) leading
to 11b or 12b is less than that between 8 and 9,10 the
trans:cis selectivity is reduced.
Alkyl or alkoxy substituents at C-3 do not exert significant
control for reactions of eight-membered ring oxocarbenium
ions. Conformers possessing a pseudoaxial or a pseudoequa-
torial substituent at a corner position of the eight-membered
ring are close in energy because the substituents experience
similar gauche-gauche interactions with the ring.7a,11 Be-
cause each conformer can react to give one of two diaster-
eomeric products, the overall selectivities for nucleophilic
substitution reactions of acetates 15a and 15b are modest
(Scheme 4). As before, steric preferences likely govern the
Acknowledgment. This research was supported by the
National Institutes of Health, National Institute of General
Medical Science (GM-61066), and by Johnson & Johnson.
K.A.W. thanks Johnson & Johnson and Merck Research
Laboratories for awards to support research. Dr. Joseph W.
Ziller is acknowledged for X-ray crystallographic analysis,
and Dr. John Greaves and Dr. John Mudd are acknowledged
for mass spectrometric data.
Supporting Information Available: Complete experi-
mental procedures and characterization data for new com-
pounds, details of control experiments and theoretical
experiments, stereochemical proofs, GC and spectral data
for selected compounds, and crystallographic data in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Theoretical experiments suggest that a bridged bicyclic oxonium
ion is the global minimum of this intermediate, but we do not believe that
this conformation can be used to explain the diastereoselectivity of this
reaction. Further explanation is provided within Supporting Information.
(20) An extreme example of transannular stabilization is seen for
µ-hydrido bridged carbocations. See: Ponec, R.; Yuzhakov, G.; Tantillo,
D. J. J. Org. Chem. 2004, 69, 2992-2996 and references cited therein.
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