Wednesday, November 9, 2005 Baran Group Meeting The Anomeric Effect Paul Krawczuk

Further Reading: G.R.J. Thatcher (ed.), The Anomeric Effect and Related Stereolectronic Effects. ACS Anomeric Effect Defined (IUPAC): Symposium Series #539, 1993. Review: Juaristi, E., Cuevas, G., Tetrahedron, 1992, 48(24), 5019-5087. Originally defined as the thermodynamic preference for polar groups bonded to C-1 (the anomeric carbon of a glycopyranosyl derivative) to take up an Historical Aspects of the Anomeric Effect axial position. First observed in 1955 by J.T. Edward and in 1958 by R.U. Lemieux.

O O Both were studying carbohydrate chemistry and noticed a preference for ~1.5 kcal alkoxy and acetyl groups to reside in the axial position. Edward proposed OR that the lone pairs on the ring oxygen were contributing to the effect. OR

-OR has an axial preferecne in a C1 substituted tetrahydropyran alkyl substituted cyclohexanes prefer equitorial orientation over axial R This effect is now considered to be a special case of a general preference R (the generalized anomeric effect) for gauche conformations about the bond C–Y in the system X–C–Y–C where X and Y are heteroatoms O having nonbonding electron pairs, commonly at least one of which alkyl substituted tetrahydropyrans O show this same preference is nitrogen, oxygen, sulfur or fluorine. R Y Y R X Electronegativites X H OH H OH of Relavant Atoms the anomeric carbon of the most H O H O abundant natural sugar, HO HO C 2.5 HO H HO OH S 2.5 D-glucopyranose, also prefers an H H OH OH R X R H N 3.0 equtorial orientation. H OH 36% : 64% H H O 3.5 I 2.5 ratio of preference gives us some R R Br 2.8 insight that something is different one gauche H two gauche X Cl 3.0 interaction interactions F 4.0

H OH H OH preferred by generalized H O H O anomeric effect conversion into a methyl ether at the HO HO anomeric carbon produces a different HO H HO OMe H H o o o result from the above OH OH !!G anomeric effect (stabilization) = " !G (heterocycle) - " !G (steric) H OMe 67% : 33% H H electronic steric Franck, R.W., Tetrahedron, 1983, 39, 3251. different from reigning cyclohexane factor factor conformational analysis model For the anomeric stabilization to effect the conformation at all it must H OAc H OAc be more stabalizing then the sum of all of the steric factors H O H O AcO AcO Linear Example: AcO H AcO OAc Me Me O H H O O O often referred to as the OAc OAc gauche effect H OAc 86% : 14% H H Me Me substitution with more electronegative groups changes the observed ratio to a greater extent H OAc H OAc H O H O H OMe H H AcO AcO AcO H AcO Cl H H OAc OAc Me Me H Cl 94% : 6% H H H OMe Baran Group Meeting The Anomeric Effect Paul Krawczuk

Further Evidence: Sovent also plays a role: Increase in anomeric stabilization associated with low solvent dipole 1.39 Å O O 1.43 Å O bond lenght: increased in the axial C-Cl bond (1.819Å) OMe O Cl e a versus the equatorial C-Cl bond (1.7181Å) OMe Cl Romers, C., et al. Topics Stereochem., 1969, 4, 39. Solvent Dipole % axial CCl4 2.2 83 benzene 2.3 82 CHCl a 3 4.7 71 O axial bond also observed to be longer then acetone 20.7 72 e MeOH 32.6 69 O equitorial bond in this constrained case MeCN 37.5 68 H2O 78.5 52

Lemieux, R.U., et al. Can. J. Chem. 1969, 47, 4427.

Most widely accepted explanation for the anomeric effect: Other Explanations:

hyperconjugation resonace form Dipole Stabilization: Opposing dipoles are stabalizing relative to aligned dipoles stabalizes axial conformation

O O O O O 2 OR 1 OR OR OR OR destabalizing dipole interaction observed bond length for bond 2 is shorter then typical O-C bond and longer for bond 1 Closer Examination of Orbitals: Electrostatic Repulsion: Decreased electrostatic interactions are favored

HOMO: non-bonding (nOxygen)

H OR H

O O OR H OR antiperiplanar destabalizing interaction of representation destabalizing interaction of electronegative atom gauche electronegative atom gauche OR with two lone pairs with only one lone pair LUMO: anti-bonding (!*C-O) This model is referd to as favored Antiperiplanar Lone Pair Hypothesis or ALPH stabalizing 2 electron interaction Net Anomeric Effect probably due to a combination of factors Baran Group Meeting The Anomeric Effect Paul Krawczuk

The Exo-Anomeric Effect: Effect is observed in tetrahydrothiopyran:

O Less significant contribution of anomeric effect with O same orbital overlap with S H tetrahydrothiopyran. However, since C-S bonds are longer H exocyclic oxygen observed as then C-C bonds 1,3-diaxial interactions are decreased and O stabalizing resonance form X as a result more axial isomer is seen then in the oxygen H O CH analogs 3 view O here minor contribution to overall resonance O relative to endo anomeric effect Effect is observed in dioxanes and dithianes:

also can be stabalizing with equitorial substituents O simple extention of the tetrahydropyran case however O now there are two oxygens that take part in the resonance structure O view O X here O O S dithianes show an even greater preference for axial H H S substituents due to greater relaxation of 1,3-diaxial O X interactions CH3 endo anomeric effect is the dominant stabalizing O interaction with axial substituents, the exo anomeric H effect is stronger with equitorial subsitutents Effect is very minimal with amine nitrogens:

Anomeric Effect=(exo-AEeq)-(exo-AEax+endo-AEax) O amine nitrogen not electronegative enough to produce a endo anomeric effect is absent in the equitorial conform so this term is zero NH2 significant anomeric effect on tetrahydropyran Praly, J. P., Lemieux, R.U., Can. J. Chem. 1987, 65, 213. Anomeric Effect of Radicals: Structures with N-C-X bonds where X is a strongly elcetronegative substitutent on piperadine are not stable so the effect cannot be studied on these systems H OAc H OAc H OAc H H O O Bu3Sn Bu3SnD AcO AcO H O Effects at sp2 centers: AcO H AcO H o AcO H -20 C H AcO H OAc OAc H R H X H OAc R O H D R R O increased barrier of rotation due to O Major Product O stabalizing interaction OAc H 98:2 H O H OAc AcO Bu3Sn AcO X H O R H OAc o AcO R O O H -20 C AcO R H H O R OAc O H H Giese, B., Dupuis, J., Tetrahedron Lett., 1983, 25, 1349. Baran Group Meeting The Anomeric Effect Paul Krawczuk

Spiroketals: found in many natural products reviews: Perron, F., Albizati, K.F. Chem.Rev. 1989, 89, 1617-1661 Brimble, M.A., Furkert, D.P. Current Organic Chemistry, 2003, 7, 1461-1484. Anomeric Control of Product Distribution: OH structural conformations that depend on the anomeric effect H PTSA (cat.) OH MeOH H OMe O cat. O stereochemistry? acid O O HO OH O H kinetic H pathway thermodynamic 1 anomeric effect pathway O O H H

HO O H O O H 2 anomeric effects O O no anomeric effects H H (most stable) (least stable) O O high energy twist-boat conformation required H for Bürgi-Dunitz angle

O O kinetic H a conditions H H O e H 100:0 1 anomeric effect O a e O thermodynamic O General considerations for spiroketal ring systems. H conditions H Actual outcome will also be dependent on substituents 45:55

G.R.J. Thatcher (ed.), The Anomeric Effect and Related Stereolectronic Effects. ACS Symposium Series #539, 1993.

The Reverse Anomeric Effect: Fact or Fiction? Preference for equatorial position with positively charged-electronegative substituents C. L. Perrin, Tetrahedron, 1995, 51, 11901.

highly debated in the literature O O -often the charged species studied are bulky and sterics have a greater contributioin NR3 -dipole interactions in equitorial state are not stabalizing (evidence for this model)

NR3 -no lone pair on axial subsituent to contribute to the exo-anomeric effect -the axial structure is weak (favored by elimination) and unlikely to exist, only the equitorial isomer is O preferred as a result O O O NR3 interesting exception: Me NR3 N N

Me Ratcliffe, A.J. Fraser-Reid, B. J .Chem. Soc. Perkin Trans. 1 1990, 747-750. Baran Group Meeting The Anomeric Effect Paul Krawczuk

Brief Sampling of Simple Spiroketal Natural Products:

Non-Anomeric spiroketal:

Agric. Biol. Chem., 1986. 50, 2693.

From: Perron, F., Albizati, K.F. Chem.Rev. 1989, 89, 1617-1661 Org. Lett., 2004, 6(21), 3849-3852. Baran Group Meeting The Anomeric Effect Paul Krawczuk

How can we use the anomeric effect? R=H Discaccharide from Apoptolidin: OH TESOTf R=TES SPh O Me OMe H H Me TBSO O Ph O OMe " < ! H H MeOH MeO Ph O OMe Me Me Me O O TEA TBSO OH O SF3N(Et)2 TBSO O OH OBn PhS SPh O MeO MeO 100% Me Ph H OTMS H PhS SnCl2 H O F Me OTMS MeOH SPh HCl OR OBn H H Ph O OMe bulky SPh groups used to discourage anomeric control of product anomeric control of axial OMe H Me Me O TBSO O Ra-Ni TBSO O SF3N(Et)2 MeO MeO O Danishefsky, S. Langer, M. J. Org. Chem. 1985, 50, 3674-3676. O 92% 100% PhS SPh O O Me Me Me Me (+)-Lepicidin A: R=TIPS OTES OBn OTES OH desired isomer HF, CH3CN ! R=H Me O NFmoc OR Me O TBSO O used in glycosylation OTIPS OAc MeO Et O O Me O Me Et O Et OMe Me O NFmoc O O H Me Me OMe O H Me H OMe O O Br Me ":! 15:1 OTES F + O H H O H H H , cat. Ph3CClO4 Ag-Zeolite O H H CH Cl 87% 2 2 Nicolaou, K.C. et. al. J. Am. Chem. Soc. 2001, 125, 15433-15442. 69% H H O H O OH 5% PdCl2 O Me Me R ":! 17:1 O O CO, MeOH OMe OMe H HO controlled by OMe OMe CuCl only " isomer OMe OMe OH OMe O COOMe anomeric effect 25oC, 25hrs OMe ":! 6:1 Pd anomeric effect gives undesired product 5% PdCl2 Evans, D. A.; Black W. C. J. Am. Chem. Soc. 1993,115, 4497-4513. CO, MeOH O H R CuCl COOMe >95 " isomer O OH OMe O OMe HO 25oC, 25hrs OH H OBn OBn Pd H H O 68% from ! anomer whereas: H O Cl BnO BnO BnO 64% from " anomer BnO NBS H H OBn 5% PdCl2 OBn O H RN O CO, MeOH H MeCN H CuCl O Cl OH o COOMe pure " and ! anomers used R=Ac 25 C, 25hrs Me NaOMe R=H 1:1

Ratcliffe, A.J. Fraser-Reid, B. J .Chem. Soc. Perkin Trans. 1 1990 747-750. Semmelhack, M.F., et al. Pure & Appl. Chem., 1990, 62(10), 2035-2040. Baran Group Meeting The Anomeric Effect Paul Krawczuk

Synthesis of Spirotekals: THPO Sequence 1: Azaspiracid: both forms show anomeric stabalization S OH OH t-BuLi S S S HgO, BF3•OEt2 THPO Br Br O O S CH2Cl2 89% S 40%

Sequence 2: THPO OR O O O LDA LiI, 2,6-lutidene 1) Li(CH2)4OTBS, 74% OR COOMe 2) POCl3, py I(CH2)4OTBS COOMe " 35% two steps 64% OH OH OR OR OR O3 PPTS O O PPh3 O O 58% 34% OR incorrect structure originally targeted and synthesized correct structure as compared to natural product O key spiroketal step: common 1.85:1 to 3.35:1 intermediate O O O O O depending on solvent O "trans" "cis" O TMSOTf S S 2 anomeric effects 4 anomeric effects S S ° major product strongly disfavored due O -90 C H to dipole repulsion OTES OTBDPS 89% O H HO O O H OTBDPS McGarvey, G.J., Stepanian, M.W. Tet. Lett., 1996, 37(31), 5461-5466. O O H O H O H Photochemical Cyclization: Nicolaou, K.C., et al. Angew. Chem. Int. Ed. 2004, 43, 4318-4324. 1,5 hydrogen abstraction Iodine(III) mediated radical cyclization to Spiroacetals: O HO OR O HO OTES O PhI(OAc)2 PhI(OAc)2 O O h! O O O O TBDPSO O TBDPSO I , h! I , h! a 2 O 2 OMe OMe OMe 90% O OMe O OH R=TES HF, py Norrish type II R=H O HO O HO " TBDPSO O * HO cat. HO spirolides B and D O O * O HO h! O Acid O OMe O O pTSA O OH OH O O 4 diastereomers 1 : 1 : 1 : 1 pTSA, CH2Cl2 O O O 3: 1 : 0.9 : 0 isomerize to anomerically Brimble, M. A. Molecules. 2004, 9, 394-404 Cottier, L.; Descotes, G. Tetrahedron 1985, 41(2), 409. stabalized isomer Baran Group Meeting The Anomeric Effect Paul Krawczuk

Examples of Spiroketal Tethering: Pauson-Khand

Olefin Metathesis O Co2(CO)8 O side reaction O Me NO O 3 O O ° undergoes O 100 C O OH O H slow elimination OAc 91% OAc O OTBDPS OH Grubbs Gen-1 O OTBDPS 10 mol % O [cis:trans] [95:< 5]

Tf2NH 95% O OTBDPS OMe OBn 89 % OMe OBn O Co2(CO)8 O side reaction O 100% ! OMe OBn Me3NO O O ° O undergoes O will be applied to the 100 C O synthesis of spirastrellolide A H facile elimination OAc 90% OAc Liu, J., Hsung, R. P., Org. Lett. 2005, 7(11), 2273-3376. anti Diels Alder [cis:trans] [< 5:95] OTBS 5 membered ring: TBSO OBn O axial HO Co (CO) 1) TBAF probable transition state O 2 8 O BnO OBn H O O O OBn 2) TBSCL, imidazole O two anomeric effects and OTBS PPTS OTBS 3) TPAP, NMO two chair conformations Me3NO H E ° CH2Cl2 OAc 100 C OAc O 66% three steps A O 79% 78% O O

1)LHMDS OBn anomeric control dominates stereochemical outcome even if substituent is forced into axial position TBSO OBn TBSO TBSO

OBn N OBn Co2(CO)8 O Co2(CO)8 O ZnCl2 O O O O O OBn O O R O O R 2) MeI O CH2Cl2 OBn Me3NO Me3NO O H O ° R ° R K2CO3 O o 100 C OAc 100 C OAc O -78 C-R.T. O O O AcO R=Me 63% AcO R=Me 49% R=Et 50% R=Et 40% only diastereomer finally able to force selectivity with bulky silyl group - sterics beat anomeric effect H R favored transition state R o H leading to product R O LA Co2(CO)8 O O equitorial o O H o o O O axial axial Me3NO H O ° OP o o 100 C OP OP endo-boat-boat 40% P=TES [cis:trans] [36:64] w/ two anomeric effects P=TBS [cis:trans] [10:90] P=TBDPS [cis:trans] [< 5:95]

Wang, J., Hsung, R. P., Ghosh, S.K. Org. Lett. 2005, 6(12), 1939-1942. Ghosh, S.K., Hsung, R.P., Liu, J. J. Am. Chem. Soc. 2005, 127, 8260-8261.