Ladderanes: Uses and Synthesis icholas Anderson Denmark Group Meeting ctober 28, 2008
utline Ladderane types and classifications Potential applications of ladderanes Synthesis of ladderanes Ladderane natural products (C 2 ) 7 C 2 Me
Types of Ladderanes - Linear Length [2]-Ladderane [3]-Ladderane [4]-Ladderane Increasing the number of fused cyclobutanes increases the heat of formation by ~20-23kcal/mol per ring Stereochemistry cis, anti, cis Lowest energy cis, syn, cis cis, trans ighest energy ouri, D..; Tantillo, D. J. Curr. rg. Chem. 2006, 10, 2055-2074.
Types of Ladderanes - Cyclic amed based on Size [3]-Prismane [4]-Prismane (cubane) exa[4]prismane [5]-Prismane Israelane Currently these structures are curiosities. ouri, D..; Tantillo, D. J. Curr. rg. Chem. 2006, 10, 2055-2074.
Ladderanes - Molecular Spacers [10]-Ladderane 10σ binane [5]polynorbornane Warrener,..; Abbenante, G. J. Am. Chem. Soc. 1994, 116, 3645-3646.
Ladderanes - Molecular Spacers xamples of capping to yield end functionalized materials = C 2 Me + 1.! 2. DDQ = C 2 Me Possible applications to molecular electronics Warrener,..; Abbenante, G.; Kennard, C.. L. J. Am. Chem. Soc. 1994, 116, 3645-3646.
Synthesis of [2]-Ladderane First optimized synthesis (1963): + Ph! Ph Cl, 2 PtCl 6 ab 4, t 2 Alternative synthesis (1986): Ph 210 C 60% 35% Thermally stable! Cl K C 2 Cl g, Br 2 MgS 4 Cl Br n-buli Br Cl a 3 a 3 Griffin, C..; epfinger,. F.; Shapiro, B. L. J. Am. Chem. Soc. 1963, 85, 2683-2684. Wiberg, K. B.; et al. Tetrahedron, 1986, 42, 1895-1902.
Synthesis of a [5]-Ladderane Fe(C) 3 + ( 4 ) 2 Ce( 3 ) 6 h! 2, Pd/C Me = C 2 Me Synthesis of ladderanes has been accomplished Ladderanes are kinetically stable Cis-trans-cis isomers are typically obtained Martin,.-D.; ekman, M. Angew. Chem. Int. d. ngl. 1976, 15, 431-432.
igher rder Ladderanes Fe(C) 3 ( 4 ) 2 Ce( 3 ) 6 u 2 C(PAr 3 ) 3 = C 2 Me Ar = p-fc 6 4 ca. 60% (2 steps) [7]-Ladderane 2 Me AlCl Me 3 Me Fe(C) Me MeMeMeMeMeMeMeMeMeMe 5 Me Me Me AlCl 3 Me MeMeMeMeMeMeMeMeMeMe Formed a statistical mixture of up to [11]-Ladderane Me Me Warrener,..; Abbenante, G. J. Am. Chem. Soc. 1994, 116, 3645-3646. Marsella, M. J.; et al. Synlett 2004, 192-194.
ne Step Synthesis C 2 t C 2 t h!, t (10-3 M) 83% yield C 2 t C 2 t 2 h! solid state quantitative Isolated polyolefins have not yet been shown to form ladderanes opf,.; et al. ur. J. rg. Chem. 2005, 567-581. Friscic, T.; MacGillivray, L.. Supramol. Chem. 2005, 17, 47-51.
Ladderanes in atural Products Anammox bacteria Deep sea bacteria Capable of ammonia oxidation 4 + + 3 - nzymes 2 2 2 nzymes 2 Produce 2 2 and 2 ighly toxic intermediates Membrane permeable Ladderane lipids isolated from the bacteria (C 2 ) 7 C 2 Me (C 2 ) 7 C 2 Me Damsté, J. S. S.; et al. ature, 2002, 419, 708-712.
Ladderanes in atural Products Ladderane lipids form dense lipid bilayers Ladderane lipid bilayers: 1.5 kg/dm 3 ormal lipid bilayers: 1.2 kg/dm 3 Denser bilayers prevent diffusion of 2 2 and 2 Study of ladderane lipids is hindered by low availability ~3mg ladderane lipids per 45g of anammox bacteria Slow growth rate of bacteria 1 cell division every 2-3 weeks Damsté, J. S. S.; et al. ature, 2002, 419, 708-712. Damsté, J. S. S.; et al. FBS Journal, 2005, 4270-4283.
Pentacycloanammoxic Acid Synthesis (C 2 ) 7 C 2 Goals of Total Synthesis: Pentacycloanammoxic Acid Verify structure Determine absolute stereochemistry Provide a larger amount of material Potential Problems: ighly strained core 2 Very little functionalization 9 Contiguous stereocenters!! f = +19.6 kcal/mol Mascitti, V.; Corey,. J. J. Am. Chem. Soc. 2004. 126, 15664-15665.
Pentacycloanammoxic Acid Br 2, C 2 Cl 2-15 C Br Br acemic Synthesis Cbz Cbz Ph, 80 C 64% 2 steps Cbz Cbz Br Br 1. 2, Pt 2, a 2, t-tf, 23 C 2. Zn, Ac, 95 C 80%, 2 steps Cbz Cbz 1. h!, 2-cyclopenten-1-one, MeC, 23 C (40%) 2. 2, Pd/C, t, 23 C 3. 2, 23 C (76%, 2 steps) 1. C(Me) 3, p-tsa Me, 40 C (91%) 2. h!, MeC, 50 C 3. Ac- 2, 23 C 6%, 2 steps 1. C 2 t, Mea, Ph, 23 C 2. Ts 3, t 3, C 2 Cl 2, 23 C 80%, 2 steps 2 1. h!, Me, t 3, 23 C (72%) 2. DIBAL, PhMe, -78 C 3. Swern, 23 C 91%, 2 steps C Mascitti, V.; Corey,. J. J. Am. Chem. Soc. 2004. 126, 15664-15665.
Pentacycloanammoxic Acid acemic Synthesis C 1. LDA, BrPh 3 P(C 2 ) 6 C 2, TF, -78 to 23 C (67%) 2. 2 2, CuS 4, 2, 23 C aq. t, (88%) (C 2 ) 7 C 2 C 2 2, t 2 95% (C 2 ) 7 C 2 Me verall yield: 0.25% Successful structure confirmation Did not establish the absolute configuration Did not provide a convenient route to large quantities of material Mascitti, V.; Corey,. J. J. Am. Chem. Soc. 2004. 126, 15664-15665.
Pentacycloanammoxic Acid nantioenriched Synthesis + h!, MeC ca. -15 C 78% 1. amds, C 2 t, TF, -30 to 0 C 2. Ts 3, t 3, C 2 Cl 2, 2 C, 62% 2 steps 2 1. h!, Me, t 3, 23 C 2. Li, 2 -TF, 23 C 86%, 2 steps C 2 3/1 endo/exo 1. (CCl) 2, DMF C 2 Cl 2, 23 C 2. 1, BrCCl 3, DMAP, 75 C, 15min; h!, 10 C, 10 min 3. t-buk, DMS, 50 C 66% 3 steps S 1 a 2, h! MeC, 23 C 50% Ph(Me) 2 Si 1. amds, TF, -78 C then TMSCl, -78 to 0 C 2. BS, TF, -50 to 30 C 3. TBAF, TF, 23 C 53%, 3 steps Si(Me) 2 Ph 2 Mascitti, V.; Corey,. J. J. Am. Chem. Soc. 2006. 128, 3118-3119.
Pentacycloanammoxic Acid nantioenriched Synthesis ate, t 23 C, 79% 1. amds, C 2 t, TF, -30 to 0 C 2. Ts 3, t 3, C 2 Cl 2, 2 C, 62% 2 steps 2 1. h!, Me, t 3, 23 C 2. Li, 2 -TF, 23 C 86%, 2 steps C 2 1. DIBAL 2. Swern 3. t 3, 6 days 43% 7 steps C 1. LDA, BrPh 3 P(C 2 ) 6 C 2, TF, -78 to 23 C 2. 2 2, CuS 4, 2, 23 C aq. t, 78%, 2 steps (C 2 ) 7 C 2 C 2 2, t 2 99% (C 2 ) 7 C 2 Me Mascitti, V.; Corey,. J. J. Am. Chem. Soc. 2006. 128, 3118-3119.
Pentacycloanammoxic Acid nantioenriched Synthesis verall yield: 1.9%, 17 steps econfirms the molecular structure nantiopure product will allow determination of absolute stereochemistry of natural product 2, h! MeC, 23 C 50% Si(Me) 2 Ph Ph(Me) 2 Si Provides only a slightly more convenient route to the natural product Development of an asymmetric [2+2] cycloaddition 2 Mascitti, V.; Corey,. J. J. Am. Chem. Soc. 2006. 128, 3118-3119.
Conclusions Synthesis of small ladderanes is well developed Synthesis of larger ladderanes and prismanes is less well developed While ladderanes have a number of potential uses, they need to be further investigated The appearance of ladderane natural products is exciting and the recent development of a reasonable synthesis of the natural product should allow their continued investigation