text:
The present invention provides (i) a process for preparing a 2-deoxy-2-fluoro-2-methyl-D-ribonolactone derivative, (ii) conversion of the lactone to nucleosides with potent anti-HCV activity, and their analogues, and (iii) a method to prepare the anti-HCV nucleosides containing the 2-deoxy-2-fluoro-2-C-methyl-β-D-ribofuranosyl nucleosides from a preformed, preferably naturally-occurring, nucleoside.
1. A compound of the following formula:
wherein R3 and R5 can be independently H, CH3, benzyl, 4-methoxybenzyl, trityl, trialkylsilyl, t-butyldialkylsilyl, t-butyldiphenylsilyl, tetraisopropyldisilyl (TIPDS), tetrahydropyranyl (THP), methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), or acyl;
alternatively, R3 and R5 are linked through �SiR2�O�SiR2� or �SiR2�, wherein R is a lower alkyl.
2. A compound of
3. A compound of
4. A compound of
5. A compound of
6. A compound of
7. A compound of
8. A compound of
9. A compound of
10. A compound of
11. A compound of
12. A compound of
13. A compound of
14. A compound of
15. A compound of
wherein R is selected from among methyl, ethyl, n-propyl, and i-propyl.
16. A process for the preparation of the compound of
(a) reacting a compound of the formula, 39,
17. The process of
18. The process of
This patent application is a continuation of U.S. patent application Ser. No. 11/185,988, entitled �PREPARATION OF ALKYL-SUBSTITUTED 2-DEOXY-2-FLUORO-D-RIBOFURANOSYL PYRIMIDINES AND PURINES AND THEIR DERIVATIVES,� filed on Jul. 21, 2005 now abandoned and assigned to the same assignee as this application. The aforementioned patent application is expressly incorporated herein by reference.
The present invention provides (i) a process for preparing a 2-deoxy-2-fluoro-2-methyl-D-ribonolactone derivative, (ii) conversion of the lactone to nucleosides with potent anti-HCV activity, and their analogues, and (iii) a method to prepare the anti-HCV nucleosides containing the 2′-deoxy-2′-fluoro-2′-C-methyl-β-D-ribofuranosyl nucleosides from a preformed, preferably naturally-occurring, nucleoside.
In light of the fact that HCV infection has reached epidemic levels worldwide, and has tragic effects on the infected patients. Presently there is no universally effective treatment for this infection and the only drugs available for treatment of chronic hepatitis C are various forms of alpha interferon (IFN-α), either alone or in combination with ribavirin. However, the therapeutic value of these treatments has been compromised largely due to adverse effects, which highlights the need for development of additional options for treatment.
HCV is a small, enveloped virus in the Flaviviridae family, with a positive single-stranded RNA genome of �9.6 kb within the nucleocapsid. The genome contains a single open reading frame (ORF) encoding a polyprotein of just over 3,000 amino acids, which is cleaved to generate the mature structural and nonstructural viral proteins. ORF is flanked by 5′ and 3′ non-translated regions (NTRs) of a few hundred nucleotides in length, which are important for RNA translation and replication. The translated polyprotein contains the structural core (C) and envelope proteins (E1, E2, p7) at the N-terminus, followed by the nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B). The mature structural proteins are generated via cleavage by the host signal peptidase. The junction between NS2 and NS3 is autocatalytically cleaved by the NS2/NS3 protease, while the remaining four junctions are cleaved by the N-terminal serine protease domain of NS3 complexed with NS4A. The NS3 protein also contains the NTP-dependent helicase activity which unwinds duplex RNA during replication. The NS5B protein possesses RNA-dependent RNA polymerase (RDRP) activity, which is essential for viral replication. It is emphasized here that, unlike HBV or HIV, no DNA is involved in the replication of HCV.
U.S. patent application (Ser. No. 10/828,753) discloses that 1-(2-deoxy-2-fluoro-2-C-methyl-β-D-ribofuranosyl)cytosine (14) is a potent and selective anti-HCV agent. The original synthetic procedures (Schemes 1-3) are quite inefficient, with overall yields at or below 4% and are not amenable to large-scale.
What is needed is a novel and cost effective process for the synthesis of 2-C-alkyl-2-deoxy-2-substituted-D-ribopyranosyl nucleosides that have activity against HCV.
The present invention as disclosed herein relates to the composition and synthetic methods of compounds of general formulas [I] and [II],
In other aspects, the present invention provides methods to prepare nucleosides containing the 2-deoxy-2-fluoro-2-C-methyl-D-ribofuranosyl moiety of general structures of III and IV,
Still another aspect of the present invention are the novel lactone intermediates of formula V and processes for the preparation of the lactone intermediates as detailed below, including precursor ester intermediates as also detailed below.
Presently no preventive means against Flaviviridae, including hepatitis C virus (HCV), Dengue virus (DENV), West Nile virus (WNV) or Yellow Fever virus (YFV), infection is available. The only approved therapies are for treatment of HCV infection with alpha interferon alone or in combination with the nucleoside ribavirin, but the therapeutic value of these treatments has been compromised largely due to adverse effects. It was recently discovered that a group of nucleosides, including 2′-deoxy-2′-fluoro-2′-C-methylcytidine (14), exhibit potent and selective activity against replication of HCV in a replicon system. However, the difficulty of chemical synthesis of this and analogous nucleosides impedes further biophysical, biochemical, pharmacological evaluations mandatory for development of clinical drugs for treatment of Flaviviridae infection.
The present invention provides an efficient preparation of nucleosides containing the 2-deoxy-2-fluoro-2-C-methyl-D-ribofuranosyl moiety III and IV, through (i) synthesis of intermediate the 3,5-protected 2-deoxy-2-fluoro-2-C-methyl-D-ribono-γ-lactone of general structure V, (ii) conversion of V into purine and pyrimidine nucleosides of general structures of III and IV, and (iii) preparation of nucleosides of general structures of III and IV from preformed, preferably natural, nucleosides.
The term �independently� is used herein to indicate that the variable, which is independently applied, varies independently from application to application. Thus, in a compound such as RaXYRa, wherein Ra is �independently carbon or nitrogen�, both Ra can be carbon, both Ra can be nitrogen, or one Ra can be carbon and the other Ra nitrogen.
As used herein, the terms �enantiomerically pure� or �enantiomerically enriched� refers to a nucleoside composition that comprises at least approximately 95%, and preferably approximately 97%, 98%, 99% or 100% of a single enantiomer of that nucleoside.
As used herein, the term �substantially free of� or �substantially in the absence of� refers to a nucleoside composition that includes at least 85 or 90% by weight, preferably 95% to 98% by weight, and even more preferably 99% to 100% by weight, of the designated enantiomer of that nucleoside. In a preferred embodiment, in the methods and compounds of this invention, the compounds are substantially free of enantiomers.
The term �alkyl,� as used herein, unless otherwise specified, refers to a saturated straight or branched hydrocarbon chain of typically C1 to C10, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl, and the like. The term includes both substituted and unsubstituted alkyl groups. Alkyl groups can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate. One or more of the hydrogen atoms attached to carbon atom on alkyl may be replaces by one or more halogen atoms, e.g. fluorine or chlorine or both, such as trifluoromethyl, difluoromethyl, fluorochloromethyl, and the like. The hydrocarbon chain may also be interrupted by a heteroatom, such as N, O or S.
The term �lower alkyl,� as used herein, and unless otherwise specified, refers to a C1 to C4 saturated straight or branched alkyl group, including both substituted and unsubstituted forms as defined above. Unless otherwise specifically stated in this application, when alkyl is a suitable moiety, lower alkyl is preferred. Similarly, when alkyl or lower alkyl is a suitable moiety, unsubstituted alkyl or lower alkyl is preferred.
The term �cycloalkyl�, as used herein, unless otherwise specified, refers to a saturated hydrocarbon ring having 3-8 carbon atoms, preferably, 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group may also be substituted on the ring by and alkyl group, such as cyclopropylmethyl and the like.
The terms �alkylamino� or �arylamino� refer to an amino group that has one or two alkyl or aryl substituents, respectively.
The term �protected,� as used herein and unless otherwise defined, refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. Non-limiting examples include: C(O)-alkyl, C(O)Ph, C(O)aryl, CH3, CH2-alkyl, CH2-alkenyl, CH2Ph, CH2-aryl, CH2O-alkyl, CH2O-aryl, SO2-alkyl, SO2-aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).
The term �aryl,� as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl, and preferably phenyl. The term includes both substituted and unsubstituted moieties. The aryl group can be substituted with one or more substituents, including, but not limited to hydroxyl, halo, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T. W. Greene and P. G. M. Wuts, �Protective Groups in Organic Synthesis,� 3rd ed., John Wiley & Sons, 1999.
The terms �alkaryl� or �alkylaryl� refer to an alkyl group with an aryl substituent. The terms �aralkyl� or �arylalkyl� refer to an aryl group with an alkyl substituent, as for example, benzyl.
The term �halo,� as used herein, includes chloro, bromo, iodo and fluoro.
The term �acyl ester� or �O-linked ester� refers to a carboxylic acid ester of the formula C(O)R′ in which the non-carbonyl moiety of the ester group, R′, is a straight or branched alkyl, or cycloalkyl or lower alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as phenoxymethyl, aryl including phenyl optionally substituted with halogen (F, Cl, Br, I), C1 to C4 alkyl or C1 to C4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl. Aryl groups in the esters optimally include a phenyl group.
The term �acyl� refers to a group of the formula R″C(O)�, wherein R″ is a straight or branched alkyl, or cycloalkyl, amino acid, aryl including phenyl, alkylaryl, aralkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl optionally substituted with chloro, bromo, fluoro, iodo, C1 to C4 alkyl or C1 to C4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, aralkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl. Aryl groups in the esters optimally comprise a phenyl group. In particular, acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, cyclopropyl carboxy, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α-methoxy-α-trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl, tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl, 7H-dodeca-fluoroheptanoyl, 7-chlorododecafluoro-heptanoyl, 7-chloro-dodecafluoro-heptanoyl, 7H-dodecafluoroheptanoyl, 7H-dodeca-fluoroheptanoyl, nona-fluoro-3,6-dioxa-heptanoyl, nonafluoro-3,6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl, methyl 3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2-methoxy-benzoyl, 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-propionyl, omega-aminocapryl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentyl-propionyl, 1-benzene-carboxyl, O-acetylmandelyl, pivaloyl acetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl, 2,6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl, perfluorocyclohexyl carboxyl, 4-methylbenzoyl, chloromethyl isoxazolyl carbonyl, perfluorocyclohexyl carboxyl, crotonyl, 1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinecarbonyl, 4-phenylbenzoyl. When the term acyl is used, it is meant to be a specific and independent disclosure of acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, diphenylacetyl, ct-trifluoromethyl-phenylacetyl, bromoacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, 2-thiopheneacetyl, tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl, methoxybenzoyl, 2-bromo-propionyl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentyl-propionyl, 1-benzene-carboxyl, pivaloyl acetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl, 2,6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl, 4-methylbenzoyl, crotonyl, 1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl, 4-phenylbenzoyl.
The term �lower acyl� refers to an acyl group in which R″, above defined, is lower alkyl.
The term �purine� or �pyrimidine� base includes, but is not limited to, adenine, N6-alkylpurines, N6-acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N6-benzylpurine, N6-halopurine, N6-vinylpurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-allcylaminopurine, N6-thioallcyl purine, N2-alkylpurines, N2-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C5-alkylpyrimidines, C5-benzylpyrimidines, C5-halopyrimidines, C5-vinylpyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-iodopyrimidine, C6-Iodo-pyrimidine, C5�Br-vinyl pyrimidine, C6�Br-vinyl pyriniidine, C5-nitropyrimidine, C5-amino-pyrimidine, N2-alkylpurines, N2-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
The term �amino acid� includes naturally occurring and synthetic α, β, γ or δ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In a preferred embodiment, the amino acid is in the L-configuration. Alternatively, the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl or β-histidinyl. When the term amino acid is used, it is considered to be a specific and independent disclosure of each of the esters of α, β γ or δ glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine in the
The term �pharmaceutically acceptable salt or prodrug� is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of a compound which, upon administration to a patient, provides the active compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art. Pharmaceutically acceptable salts may also be acid addition salts when formed with a nitrogen atom. Such salts are derived from pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, sulfuric, phosphoric, acetic, citric, tartaric, and the like. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
Wittig reaction of 2,3-O-isopropylidene-D-glyceraldehyde 39 (Scheme 4) with commercially available 40 affords the (E)-product 41 as a major product. Sharpless dihydroxylation (J. Org. Chem. 1992, 57, 2768-2771) using AD-mix-β as a dihydroxylation reagent gives only the desired product 42 in very high yield. High yield lactonization of 42 to 2-C-methyl-D-arabino-γ-lactone (46) is achieved by HCl/MeOH treatment. Selective O-benzoylation of primary and secondary OH groups yields 3,5-di-O-benzol derivative 47 in high yield. Treatment of 47 with DAST or Deoxofluor, [bis(2-methoxyethyl)amino]sulfur trifluoride, under various conditions gives trace amounts of the desired 2′-fluoro-ribono-γ-lactone 49, but mostly a mixture from which the non-fluorinated ribonolactone (48) is isolated. However, treatment of 47 with excess, preferably three (3) equivalents, of tertiary amine, preferably diisopropylethylamine, and excess, preferably five (5) equivalents, of DAST or Deoxofluor provides 49 in �50% yield. It was also found that using 3,5-O-MOM instead of benzoyl protection, the yield of 48 approaches 90%. Thus, treatment of 46 with dimethoxymethane in the presence of strong acid such as trifluoromethylsulfonic acid affords 50, which upon reaction with DAST or Deoxofluor in the presence of base yielded 87% isolated yield of 49.
It was also discovered that smooth fluorination can occur upon treatment of the open-chain monobenzoate 43, which can be readily obtained by selective benzoylation of 42, with DAST or Deoxofluor giving rise to the desired ethyl 2-deoxy-2-fluoro-2-C-methyl-3-O-benzoyl-4,5-O-isopropylidene-D-ribonate 44. Lactonization of 44 gives only the γ-lactone 45. Further benzoylation of 45 affords dibenzoate 49.
In one embodiment of the present invention, a method is provided for the synthesis of intermediate 49 through Reformatsky condensation of 39 with an alkyl 2-bromopropionate such as 53 (Scheme 5) in the presence of activated zinc in an ethereal solvent such as diethyl ether or tetrahydrofuran (or a mixture of the two solvents) to give 54, which is converted to 55 by oxidation. Possible oxidizing agents are: activated dimethylsulfoxide, such as a mixture of dimethylsulfoxide, trifluoroacetic anhydride or acetic anhydride (a Swern/Moffat oxidation); chromium trioxide or other chromate reagent; Dess-Martin periodinane; or tetrapropylammonium perruthenate (TPAP) with or without molecular sieves. This oxidation to provide the C-3 ketone preferably proceeds without affecting the stereochemistry at C-4.
Fluorination of 55 is performed at the 2-position using an electrophilic fluorination (�F+�) in an appropriate solvent such as dimethylformamide, tetrahydrofuran, ethanol, tert-butanol, or diethyl ether or any combination of these solvents known to those skilled in the art (Rozen, et. al., J. Org. Chem., 2001, 66, 7646-7468; Jun-An Ma and Dominique Cahard, Journal of Fluorine Chemistry, 2004, in press, and references cited therein), to afford 56. Some non-limiting examples of electrophilic fluorinating reagents are Selectflour�, N-fluorosulfonimide (NFSI), and AcOF. Stereoselective fluorination can be achieved by using a catalyst such as an asymmetric transition metal complex catalyst as taught by Sodeoka, et al. (JP2004010555) or by other catalysts. The starting β-keto ester 55 may also be first converted to a ketene silyl acetal prior to fluorination (Rozen, et. al., J Org. Chem., 2001, 66, 7646-7468).
Selective reduction of the C-3 ketone 56 using triphenylsilane in the presence of a Lewis acid such as AlCl3 or in the presence of an organic acid such as trifluoroacetic acid (Kitazume, et al., J. Org. Chem., 1987, 52, 3218-3223) provides two 2,3 anti products 57 and 58. However, by utilizing a stereoselective fluorination combined with the selective reduction, a good yield (with high diastereomeric excess) of 58 can be achieved. Benzoylation of 58 gives 44 which is converted to lactone 45 as described earlier.
A lactone such as 49 can be reduced to the corresponding lactol with DIBAL-H. After acetylation of the anomeric hydroxyl group, 59 (Scheme 6) is obtained in high yield. Condensation of 59 with silylated base (e.g., silylated N4-benzoylcytosine under Vorbr�ggen's conditions) affords a mixture of protected anomeric nucleosides 60 and 60-α. After separation of the anomers, the desired β-nucleoside 14 is prepared by deprotection with metal alcoholate in alcohol, preferably NaOMe/MeOH, or methanolic ammonia.
Compound 59 can be converted into the bromo sugar 61, (Scheme 7) which is condensed with a sodium salt of purine, e.g., sodio-N6-benzoyladenine to give the corresponding protected purine nucleoside 62. The desired free nucleoside 63 is readily obtainable by saponification.
Using preformed nucleosides as starting materials for preparation of the desired 2′-C-alkyl-2′-deoxy-2′-fluoro-β-D-ribonucleosides has certain advantages, as the formation of anomers and their subsequent separation can be circumvented, resulting in high yields of the targeted nucleosides.
Two procedures to prepare the desired nucleoside 14 from nucleoside starting materials have been disclosed (Schemes 2 and 3). As mentioned earlier, however, these procedures also produced two undesirable products 22 and 23, the latter produced by neighboring group participation as shown in Scheme 8. The separation of the desired nucleoside 14 from the mixture is rather cumbersome. Thus, this invention prevents production of 23 using non-participating protecting group, such as THP, methyl, ethyl, benzyl, p-methoxybenzyl-, benzyloxymethyl, phenoxymethyl, methoxymethyl, ethoxymethyl, mesyl, tosyl, trifluoroacetyl, trichloroacetyl, at the 3′-OH group.
An example is shown in Scheme 9. When N4,5′-O-dibenzoyl-3′-O-mesyl-2′-deoxy-2′-C-methyl-β-D-arabinofuranosylcytosine (64) is treated with DAST or Deoxofluor, the desired fluorinated product 65 is obtained in 54% yield along with the olefin 66 in 39% yield. As expected, no unfluorinated cytidine derivative 67 is formed in detectable amounts. There are several ways to de-protect 65 to 14. An example is shown in Scheme 9 that requires a double inversion of the 3′-configuration.
When the 3′-O-substituent is a non-participating and non-leaving group, such as methoxymethyl (MOM), methyl, benzyl, methoxybenzyl or tetrahydropyranyl, the intermediate is fluorinated more effectively than 64.
The following examples are presented to illustrate the present invention but are not to be limited thereto.
Experimental: 2,3-O-Isopropylidene-D-glyceraldehyde (39) is prepared by literature procedures (Organic Synthesis, Annual Volume 72, page 6; J. Org. Chem. 1991, 56, 4056-4058) starting from commercially available protected D-mannitol. Other reagents, including 40 and AD-mix-β, are from commercial sources.
To a solution of (carbethoxyethylidene)triphenylphosphorane (40, 25 g, 69 mmol) in dry CH2Cl2 (65 mL) at room temperature is added dropwise a solution of 2,3-O-isopropylidene-D-glyceraldehyde (39, 9.41 g, 72.3 mmol) in CH2Cl2 (30 mL). The mixture is stirred at room temperature overnight. The reaction mixture is then concentrated to dryness, diluted with light petroleum ether (300 mL), and kept at room temperature for 2 h. Triphenylphosphine oxide precipitated is removed by filtration and an aliquot is concentrated in vacuo. The residue is purified by silica gel column chromatography with 0-1.5% EtOAc in hexanes to give 41 (10.4 g, 71%) as an oil (Carbohydrate Res., 115, 250-253 (1983)). 1H NMR (CDCl3) δ 1.30 (t, J=6.8 Hz, 3H, �OCH2 CH3 , 1.41 (, s, 3H, CH3), 1.45 (,s, 3H, CH3), 1.89 (d, J=1.2 Hz, 3H, 2-CH3), 3.63 (t, J=8.0 Hz, 1H, H-5), 4.14-4.23 (m, 3H, H-5′ and �OCH2 CH3), 4.86 (dd, J=7.6 and 13.6 Hz, 1H, H-4), 6.69 (dd, J=1.6 and 8.0 Hz, 1H, H-3),
A round-bottomed flask, equipped with a magnetic stirrer, is charged with 25 mL of t-BuOH, 25 mL of water, and 7.0 g of AD-mix-β. Stirring at room temperature produced two clear phases; the lower aqueous phase appears bright yellow. Methanesulfonamide (475 mg) is added at this point. The mixture is cooled to 0� C. whereupon some of the dissolved salts precipitated, 1.07 g (5 mmol) of 41 is added at once, and the heterogeneous slurry is stirred vigorously at 0� C. for 24 h. After this time, while the mixture is stirred at 0� C., solid sodium sulfite (7.5 g) is added and the mixture allowed to warm to room temperature and stirred for 30-60 min. EtOAc (50 mL) is added to the reaction mixture, and after separation of the layers, the aqueous phase is further extracted with EtOAc. The organic layer is dried over Na2SO4 and concentrated to dryness. The residue is purified by silica gel column chromatography with 20% EtOAc in hexanes to provide 42 (1.13 g, 91%) as a solid. 1H NMR (DMSO-d6) □ 1.18 (t, J=6.8 Hz, 3H, �OCH2 CH3 , 1.24 (, s, 3H, CH3), 1.25 (, s, 3H, CH3), 1.28 (s, 3H, 2-CH3), 3.67 (t, J=7.2 Hz, 1H), 3.85, 4.06 and 4.12 (m, 4H), 4.96 (s, 1H, 2�OH, D2O exchangeable), 5.14 (d, J=7.6 Hz, 2-OH, D2O exchangeable). Anal. Calcd for C11H20O6: C, 53.22; H, 8.12. Found: C, 53.32; H, 8.18.
To a solution of compound 42 (245 mg, 0.99 mmol) in dry pyridine (3 mL) is added dropwise a solution of BzCl (300 mg, 2.1 mmol) in pyridine (1 mL). After the mixture is stirred at room temperature for 2 h, the reaction is quenched with H2O (1 mL). The mixture is concentrated to dryness and the residue is partitioned between CH2Cl2 and sat. NaHCO3 solution. The organic phase is dried (anh. Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography with 5% EtOAc in hexanes to give 43 (247 mg, 71%) as a solid. Anal. Calcd for C18H24O7: C, 61.35; H, 6.86. Found: C, 60.95; H, 6.73.
To a solution of compound 43 (36 mg, 0.102 mmol) in anhydrous THF (1.5 mL) is added DAST or Deoxofluor (0.08 mL, 0.68 mmol) at 0� C. under argon. The reaction mixture is stirred at room temperature for 3 h, then cooled down to 0� C., and carefully treated with cold saturated NaHCO3 solution (2 mL). The organic layer is dried over Na2SO4 and concentrated to dryness. The residue is purified by silica gel column chromatography with 1-3% EtOAc in hexanes to give 44 (24.6 mg, 68%) as a syrup. HR-FAB MS; Obsd: m/z 361.1621. Calcd for C18H23O6FLi: m/z 361.1639 (M+H)+.
A mixture of compound 44 (308 mg, 0.86 mmol), MeCN (20 mL), water (1 mL) and CF3CO2H (0.17 mL) is refluxed at 80-85� C. for 3 h. The open-chain intermediate is not isolated, but converted directly to 45 by azeotropic distillation using a Dean-Stark water separator. The removed MeCN is replaced with dry toluene, and the azeotropic distillation continued until the oil bath temperature reached 130� C. Stirring at 130� C. is continued overnight. The mixture is then cooled to room temperature and the solvent is removed in vacuo to give a syrup, which is purified by silica gel column chromatography with 10-15% EtOAc in hexanes to give, after solvents evaporation, solid 45 (136 mg, 58.3%).
To a solution of 45 (60 mg, 0.224 mmol) in EtOAc (1 mL) are added pyridine (100 mg, 1.26 mmol) and 4-dimethylaminopyridine (2.7 mg). The mixture is warmed to 60� C. and BzCl (110 mg, 0.79 mmol) in EtOAc (0.4 mL) is added dropwise. After stirring for 3 h, the mixture is cooled to 0� C. and pyridine HCl salt is filtered off. The filtrate is diluted with EtOH and the mixture is evaporated to dryness. The residue is purified by silica gel column chromatography with 3-6% EtOAc in hexanes to provide, after solvents evaporation, solid 49 (75 mg, 91%).
A solution of compound 42 (248 mg, 1 mmol) in 1.5 mL of EtOH is treated with 0.3 mL of concentrated HCl. The reaction mixture is stirred at room temperature for 2 h. The solvent is removed in vacuo (bath temp. <45� C.). The residue is co-evaporated with toluene (3�10 mL) to give a residue, which is purified by silica gel column chromatography with 70% EtOAc in hexanes. Evaporation of solvents give oily 46 (170 mg, 105%). Anal. Calcd for C6H10O5: C, 41.24; H, 6.22. Found: C, 41.00; H, 6.74.
To a stirred solution of compound 46 (880 mg, 5.4 mmol) in dry pyridine (80 mL) is added dropwise a solution of BzCl (1.73 g, 12.29 mmol) in dry pyridine (45 mL) at room temperature over a period 75 min. The mixture is stirred for another 90 min, then treated with MeOH (5 mL), and concentrated to dryness. The residue is purified by silica gel column chromatography with 12-20% EtOAc in hexanes to give 47 (1.1 g, 55%) as an oil.
To a solution of 47 (430 mg, 1.16 mmol) in anhydrous THF (20 mL) and diisopropylethylamine (1 mL, 5.74 mmol) is added DAST or DEOXOFLUOR (0.48 mL, 3.66 mmol) at room temperature under argon. The reaction mixture is stirred at room temperature for 3 h, then cooled down to 0� C., and carefully treated with cold saturated NaHCO3 solution (5 mL). The reaction mixture is partitioned between EtOAc (100 mL) and water (20 mL). The organic layer is dried over (Na2SO4) and concentrated to dryness. The residue is purified by silica gel column chromatography with 3-6% EtOAc in hexanes to provide 49 (220 mg, 51%) as a solid.
To a solution of 47 (160 mg, 0.432 mmol) in anhydrous CH2Cl2 (5 mL) is added DAST or DEOXOFLUOR (0.15 mL, 1.14 mmol) at 0-5� C. under argon. The reaction mixture is stirred at 0-5� C. for 1 h then at room temperature. After 24 hrs, the reaction still does not go well as there is no major less polar product appears in the TLCs. The reaction mixture is cooled to 0� C., and carefully treated with cold saturated NaHCO3 solution. The organic layer is dried over Na2SO4 and concentrated to dryness. The residue is checked by proton NMR. It shows that the major product is 3,5-dibenzoyl-2-methyl-D-ribono-γ-lactone (48), which is identical with authentic sample. Traces of 49 are detected on the spectrum.
To a solution of 2-methylarabinolactone (46) (324 mg, 2 mmol) in CH2(OMe)2 (30 mL) and CH2Cl2 (30 mL) was added CF3SO3H (50 μL), and the solution was stirred at RT under argon for 14 h. The reaction was quenched by addition of 28% NH4OH (0.1 mL), and the mixture was dried by addition of Na2SO4. After removal of the solvent by evaporation, the residue was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (95:5 to 9:1) to give 450 mg (90%) of product as a pale yellow oil. 1H-NMR (DMSO-d6): 6.10 (s, OH, D2O exchangeable), 4.70 (q, 2H, CH2), 4.62 (d, 2H, CH2), 4.30 (m, 1H, H-4), 4.20 (d, 1H, H-3), 3.80-3.65 (m, 2H, H-5), 3.30, 3.28 (2s, 6H, 2 CH3), 1.26 (s, 3H, CH3).
To a solution of 50 (100 mg, 0.4 mmol) in CH2Cl2 (3 mL) and pyridine (0.5 mL) at −78� C. is added DAST or DEOXOFLUOR (0.21 mL, 1.6 mmol), and the solution is stirred at −78� C. for 15 min. Then the solution is allowed to warm up to room temperature and stirred at room temperature for 2 h. The reaction is quenched by addition of saturated aqueous NaHCO3 (0.5 mL) and ice-water (0.5 mL), followed by CH2Cl2 (20 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous layer is extracted with CH2Cl2 twice, the combined organic layers are washed with NaHCO3, and dried over Na2SO4. The evaporation of the solvent gives 51 (88 mg, 87%) as a brownish-yellow oil. 1H-NMR (DMSO-d6): 4.74 (q, J=6.9 & 18.1 Hz, 2H, CH2), 4.63 (d, J=0.77 Hz, 2H, CH2), 4.54 (m, 1H, H-4), 4.18 (dd, J=7.8 & 20.0 Hz, 1H, H-3), 3.86-3.71 (m, 2H, H-5), 3.34, 3.28 (2s, 6H, 2 CH3), 1.59 (d, J=24.26 Hz, 3H, CH3).
To activated zinc (6.5 g, 0.10 mmol) is added about 20 mL of a solution containing 39 (13.0 g, 0.1 mmol), 53 (13.0 mL, 0.10 mmol), THF (50 mL), and diethyl ether (50 mL). After the addition, one crystal of 12 is added, whereby an exotherm is generated, causing the solution to reflux. The remaining solution is added over about 0.75 h as to maintain a gentle reflux. The mixture is gently heated to reflux for an additional 1 h after the final addition. The mixture is cooled to room temp, poured into ice (200 mL) and 1 N HCl (200 mL) and allowed to stir until most of the ice had melted (about 0.5 h). The organic layer is separated and the aqueous layer is extracted with diethyl ether (2�75 mL). The combined organic layers are washed with satd NaHCO3 (1�150 mL), brine (1�150 mL), dried (Na2SO4), filtered, and concentrated to dryness in vacuo. Further drying in vacuo provides 54 as a mixture of diastereomers (15.1 g, 65.1%). This compound is used without further purification.
Compound 54 (9.85 g, 0.042 mol) is dissolved in dry THF (50 mL). Anhydrous DMSO (16.0 mL, 0.22 mol) is added and the resulting solution is cooled to between −20� C. and −15� C. Trifluoroacetic anhydride (9.8 mL, 0.69 mol) is added dropwise over 15 minutes and the solution is stirred between −20� C. and −15� C. for 2 h after which anhydrous NEt3 (24.0 mL, 0.17 mol) is added over 20 min. The resulting solution is stirred at room temp for 1 h, diluted with diethyl ether (50 mL), and washed with H2O (3�100 mL), dried (Na2SO4) and concentrate in vacuo to compound 55 as a yellow oil (8.1 g, 82.0%) that is used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.24-1.38 (m, 26H), 3.81 (q, 1.3; H, J=7.3 Hz), 3.89 (q, 1.0H, J=7.3 Hz), 3.99-4.04 (m, 3H), 4.10-4.20 (m, 7H), 4.21-4.29 (m, 3H), 4.51 (dd, 1.0H, J=8.1, 6.2 Hz), 4.58 (dd, 1.3H, J=7.7, 5.0 Hz).
Compound 55 (7.36 g, 0.042 mol) is dissolved in anhydrous DMF (5.0 mL) and treated with a slurry of Selectfluor (55.0 g, 0.155 mol) in DMF (45.0 mL). The mixture is placed in an oil bath maintained at 45-50� C. and the suspension is maintained with stirring at that temperature overnight under an argon atmosphere. The solution is concentrated to near dryness in vacuo, treated with diethyl ether (�25 mL) and washed with water (3�100 mL). The organic phase is dried (Na2SO4) and concentrate in vacuo to compound 56 as a yellow oil (5.65 g, 71.2%) that was an approximate 1:1 mixture of 2R:2S fluorinated compound as judged by 19F NMR. 1H NMR (CDCl3, 400 MHz): δ 1.20-1.46 (m, 16H), 1.70 (2d, 3H, J=22.8 Hz), 4.05-4.10 (m, 2H,), 4.12-4.32 (m, 2H,), 4.90-97 (m, 1H). 19F NMR (CDCl3, 376 MHz, C6F6 external standard): δ 4.30 (q), 4.01 (q).
To a solution of 42 (4 mmol, 897 mg) in EtOH (20 mL) was added concentrated HCl (2.0 mL), and the solution stirred at room temperature for 1 h. The solution was concentrated to dryness and the residue was co-evaporated with THF (10 mL) and dissolved in pyridine (6 mL) and CH2Cl2 (14 mL). The solution was cooled in ice-bath. To the solution was added pivaloyl chloride (8 mmol, 0.98 mL) and the solution stirred at 0� C. for 30 min. To the solution was added an additional pivaloyl chloride (4 mmol, 0.49 mL) and the solution stirred at room temperature for 5 h. To the solution was added 4-dimethylaminopyridine (100 mg) and the solution was stirred at room temperature for 20 h. H2O (5 mL) was added and the mixture was stirred at room temperature for 20 min. EtOAc (50 mL) was added. The mixture was washed with water, brine and dried (Na2SO4). Solvent was removed and the residue was recrystallized from EtOAc-Hexanes to give fine crystals (625 mg, 47%). H-NMR (CDCl3): δ 5.18 (d, J=6.80 Hz, 1H, H-3), 4.45, 4.22 (m, 2H, H-5), 4.41 (m, 1H, H-4), 3.32 (br s, 1H, OH, D2O exchangeable), 1.43 (s, 1H, Me), 1.25, 1.22 [ss, 18H, C(Me)3].
To a solution of 47B (100 mg, 0.3 mmol) in THF (5 mL) were added EtNPr2 (2 mmol, 0.35 mL) and Deoxo-Fluor (0.18 mL, 0.9 mmol), and the solution was stirred at room temperature for 4 h. To the solution was added additional Deoxo-Fluor (0.18 mL, 0.9 mmol) and the solution was stirred at room temperature for 16 h, refluxed for 1 h. EtOAc (50 mL) was added. The solution was washed with aqueous NaHCO3, brine, dried (Na2SO4). Solvent was removed and the residue was purified by column (10% EtOAc in hexanes) to give product as a solid (65 mg, 65%). H-NMR (CDCl3): δ 5.12 (m, 1H, H-3), 4.68 (m, 1H, H-4), 4.41, 4.18 (mm, 2H, H-5), 1.63 (d, J=23.2Hz, 1H, Me), 1.25, 1.20 [ss, 18H, C(Me)3].
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Bur Oak Planting Problems (Too much water?)
Hi, this is my first time posting here, so keep in mind I'm a noob.
Last Saturday (5/5/12) I planted a 5" caliper, 18-20' tall Bur Oak in my back yard. It was B&B and had been out of the ground for close to a month. The root ball was 50" across and 3' deep, tapered.
It has been just over a week since I planted the tree, and now I am worried that something is wrong. The leaves are all turning brown and shriveling. We have had a crazy amount of rain since I planted it, not to mention I watered it like crazy the day that I planted it. Would this be as a result of too much water?
This is my first time planting a tree, so I really have no clue. I definitely don't want it to die, so please help.
I have posted pictures here: http://www.flickr.com/photos/20807577@N07/sets/72157629707692920/
If there is a way to post them here, let me know. Thanks!
Here is a link that might be useful: Pictures
Hey Daniel,
I haven't myself planted a tree that large, but I suspect that your tree is suffering from transplant shock. I am providing a link to a a Mr. Smarty Plants question and answer that may be helpful to you. Basically, it will indicate that in Texas, generally, you should plant trees in the winter, as when they are dormant they are less likely to suffer from transplant shock. It also has some tips on how you might be able to save your tree. I hope this helps, and good luck on saving it, bur oaks are magnificent trees.
Here is a link that might be useful: Planting a tree in Texas
Of course you're concerned about your newly planted tree, but it's probably not overwatering that is causing the leaves to drop, but transplant shock. The fine little feeder roots have been severed due to shifting of the soil around them and need time to grow back. It's good to keep the root ball moist while it does this. In the meantime a tree that size has the capability to grow another set of leaves if all those should drop. The rain is keeping the soil wet now, but when the rain lets up you'll need to keep watering during the next couple of years until a good root system developes.
Let us know how it does.
Here is a link that might be useful: Newly Planted Tree - Strategies for Survival
From your pictures I planted about the same size Bur in late May and it is having the exact same problem. It was doing really well, but now the leaves have holes and are turning brown. Shouldn't it be past the shock stage? My established oaks are doing fine and I want to make sure they stay that way!

subset: commoncrawl


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Nine of North Springs' Top Ten were joined by their parents, counselors and staff at a recent lunch honoring their academic success. The Top Ten in order are: Madhu Baskaran - Valedictorian, Lucas Capps - Saluatorian, Hayley Katzenstein, Ali Shutzberg, Helena Weibel, Nicholas Redd, John David Grider, Campbell Viersen, Daniel Charanis, and Juliana Abel. Missing- STAR student Nicholas Redd who attends the University of West Georgia's Advanced Academy. Congratulations Spartans!!
Science teacher Zach Luna, our 2014 teacher of the year, is one of three Fulton County "Difference Makers" featured in this video. Check it out-he's inspiring and it's easy to see why he makes a difference!
Congratulations to "Mr. G" - math teacher Rahim Ghassemian, chosen by STAR Student Nicholas Redd! Read more . . .
Due to our weather-related school closing - the Expo will now be on Friday, March 31- from 8:30am -12 noon. The Expo will include a College and Career Fair, break-out sessions for Career Tech Student Organizations and specific career content areas, resume workshops, career surveys and a great guest speaker- Kevin Taylor, former Jobs for Georgia Graduates Teacher!
More than 20 students, members of ACDC- Architecture, Construction and Design Club received hard hats at the induction ceremony kicking off a new 14 week after-school mentoring program with construction industry professionals.
Friends of North Springs is getting closer to its goal of $20,000 to renovate the Media Center for the 21st century!
Click here to get started.


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Lord Snow at the Black Lodge in Seattle on 4.28.2013
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Launcher Update
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Win 750 1v1 Unranked or Ranked games as Terran.
Destroy 6 units with a single Seeker Missile in an Unranked or Ranked game.
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Finished a season in the Top 25 of a 1v1 Platinum Division.
Kill 15 enemy units with a single Nuke in an Unranked or Ranked game.


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Author has written 4 stories for Final Fantasy VII, and South Park.
Hello, welcome to my profile. I'm just someone who loves to read and write, but I'm also a (poor) artist in my spare time. My current obsession is South Park, and my favorite ship is Bunny, though I secretly like lots of other pairings. I ship a lot. I cross-ship a lot. I don't mind switching up pairings, I don't even mind breaking up my OTPs on occasion. I am a huge fan of AUs, horror, action/adventure, drama and the strange. I love all my readers and reviewers.
Have a nice day! LiveJournal: XOXO Tumblr: XOXO Archive Of Our Own: XOXO
January 2015 Update: I'm in school right now, and extremely busy. It can take me anywhere from a week to three months to update a story, but I will finish everything, and often post smaller oneshots on LiveJournal or my Tumblr. Please don't hesitate to leave me some critique or send a comment, even just to chat! They keep me going. Thanks for all the support!
March 2015 Update: Still very busy! The new chapter of ypiac is just about done, and is in the heavy editing stage right now. Soon.
All other fic is completed. Author is subject to random oneshots. Stories are occasionally deleted. Check the Archive of Our Own link for missing stories, I've decided to dump them there until I can work on them.
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|Lefthand Canyon - Main
|USGS 7.5' Map:
|Boulder, Lyons
|Adopted by:
|Trailridge Runners 4WD Club
|P.O. Box 1716, Longmont, CO 80502
|Managed by:
|Roosevelt National Forest,
Boulder Ranger District
|2140 Yarmouth Ave.
Boulder, CO 80301
|The Lefthand Canyon Main 4WD road is the central route into the Lefthand Canyon OHV area. It runs from County Road 94 to the top of Spruce Gulch Ridge with multiple side 4WD roads and motorcycle trails that loop off of and back onto Lefthand Canyon Main, FR286.
|Multiple Routes, Challenge, Easy Access.
|The Lefthand Canyon OHV routes are
open all year.
When there has been heavy rain or snow it is recommended not to recreate on the 4WD roads and motorcycle trails.
|Best Time:
- Early season use when other routes are still seasonally closed.
May-October - The summer and fall season is the heaviest use.
November - Late season use.
|Trail Heads
|Bauman's Ridge Trail, FT844
(motorcycle only)
Wiltz's Trail, FT843, FT843A, FT843B (motorcycle only)
|There are a few dispersed camp sites at the start of Lefthand Main and at the top near the third information kiosk.
|Base Camp:
|The Lefthand Canyon OHV area is not necessarily a good place to base camp due to the limited size of the network. You can explore the entire area in a day.
|Fall Colors:
|Poor - There are very few aspen in the Lefthand Canyon OHV area.
|From Boulder take Hwy 36 north to Altona. Head west on County Road 94 for about 4 miles. You will pass Buckingham Park where Old Stage Road ties in with County Road 94. Continue west on County Road 94 to the Lefthand Canyon OHV network parking lot.
|There was minimal mining done in the area. Most of the mining activity took place in Castle Gulch to the west at the Golden Age Hill mines. The first part of Lefthand Main follows the old stage road that ran to Jamestown overlooking County Road 94.
|The Lefthand Canyon Main road climbs from County Road 94 through a series of easy switchbacks. In a few places you will be looking down at the County Road. Just after the last switchbacks near the upper connection with Mother Hill, FR286C, there is an open area with a rock outcropping that the road traverses. Just past this obstacle is Five Points and the second information kiosk. Lefthand Canyon Main continues from Five Points as a narrower ledge road. You will continue to climb heading for Spruce Gulch Ridge. After passing the intersection with Upper Carnage, FR286E, you will come to the intersection with Castle Gulch Ridge, FR287B. Past this intersection is the main obstacle, Squeeze Rock, a larger rock outcropping with an upper more challenging route, and a lover route. Continue climbing for another half mile to reach the third information kiosk at Spruce Gulch Ridge. From here is the interscetion with East Golden Age, FR288, Fiarview View, FR286H, and Fireman Hill, FR286D.
|Data updated 10/29/10 4WD Road driven 05/07/10 Copyright 4X4Explore.com - 2000-2011


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A collection of news and information related to The Other Boleyn Girl (movie) published by this site and its partners.
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Review: Nelson Mandela's involving 'Long Walk to Freedom'
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Drinks With FriendsStory | Jan 17, 2012 | 11:19 AMOur book club has been meeting for 10 years and is composed of 30-somethings with very busy lives. We hold our discussions at a different house each month. Most of us live in Chicago's south suburbs; a couple members live in the city. When members don'...
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Video/Q&A: 'Les Miserables' stars Eddie Redmayne and Samantha Barks


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<< Previous page | Solo Duo and Trios > | Buckinghamshire >
Solo Singers, Music Duos & Trios for hire in Buckinghamshire
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Also browse Solo Singers, Music Duos & Trios in Buckinghamshire by city/town: Buckinghamshire, Amersham, Aylesbury, Beaconsfield, Buckingham, Chesham, Gerrards Cross, High Wycombe, Marlow, Milton Keynes, Newport Pagnell, Princes Risborough, Wendover,
Amaryllis Duo
Highly Recommended Solo, Duo or Trio for hire in Buckinghamshire
A unique combination, the London based flute & cello/harp duo offer a beautiful blend of sounds and a real feast for the ears. Their wide range of repertoire includes jazz, west end musicals and pop!2 members
Viva Cello
Recommended Solo, Duo or Trio for hire in Buckinghamshire
Professional, highly experienced & performing a range of genres from classic & contemporary popular music to classical, folk & jazz, instrumental duo Viva Cello make a beautiful sound that will compliment any occasion!2 members Video
Luv The Sax
Recommended Solo, Duo or Trio for hire in Buckinghamshire
Luv The Sax is a talented musician with plenty of performing experience. He can cater his show to suit any needs, being able to perform many music genres and pick the right songs to suit the atmosphere of your event.1 members
Recommended Solo, Duo or Trio for hire in Buckinghamshire
Songbird is a trained singer with a beautiful voice who performs a variety of jazz, blues and romantic classics perfect for your special occasion.1 members
Reccommended Solo, Duo or Trio for hire in Buckinghamshire
A fun, professional entertainer from Kent who has had over 10 years experience playing all over the world. Playing music from the 60's to todays chart hits, Richie promises a great show that will provide everything you need.1 members Video
Miss Know It All
Highly Recommended Solo, Duo or Trio for hire in Buckinghamshire
Miss Know It All is a well established, highly respected singer. Performing here in her New-to-Alive Network set-up as a solo performer, she performs many huge hits from ABBA to Madness to Duffy!1 members
Kitty Brucknell
Recommended Solo, Duo or Trio for hire in Buckinghamshire
Captivating audiences with her outstanding theatrical performances, Kitty rose to fame in 2011 when she became the most talked about finalist on the 8th season of The X Factor. Now available for your event, Kitty is back & better than ever!1 members Video
The 2weet Arts
Recommended Solo, Duo or Trio for hire in Buckinghamshire
Take two sassy voices, a collection of popular swing songs, add some sharp dance routines and you have The 2weet Arts, an exciting vintage duo who will give your event the WOW factor!2 members
Swing Vixen
Recommended Solo, Duo or Trio for hire in Buckinghamshire
Take one sassy vintage voice, add a classic mix of swing & jazz favourites, sprinkle with a cheeky personality & dotty dress, & you have your Swing Vixen; the perfect accompaniment to welcome drinks, afternoon tea parties, birthday celebrations & more!1 members
Stax Of Soul
Recommended Solo, Duo or Trio for hire in Buckinghamshire
With outstanding male & female vocals plus live piano & custom made backing tracks, Stax Of Soul are experts at providing amazing entertainment whether a background set of swing & easy listening or a full-on party set spanning the 50's to present day!2 members Video
Other Live Entertainment Available To Hire in Buckinghamshire
Alive Network hires live bands and live music throughout the whole of the UK. View artists in your area >>
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Alive Network are one of Buckinghamshire's leading Solo, Duo or Trio Agents. Our agency covers not just Buckinghamshire but also the whole of the UK so we can supply high quality Solo, Duos & Trios in Buckinghamshire and also many other locations. If you would like to hire a Solo, Duo or Trio please complete an online enquiry or call us on 0845 108 5500.
Alive Network is the UK's largest live music entertainment agency with many Solo, Duos & Trios for hire. Established in 1999, we provide high quality live entertainment for over 7500 events per year. Your own personal entertaiment coordinator will help you to choose exactly the right Solo, Duo or Trio for you, and help to answer any questions or queries that you might have. Booking a Solo, Duo or Trio from Alive Network is easy, safe and secure. Each booking is secured with a legally binding contract giving you complete peace of mind that you're in safe hands. Alive Network personally vets all of the Solo, Duos & Trios that we accept onto our agency and we continually monitor their performance & customer feedback to ensure standards are met.
In short, hiring Solo, Duos & Trios from Alive Network ensures you'll remember your live entertainment for all the right reasons.
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text: I got linux working! I am so very happy. does anyone have any advice for what I should do now? I am learning how to install stuff atm and it's great fun using a new operating system. btw I am using Mandrake 10.0. Maybe someday I will try some other linux flavors too


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Video: Harlem stabbing sparks chaotic clash between crowd and NYPD
As NYPD officers responded to the scene, spectators grew in number and about 100 additional officers were called to the scene
By PoliceOne Staff
HARLEM, N.Y. — Multiple videos taken by citizens captured a tense scene between a crowd and NYPD officers responding to a stabbing in Harlem Monday.
According to the Gothamist, police responded to reports of a stabbing around 10:15 p.m.
As NYPD officers responded, spectators grew in number and about 100 additional officers were called in.
In the video, bystanders shout obscenities at the officers and the sound of glass shattering can be heard.
The growing crowd rebeled as police arrested an unruly subject. The victim of the stabbing, who remains unidentified, was transported to a hospital with minor injuries. The suspect in the attack, 38-year-old Adela Leon, was charged with assault, criminal possession of a weapon, and resisting arrest.
An NYPD spokesperson said no other arrests were made, according to the report.
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I think this is the first valid list I've seen. Even though I'm …
Comment on Top 10 Anime Girls You'd Rather Die Than Marry by Erranty:
I think this is the first valid list I've seen.
Even though I'm a Taiga fan, I know that she can't cook, sew, make friends, control herself, and god knows what else. And of course being branded a lolicon for life isn't a good prospect either…
Erranty made other comments on this post:
- Top 10 Anime Girls You'd Rather Die Than Marry:
That automatically popped an image of Taiga being walked down the street, naked except for a leash and collar, into my head.
Recent comments by Erranty:
- Top 20 Most Anticipated Anime of Spring 2015:
Sidonia is the only one out of those I'd watch, and even then its first season was only fair at best.
- Kiseijuu Mass Murder Anime:
I read the manga. It was a glorious manga.
- Top 10 Manga That Deserve An Anime:
Uwagaki needs one. http://myanimelist.net/manga/41893/Uwagaki
- Pokken Tournament Reveals New Combatants:
Not enough Mudkip.
- Jessica Nigri Voices Super Sonico's English Dub:
People made a big fuss saying she got a boob job after her popularity grew. But when you actually arrange the pics in order of the photo shoots, you can see it's just a gradual increase. Considering there are a lot of girls who are late bloomers it's not all that surprising. People just think they're fake because of the shape. Which the last pic in this galley really does make the look fake, but it's also pretty photoshopped.


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RacingJunk.com Named the Official Classifieds of the National Hot Rod Diesel Association
NHRDA and RacingJunk.com Develop Long-Term Promotional Partnership. Read More
NHRDA and RacingJunk.com Develop Long-Term Promotional Partnership. Read More
It looks like the Dodge Challenger Hellcat has some new competition coming from Shelby and the boys in blue. Read More
The 2015 Ford F150 will have a new look with plenty of exterior technology and a body that is comprised heavily of aluminum rather than steel – and this choice to use lightweight body panels has many people concerned about the durability of the new half ton Ford pickup. Fortunately, I am here to tell […] Read More
Starting in the 2014 NASCAR Sprint Cup season, there is a new version of the Chase system that will guarantee the every single race matters – if a driver doesn't do well in the last race of the season…he or she doesn't win the championship. Read More


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Plasticville "O" Gauge Diner with Box
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Offered here for auction is Plasticville "O" Gauge Diner. Complete, has small piece broken off one side (see pictures). Box is C6 or 7 with inside flaps missing on one side. Nice and solid. I always combine multiple auction wins for shipping cost savings. Buyer pays $5.00 shipping.
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The U of I Sousa Archives and Center for American Music will continute the display World War 1 with America's March King. This exhibit explores Sousa's musical contributions to America's war effort and how this music reflected the era. Exhibit runs March 17th 2014-May 6th 2015. Hours are Monday, Tuesday, Thursday and Friday 8:30am-5pm and Wednesday 10am-5pm. Closed during the noon hour. Click Here to find out more.
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Texas Irons Happy Jalapeno Grill
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OUR SKU # TRN1033Happy Jalapeno Grill is also sometimes listed under the following manufacturer numbers: dsjalapgrill


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Scott A. Lukas, a college professor, began the Gender Ads Project, a website that analyzes women's roles in advertising in 2002. Now there's nearly 4,000 examples on the site.
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Bosch downdraft installation - help!
We're beginning construction on a new home and have planned on a Bosch 30" induction cooktop and downdraft ventiliation with a remote blower. According to the Bosch website, we also need to install a 6" transition piece, # DHZDHR6. Our builder needs to know the dimensions of the transition piece, but they're not available on the Bosch website, or any of the appliance websites. And a phone call to Bosch resulted in them saying that 'yes, you need the piece, and yes, we have no information on it!' Since I won't be taking delivery of the appliances for a few months, I'm wondering it anyone has any information on this system and what the requirements are. Thanks!
Many manufacturers provide on-line copies of their products' installation manuals. You may find one on the Bosch website. If so, it may be possible to answer the question from the information it provides.
Appliance showrooms carrying the product should also be able to dig up the installation manuals that were shipped with the units that they have on display.
While having a bunch of appliances hanging around during construction may be inconvenient, their presence can facilitate answering a lot of questions. And the installation manuals are then at hand for planning and design.


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April 15, 2013 - General
Early on, Joe Cowan had his sights set on football. He had a chance to play for the Baltimore Colts, but could not forget another dream he'd had since he was a boy.
"When you're a kid, you're so proud of what your father created," he says. His father, W.T. Cowan, had founded and built a less-than-truckload business that served the Mid-Atlantic out of Baltimore.
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Simplify tax season by moving to these 9 states with no income tax
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There are nine states without income taxes, though two states tax on dividends and interest, according to a recent article by Dex Knows. See how these states make up for their total tax revenue through other ways. Revenue statistics came from the Tax Foundation.
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Rams continue Commons talks
Derby manager Nigel Clough is hoping the club can agree a deal to keep Kris Commons at Pride Park.
Last Updated: 01/11/10 11:32am
Derby County manager Nigel Clough is hoping the club can agree a deal to keep Kris Commons at Pride Park.
The forward's current contract expires at the end of the season and talks were held last week regarding an extension for the Scotland international.
Commons has expressed a wish to stay at the Championship club and Clough believes an agreement can be reached with the 26-year-old.
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"There was a meeting last week which was positive and I think another will be scheduled for possibly this week or next," said Clough.
"We are doing everything we can to keep him here. He has said he would like to stay and we would like him to stay.
"If that is the case and you have got two parties who want to do a deal, then we hope one will get done soon."


text:
Insteon is a home automation technology that enables light switches, lights, thermostats, motion sensors, and other electrical devices to interoperate through power lines, radio frequency (RF) communications, or both.[1] It employs a dual-mesh networking topology[2] in which all devices are peers and each device autonomously transmits, receives, and repeats messages.[3]
Every message received by an Insteon compatible device undergoes error detection and correction and is then retransmitted to improve reliability of the network. All devices retransmit the same message at the same time so that message transmissions collide synchronously, thus preserving the integrity of the message. The power line AC frequency serves as the synchronization reference for message transmissions. The power line protocol uses phase-shift keying.
Insteon was invented by, and is a registered trademark of, Smartlabs, Inc. Like other home automation network protocols, it has been associated with the hyper-connected environment known as the Internet of Things.[4]
- 1 History
- 2 Device categories
- 3 Network topology
- 4 Transmission
- 5 Security
- 6 Installation and programming
- 7 Compatibility
- 8 Specifications
- 9 See also
- 10 References
- 11 External links
Insteon technology was created under the direction of home automation entrepreneur Joe Dada. In 1992, Dada founded Smarthome, a home automation product catalog company. Dada then acquired two product engineering firms to explore proprietary product development. In 2005, the company released Insteon's patented, dual-band (RF and powerline) mesh networking technology. Dada later established Insteon as a separate company.[5] The company now markets over 200 different Insteon-enabled home automation products which are sold at national retail chains as well as online.[6]
Device categories[edit]
Most Insteon modules fall into one of three categories: Wire-in, plug-in, and battery powered.
Central controllers[edit]
Unlike other wireless control technologies, Insteon does not require a central controller.[citation needed] For example, a keypad can be configured locally to control switches throughout the home. However, there are features only available when central controllers are employed. These features include scheduling, events, conditional logic, advanced device properties and diagnostic tools.
An Insteon installation can be managed from iOS, Android, Windows, Linux and Mac OS X. The company has a series of "power line modems" that interface a computer to the Insteon network. In January 2015 Insteon announced a gateway to allow it to interconnect with Apple's HomeKit system [7]
Insteon markets its own brand of central controller: the Insteon Hub, a device to ontrol Insteon light bulbs, wall switches, outlets, and thermostats at home or remotely and receive email or text message alerts from disrupted sensors, as well as to schedule the operation of Insteon devices, such as turning lights on at sunset.
Plug-in devices[edit]
Insteon Plug-In modules make any plug-in lamp or appliance part of the connected home. Plug-in modules are the easiest Insteon module type to install, as their installation merely requires plugging in a lamp or appliance into the bottom of a unit that then plugs into a power outlet. Insteon has manufactured plug-in modules containing TRIAC dimmers, relays, and low-voltage controllers that offer a dry-contact relay. The Insteon product line has reused the plug-in module form factor to add support for smoke detectors and electronic door deadbolts. When remote controls aren't handy, Insteon has button modules to turn connected device on or off. Additionally, Insteon offers a ruggedized plug-in device, the Outdoor On/Off Module, equipped with a special, weather-resistant enclosure for all-year control.
Lights and LED bulbs[edit]
In 2012, the company introduced the first network-controlled light bulb.[8] As the bulb has no on-device controls and a lamp's built-in switch when turned off disables the bulb, such bulbs work best in more advanced automation systems with multiple Insteon devices or in systems that use a central controller that enables remote control (e.g., from a smartphone). Bulbs come in both traditional A19 size and a larger PAR38 size for recessed lights.
Wall switches[edit]
An Insteon wall switch replaces a conventional wall switch, thus enabling remote control of the switch's electric load. Depending on its intended purpose, an Insteon switch contains either a TRIAC-based dimmer or a relay. Insteon wall switches allows every wall switch to control every other wall switch without the addition of extra wires. Multiway switching can be done with a few taps of the set button. An Insteon rechargeable battery powered switch allows for a wall switch anywhere in the home. An Insteon Keypad allows for the control of other switches and devices.
Wall keypads[edit]
Wall keypads have multiple, programmable pushbuttons that are commonly used as "scene" selectors to recall preprogrammed control levels. For example, they may be used at building entry and egress points to program lights and thermostats to "occupied" or "unoccupied" states.
The Insteon Wall Keypad is a blend of wall switch and multi-button remote control. When a wall switch is replaced with an Insteon Keypad, the control of a light fixture remains while adding remote control of other Insteon devices. The On and Off buttons take the place of the original wall switch. Tapping the buttons controls the lights while the Dimmer Keypad brightens and dims lights by pressing and holding each button.
The scene buttons can be used to control individual devices like an LED Bulb or other Insteon wall switch, or groups of Insteon devices like every lighting fixture in a living room. The keypad can in turn be controlled by other devices.
Wall outlets[edit]
Wall outlets can be installed to add Insteon control of plug-in devices in areas where a plug-in module might be unsightly. An Insteon dimmer outlet has one of the two outlets of a duplex receptacle configured for Insteon control so that it can be activated remotely. The other outlet is labeled as "always on" and behaves like a normal outlet. Like the wall switches and keypads, a homeowner would replace their existing outlet with the Insteon outlet. The On/Off Outlet can remotely control both the upper and lower outlets independently.
Wall outlets can be installed to add Insteon control of plug-in devices in areas where a plug-in module might be unsightly. An Insteon outlet has one of the two outlets of a duplex receptacle configured for Insteon control so that it can be activated remotely. The other outlet is labeled as "always on" and behaves like a normal outlet. Like the wall switches and keypads, a homeowner would replace their existing outlet with the Insteon outlet. The On/Off Outlet can control both the upper and lower outlets independently.
In-line modules[edit]
In-line modules are designed to be mounted inside or behind a fixture or electrical junction box. Insteon in-line modules have been used to provide Insteon-enabled lighting circuits that didn't have a directly accessible wall switch (e.g., a home owner could wire a circuit of recessed ceiling lights with an in-line module and remotely activate them from an Insteon wall switch elsewhere in the house).
With the expansion of Insteon into international markets in Europe, Insteon produced a line of miniature in-line modules that include switch-sensing technology. Rather than replace a wall switch with an Insteon switch, a home owner can connect their existing wall switch to the micro module, tuck the module behind their wall switch plate and still have remote control to the load.
Both in-line modules and micro modules are available as a dimmer or as a relay.
Plug-in modules[edit]
Plug-in modules are the easiest Insteon module type to install, as their installation merely requires plugging in a lamp or appliance into the bottom of a unit that then plugs into a power outlet. Insteon has manufactured plug-in modules containing TRIAC dimmers and relays that include a set of on-device buttons that let a homeowner turn a device on, off or adjust the brightness without needing another Insteon controller. The Insteon product line has reused the older plug-in module form factor to add support for smoke detectors and electronic door deadbolts. A low-voltage controller offers a dry-contact relay. Additionally, Insteon offers a plug-in device, the Outdoor On/Off Module, equipped with a weather-resistant enclosure for all-year control.
Since the release of battery-powered Insteon devices, Insteon has offered motion sensors, contact-closure sensors, water leak sensors, and smoke detectors. Wired magnetic contact sensors can be added to an Insteon system using Insteon wireless open/close sensors. As battery- powered Insteon devices do not have a direct connection to the power line, their use with wired Insteon devices requires at least one Insteon device that can receive and rebroadcast RF messages.
Remote controls[edit]
Insteon remote controls are offered in four designs: a wireless single-function switch, Mini Remote (4-Scene), Mini Remote (8-Scene), and Tabletop Enclosure. The wireless switch can be mounted anywhere for easy accessibility. The Mini Remote (4-Scene) can control four or more devices from anywhere in the home, while the Mini Remote (8-Scene) can control eight or more devices. Any Insteon wired switch or keypad can be installed in a Tabletop Enclosure. The Tabletop Encolsure can be placed on a tethered cord.
Other products[edit]
Other products offered by Insteon include a traditional programmable thermostat that works with 24 volt AC systems and also functions with a companion wireless thermostat that runs on AA batteries. The wireless thermostat does not directly control a heating or air-conditioning system but can send commands to the wired thermostat or less commonly, in-line modules that control a line-voltage heating system. Enterprising home owners have found methods of controlling most heating and cooling systems even when not officially supported by Insteon through the use of relays, in-line modules and low-voltage interfaces that even work with millivolt gas furnaces.
Network topology[edit]
Insteon is an integrated dual-mesh (formerly referred to as "dual-band") network that combines wireless radio frequency (RF) and the home's existing electrical wiring. This is intended to improve reliability by providing a backup system in case of wireless interference.[citation needed] As a peer-to-peer network, devices do not require network supervision, thus dispensing with the need for controllers and routing tables.
Insteon uses digital signal processing to encode and transmit messages, enabling rapid transmission of control data between Insteon devices. Individual Insteon messages can also carry up to 14 bytes of arbitrary user data to support home-control applications from developers. Each transmission contains a two-bit "hops" field that starts at 3 and is decremented each time a node in the network repeats a message. The repetition scheme is designed so that all of the nodes repeat the messages in precise synchrony with one another, so the repetitions collide by design and strengthen one another.
Insteon network security is maintained via linking control to ensure that users cannot create links that would allow them to control a neighbors' INSTEON devices, and via encryption within extended Insteon messages for applications such as door locks and security systems that make use of extended messages to send sensitive data.[9]:53
Insteon enforces linking control by requiring users to have physical possession of devices in order to create links. Firmware in INSTEON devices prohibits them from identifying themselves to other devices unless a user physically presses a button on the device during the installation process. Linking to a device by sending INSTEON messages (e.g., from a computer or central controller) requires knowledge of the 3-byte address of the target INSTEON device. As these addresses are unique for each device and assigned at the factory (and displayed on a printed label attached to each device), users must have physical access to the device to read the device address from the label and manually enter it when prompted during installation by a computer program or controller.
Installation and programming[edit]
Insteon devices are set up using a "plug and tap" method. A homeowner performs a series of taps using each device's set button to form direct device-to-device control links; no central controller is required. While this procedure of linking Insteon devices can be done manually at the devices, a central controller or computer-enabled interface may be added for advanced home management. Some controllers are able to save and restore the configuration of individual devices on the network.
Each Insteon device has its own unique identifier code, similar to a MAC address. When devices are directly linked using the "plug and tap" method, the devices take care of managing device identifiers on their own. Adding a computer for control requires home control software but allows for very advanced configuration, including schedules, triggers, and conditional events.
Insteon driver chip sets manufactured by Smartlabs include the capability of transmitting, receiving, and responding to X10 power line messages in addition to Insteon messages. Homeowners with existing X10 networks can therefore migrate to an Insteon network without having to discard existing X10 devices. While Insteon devices repeat Insteon signals, they do not repeat X10 signals.
In 2014, Insteon teamed with Microsoft to release the first home automation system compatible with the touch-enabled Metro interface, with controlled devices appearing as "live tiles"[10] and later enabling voice-activated commands.[11][12] using Microsoft Cortana.
In 2015, Insteon announced an initiative to integrate the Google-owned Nest learning thermostat with Insteon.[13]
- Data rate
- Instantaneous (within a single packet): 13,165 bit/s
- Sustained best case (over multiple packets): 2,880 bit/s
- Sustained average case: 180 bit/s[14]
- Message types
- Standard: 10 bytes
- Extended: 24 bytes
- Message format/structure
- Source Address: 3 bytes
- Destination Address: 3 bytes
- Flags: 1 byte
- Command: 2 bytes
- User Data: 14 bytes
- Message Integrity: 1 byte
- Devices supported
- Unique IDs: 16,777,216
- Device Types: 65,536
- Commands: 65,536
- Group Members: 256
- Insteon engine memory requirements
- RAM: 80 bytes
- ROM: 3 kilobytes
- Typical application (light switch, lamp dimmer) memory requirements
- RAM: 256 bytes
- EEPROM: 256 bytes
- Flash: 7 kB
- Power line physical layer
- Frequency: 131.65 kHz
- Modulation: Binary phase-shift keying (BPSK)
- Min Transmit Level: 3.16 Vpp into 5 ohms
- Min Receive Level: 10 mV
- Phase Bridging: Insteon RF or hardware
- RF physical layer
- Frequency: 902 to 924 MHz
- Modulation: FSK
- Sensitivity: -103 dBm
- Range: 150 ft unobstructed line-of-sight[9]:53
See also[edit]
- ^ "How to Control Your Home with your Cell Phone". Popular Mechanics. October 1, 2009. Retrieved August 19, 2010.
- ^ "Refresh!: Insteon Technology". Electronic Design. Penton Media, Inc. April 5, 2006. Retrieved August 19, 2010.
- ^ "What is Insteon?". Retrieved 2007-06-25.
- ^ Patrick Thibodeau, "Can we talk? Internet of Things vendors face a communications 'mess'", Computerworld, April 18, 2014
- ^ "Jo Dada's Page". wired.com. Wired. 12 June 2014. Retrieved 29 December 2014.
- ^ Joseph Palenchar, "INSTEON Expands Best Buy Presence", TWICE Magazine, March 27, 2014
- ^ Ricker, Thomas; Kastrenakes, Jacob. "First HomeKit devices confirm Apple TV's limited role in home automation". http://www.theverge.com. The Verge. Retrieved 2 February 2015.
- ^ Molly Oswaks, "Here it Is: The World's First Remote-Controlled (LED) Light Bulb", Gizmodo, June 20, 2012
- ^ a b "INSTEON The Details" (PDF). Insteon. 2013.
- ^ Hachman, Mark (15 May 2014). "Microsoft teams with Insteon to sell connected-home kits". pcworld.com. IDG Consumer & SMB. Retrieved 29 December 2014.
- ^ Ochs, Susie (16 July 2014). "Insteon's Cortana integration will let Windows Phone users talk to their house". techhive.com. IDG Consumer & SMB. Retrieved 29 December 2014.
- ^ Darryl Taft, "INSTEON Taps Microsoft Cortana for Windows Phone 8.1 Home Automation App", eWeek, July 16, 2014
- ^ Brown, Michael (5 January 2015). "'Works with Nest' program gains traction with 15 new smart device integrations". www.techhive.com. IDG Consumer & SMB. Retrieved 8 January 2015.
- ^ Irwin et al. (2011). "Exploiting Home Automation Protocols For Load Monitoring In Smart Buildings".
External links[edit]


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31 year old man | Washington, DC, USA | Seeking women 20-25 within 35 miles
Don't Click If You're Boring
New to the dating site world but decided to give it a try since I'm new to the area and enjoy meeeting new people. I'm originally from San Mateo, California. Moved to DC for work three months ago. I am a fun loving guy who loves a woman with great conversation. Stimulate my mind, please and thank you. Making people laugh is my forte. Between me and you, I'm the ghost writer for Kevin Hart. No...I'm serious. Spontaneity is key in life as you only live it once. I work hard, but I also play hard. I would like to begin trying new foods, new experiences and I would love to find someone that can do this with me. Always in the mood to explore. My father always taught me to be a provider and protector for loved ones. Family is very important to me. A woman that has a strong bond with hers is something that I look for. I'm a bit of a health and fitness freak. Don't like to workout? I'll be your trainer. At the end of the day I'm just a guy that is extremely driven for what he wants in life, a little stubborn (in a good way), and has a huge heart. What I'm looking for: Driven and straightforward are at the top of my list. She must know what she wants and be able to add to the relationship. I love to have fun outdoors, so please do not be afraid of getting your hair or nails messed up. Can you cook? Well, you've found the way to my heart. I've learned a ton about cooking from my grandmother. We can cook together.
Coffee and conversation , Cooking , Dining out , Fishing/Hunting , Movies/Videos , Music and concerts , Exploring new areas , Performing arts , Playing cards , Playing sports , Travel/Sightseeing , Watching sports
Baseball, Basketball, Billiards / Pool, Bowling, Cycling, Football, Running, Swimming, VolleyBall, Walking / Hiking, Weights / Machines
I exercise 3-4 times per week.
I like Dogs
Middle of the Road
Redwoods and Mavericks in Cali. Love the trees and huge waves. Surfing is my passion. Still learning the DC area. Love live music venues. If you know of any please do tell.
University of Southern California, Los Angeles, CA
Not much of a TV person as I'm always on the go. I do enjoy horror movies and a good comedy. Always have my ipod with me wherever I go. Everything from Jay-Z to Eric Clapton.
Random acts of adventure. Road trips, mountain biking, diving. I'm all for anything new. Love going to Clippers games at the Staples Center. That's right..the Clippers. We're back on top this year!
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|What he is looking for
|6'0" (182cms)
|5'0" (152cms) to 5'11" (180cms)
|Body type:
|Athletic and toned
|Athletic and toned
|No preference
|Dark brown
|No preference
|No Way
|No Way
|Social Drinker
|Never, Social Drinker
|No preference
|I'll tell you later
|No preference
|Never Married
|No preference
|Have kids:
|Wants kids:
|Definitely, Someday, Not sure
|White / Caucasian
|No preference
|Spiritual but not religious
|No preference
|Bachelors degree
|No preference


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