Method For The Synthesis Of Phosphorus Atom Modified Nucleic Acids

  *US10329318B2*
  US010329318B2                                 
(12)United States Patent(10)Patent No.: US 10,329,318 B2
  et al. (45) Date of Patent:*Jun.  25, 2019

(54)Method for the synthesis of phosphorus atom modified nucleic acids 
    
(75)Inventor: WAVE LIFE SCIENCES LTD.,  Singapore (SG) 
(73)Assignee:WAVE LIFE SCIENCES LTD.,  Singapore (SG), Type: Foreign Company 
(*)Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. 
  This patent is subject to a terminal disclaimer. 
(21)Appl. No.: 15/608,123 
(22)Filed: May  30, 2017 
(65)Prior Publication Data 
 US 2018/0111958 A1 Apr.  26, 2018 
 Related U.S. Patent Documents 
(62) .
Division of application No. 15/167,583, filed on May  27, 2016, now Pat. No. 9,695,211 , which is a division of application No. 13/131,591, now Pat. No. 9,394,333 .
 
(60)Provisional application No. 61/119,245, filed on Dec.  2, 2008.
 
Jan.  1, 2013 C 07 H 21 00 F I Jun.  25, 2019 US B H C Jan.  1, 2013 C 07 H 1 00 L I Jun.  25, 2019 US B H C
(51)Int. Cl. C07H 021/00 (20060101); C07H 021/02 (20060101); C07H 021/04 (20060101); C07H 001/00 (20060101)
(58)Field of Search  536/23.1, 24.3, 25.3

 
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 2013//0084576  A1  4/2013    Prakash et al.     
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 2013//0116420  A1  5/2013    Prakash et al.     
 2013//0156845  A1  6/2013    Manoharan et al.     
 2013//0178612  A1  7/2013    Wada et al.     
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 2013//0243725  A1  9/2013    Clarke     
 2013//0253033  A1  9/2013    Wilton et al.     
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 2013//0253180  A1  9/2013    Wilton et al.     
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 2013//0302806  A1  11/2013    Van Deutekom     
 2013//0316969  A1  11/2013    Boojamra et al.     
 2013//0323836  A1  12/2013    Manoharan et al.     
 2013//0331438  A1  12/2013    Wilton et al.     
 2014//0080769  A1  3/2014    Platt et al.     
 2014//0080896  A1  3/2014    Nelson et al.     
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 2014//0194610  A1  7/2014    Verdine et al.     
 2014//0213635  A1  7/2014    Van Deutekom     
 2014//0220573  A1  8/2014    Hrdlicka     
 2014//0221395  A1  8/2014    Dhanoa     
 2014//0235566  A1  8/2014    Amblard et al.     
 2014//0243515  A1  8/2014    Wilton et al.     
 2014//0243516  A1  8/2014    Wilton et al.     
 2014//0255936  A1  9/2014    Rademakers et al.     
 2014//0256578  A1  9/2014    Hayden et al.     
 2014//0275212  A1  9/2014    van Deutekom     
 2014//0303238  A1  10/2014    Linsley et al.     
 2014//0309190  A1  10/2014    Thomas et al.     
 2014//0309283  A1  10/2014    Wilton et al.     
 2014//0309284  A1  10/2014    Wilton et al.     
 2014//0309285  A1  10/2014    Wilton et al.     
 2014//0316121  A1  10/2014    Prakash et al.     
 2014//0323707  A1  10/2014    Seth et al.     
 2014//0350076  A1  11/2014    van Deutekom     
 2014//0357698  A1  12/2014    Van Deutekom et al.     
 2014//0357855  A1  12/2014    Van Deutekom et al.     
 2014//0373188  A1  12/2014    Zamore et al.     
 2014//0378527  A1  12/2014    van Deutekom     
 2015//0025039  A1  1/2015    Boojamra et al.     
 2015//0051389  A1  2/2015    Seth et al.     
 2015//0057330  A1  2/2015    Wilton et al.     
 2015//0080457  A1  3/2015    Manoharan et al.     
 2015//0080563  A2  3/2015    van Deutekom     
 2015//0096064  A1  4/2015    Tuschl et al.     
 2015//0126725  A1  5/2015    Swayze et al.     
 2015//0148404  A1  5/2015    de Visser et al.     
 2015//0159163  A1  6/2015    Prakash et al.     
 2015//0166999  A1  6/2015    Gemba     
 2015//0167006  A1  6/2015    Swayze et al.     
 2015//0197540  A1  7/2015    Shimizu et al.     
 2015//0211006  A1  7/2015    Butler et al.     
 2015//0218559  A1  8/2015    Van Deutekom et al.     
 2015//0259679  A1  9/2015    Bennett et al.     
 2015//0267197  A1  9/2015    Bennett et al.     
 2015//0275208  A1  10/2015    Oestergaard et al.     
 2015//0291636  A1  10/2015    Atamanyuk et al.     
 2015//0292015  A1  10/2015    Bennett et al.     
 2015//0307877  A1  10/2015    Freier     
 2015//0315594  A1  11/2015    Prakash et al.     
 2015//0322434  A1  11/2015    van Deutekom     
 2015//0329859  A1  11/2015    Bennett et al.     
 2015//0335708  A1  11/2015    Froelich et al.     
 2015//0353931  A1  12/2015    Wilton et al.     
 2015//0361424  A1  12/2015    van Deutekom     
 2015//0376615  A1  12/2015    Wilton et al.     
 2015//0376616  A1  12/2015    Wilton et al.     
 2015//0376624  A1  12/2015    Gryaznov et al.     
 2015//0376625  A1  12/2015    Oestergaard et al.     
 2016//0002281  A1  1/2016    Mayes et al.     
 2016//0002631  A1  1/2016    Wilton et al.     
 2016//0002632  A1  1/2016    Wilton et al.     
 2016//0002635  A1  1/2016    Wilton et al.     
 2016//0017327  A1  1/2016    Rudnicki et al.     
 2016//0024496  A1  1/2016    Bennett et al.     
 2016//0040161  A1  2/2016    Packard et al.     
 2016//0046939  A1  2/2016    Prakash et al.     
 2016//0050929  A1  2/2016    Benfatti et al.     
 2016//0050930  A1  2/2016    Benfatti et al.     
 2016//0053256  A1  2/2016    Hung et al.     
 2016//0068837  A1  3/2016    Chang et al.     
 2016//0076033  A1  3/2016    Torii et al.     
 2016//0108396  A1  4/2016    Jensen et al.     
 2016//0122761  A1  5/2016    Prakash et al.     
 2016//0128928  A1  5/2016    Fukuhara et al.     
 2016//0129023  A1  5/2016    Thomas et al.     
 2016//0138022  A1  5/2016    Kandimalla et al.     
 2016//0159846  A1  6/2016    Prakash et al.     
 2016//0168570  A1  6/2016    Van Deutekom et al.     
 2016//0186175  A1  6/2016    Seth et al.     
 2016//0186178  A1  6/2016    Radovic-Moreno et al.     
 2016//0186185  A1  6/2016    Prakash et al.     
 2016//0194349  A1  7/2016    Prakash et al.     
 2016//0194636  A1  7/2016    Van Deutekom et al.     
 2016//0214974  A1  7/2016    Schaetzer et al.     
 2016//0230172  A1  8/2016    Rigo     
 2016//0237108  A1  8/2016    Fraley et al.     
 2016//0237432  A1  8/2016    Bennett et al.     
 2016//0251653  A1  9/2016    Davidson et al.     
 2016//0251655  A1  9/2016    Freier et al.     
 2016//0251658  A1  9/2016    Van Deutekom et al.     
 2016//0264964  A1  9/2016    Cancilla et al.     
 2016//0312217  A1  10/2016    Hung et al.     
 2016//0331835  A1  11/2016    Gemba et al.     
 2016//0331836  A1  11/2016    Gemba et al.     
 2016//0333349  A1  11/2016    Gemba et al.     
 2016//0347780  A1  12/2016    Wada et al.     
 2016//0347784  A1  12/2016    Verdine et al.     
 2016//0355810  A1  12/2016    Van Deutekom     
 2016//0369273  A1  12/2016    Freier     
 2017//0009233  A1  1/2017    Wilton et al.     
 2017//0009234  A1  1/2017    Wilton et al.     
 2017//0029445  A1  2/2017    Shimizu et al.     
 2017//0029457  A1  2/2017    Verdine et al.     
 2017//0037399  A1  2/2017    Meena et al.     
 2017//0044526  A1  2/2017    Wan et al.     
 2017//0067050  A1  3/2017    Tuschl et al.     
 2017//0114086  A1  4/2017    Clarke     
 2017//0114340  A1  4/2017    Mueller et al.     
 2017//0130224  A1  5/2017    Oestergaard et al.     
 2017//0197903  A1  7/2017    Hoashi     
 2017//0239280  A1  8/2017    Thomas et al.     
 2017//0275621  A1  9/2017    Butler et al.     
 2017//0327824  A1  11/2017    Oestergaard et al.     
 2017//0349897  A1  12/2017    Rigo     

 
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       CN       102675386       A                9/2012      
       DE       1144279       B                2/1963      
       DE       01934150       A1                1/1970      
       EP       0 002 322       A2                6/1979      
       EP       192521       A1                8/1986      
       EP       269258       A2                6/1988      
       EP       0506242       A1                9/1992      
       EP       0531447       A1                3/1993      
       EP       0604409       A1                7/1994      
       EP       0655088       A1                5/1995      
       EP       0779893       A2                6/1997      
       EP       0831854       A1                4/1998      
       EP       0973945       A1                1/2000      
       EP       1097162       A2                5/2001      
       EP       1100807       A1                5/2001      
       EP       1185305                         3/2002      
       EP       1244682       A1                10/2002      
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       EP       1957507       A2                8/2008      
       EP       1984381       A2                10/2008      
       EP       2021472       A2                2/2009      
       EP       2062980       A2                5/2009      
       EP       2066684       A2                6/2009      
       EP       2149571       A1                2/2010      
       EP       2161038       A1                3/2010      
       EP       2170917       A2                4/2010      
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       EP       15182401.8                         8/2015      
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       EP       15191076.7                         10/2015      
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       GB       1448437       A                9/1976      
       GB       2016273       A                9/1979      
       JP       H03-074398       A                3/1991      
       JP       3072345       B1                7/2000      
       JP       2003/238586       A                8/2003      
       JP       2009-190983       A                8/2009      
       JP       4348044       B2                10/2009      
       JP       04348077       B2                10/2009      
       JP       2011/088935       A                5/2011      
       WO       WO-9/1/10671       A1                7/1991      
       WO       WO-9/1/16331       A1                10/1991      
       WO       WO-9/1/17755       A1                11/1991      
       WO       WO-9/2/03452       A1                3/1992      
       WO       WO-9/2/20822       A1                11/1992      
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       WO       WO-2/018/067973       A1                4/2018      

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     * cited by examiner
 
     Primary Examiner —Jezia Riley
     Art Unit — 1637
     Exemplary claim number — 1
 
(74)Attorney, Agent, or Firm — Choate, Hall & Stewart LLP; Brenda Herschbach Jarrell; Xiaodong Li

(57)

Abstract

Described herein are methods of syntheses of phosphorous atom-modified nucleic acids comprising chiral X-phosphonate moieties. The methods described herein provide backbone-modified nucleic acids in high diasteteomeric purity via an asymmetric reaction of an achiral molecule comprising a chemically stable H-phophonate moiety with a nucleoside/nucleotide.
17 Claims, 58 Drawing Sheets, and 58 Figures


FIELD OF THE INVENTION

[0001] Described herein are methods of syntheses of phosphorous atom-modified nucleic acids comprising chiral X-phosphonate moieties. The methods described herein provide backbone-modified nucleic acids in high diastereomeric purity via an asymmetric reaction of an achiral molecule comprising a chemically stable H-phosphonate moiety with a nucleoside/nucleotide.

BACKGROUND OF THE INVENTION

[0002] Oligonucleotides are useful in therapeutic, diagnostic, research, and new and nanomaterials applications. The use of natural sequences of DNA or RNA is limited by their stability to nucleases. Additionally, in vitro studies have shown that the properties of antisense nucleotides such as binding affinity, sequence specific binding to the complementary RNA, stability to nucleases are affected by the configurations of the phosphorous atoms. Therefore, there is a need in the field for methods to produce oligonucleotides which are stereocontrolled at phosphorus and exhibit desired stability to degradation while retaining affinity for exogenous or endogenous complementary DNA/RNA sequences. There is a need for these compounds to be easily synthesized on solid support or in solution, and to permit a wide range of synthetic modifications on the sugars or nucleobases of the oligonucleotide.
[0003] Described herein are stereocontrolled syntheses of phosphorous atom-modified polymeric and oligomeric nucleic acids, which in some embodiments, is performed on solid support.

SUMMARY OF THE INVENTION

[0004] In one aspect of the invention, a method for a synthesis of a nucleic acid is provided comprising a chiral X-phosphonate moiety comprising reacting a molecule comprising an achiral H-phosphonate moiety and a nucleoside comprising a 5′-OH moiety to form a condensed intermediate; and converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety.
[0005] In some embodiments, the method wherein the step of reacting the molecule comprising an achiral H-phosphonate moiety and the nucleoside comprising a 5′-OH moiety to form a condensed intermediate is a one-pot reaction.
[0006] In some embodiments, the method provides a nucleic acid comprising a chiral X-phosphonate moiety of Formula 1.
[0007]  [see pdf for image]
[0008] In some embodiments of the compound of Formula 1, R1 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —HP(O)(Re), —ORa or —SRc. Y1 is O, NRd, S, or Se. Ra is a blocking moiety. Rc is a blocking group. Each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Re)2, or —HP(O)(Re). Each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1. Y2 is O, NRd, or S. Each instance of R2 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, wherein Rb is a blocking moiety. Each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase. Each instance of X is independently alkyl, alkoxy, aryl, alkylthio, acyl, —NRfRf, alkenyloxy, alkynyloxy, alkenylthio, alkynylthio, —SZ+, —SeZ+, or —BH3Z+. Each instance of Rf is independently hydrogen, alkyl, alkenyl, alkynyl, or aryl. Z+ is ammonium ion, alkylammonium ion, heteroaromatic iminium ion, or heterocyclic iminium ion, any of which is primary, secondary, tertiary or quaternary, or Z is a monovalent metal ion. R3 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid; and n is an integer of 1 to about 200.
[0009] In some embodiments of the method, each X-phosphonate moiety of the compound of Formula 1 is more than 98% diastereomerically pure as determined by 31P NMR spectroscopy or reverse-phase HPLC. In some embodiments of the method, each X-phosphonate moiety has a RP configuration. In other embodiments of the method, each X-phosphonate moiety has a SP configuration. In other embodiments of the method, each X-phosphonate independently has a RP configuration or a SP configuration.
[0010] In further embodiments of the method, the molecule comprising an achiral H-phosphonate moiety is a compound of Formula 2.
[0011]  [see pdf for image]
[0012] In Formula 2, R1 is —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —HP(O)(Re), —ORa, or —SRc. Y1 is O, NRd, S, or Se. Ra is a blocking moiety. Rc is a blocking group. Each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Re)2, or —HP(O)(Re). Each instance of Re is independently alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—. Y2 is O, NRd, or S. R2 is hydrogen, —NRdRd, N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, wherein Rb is a blocking moiety. Ba is a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase. Z+ is ammonium ion, alkylammonium ion, heteroaromatic iminium ion, or heterocyclic iminium ion, any of which is primary, secondary, tertiary or quaternary, or a monovalent metal ion.
[0013] In some embodiments of the method, the method further comprises a chiral reagent. In yet other embodiments of the method, the chiral reagent is a compound of Formula 3.
[0014]  [see pdf for image]
[0015] W1 and W2 are independently —NG5-, —O—, or —S—. G1, G2, G3, G4, and G5 are independently hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetaryl, or aryl, or two of G1, G2, G3, G4, and G5 are G6 taken together form a saturated, partially unsaturated or unsaturated carbocyclic or heteroatom-containing ring of up to about 20 ring atoms which is monocyclic or polycyclic, fused or unfused, and wherein no more than four of G1, G2, G3, G4, and G5 are G6.
[0016] In some embodiments of the method, the nucleoside comprising a 5′-OH moiety is a compound of Formula 4.
[0017]  [see pdf for image]
[0018] Each instance of R2 is independently hydrogen, —NRdRd, N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, wherein Rb is a blocking moiety. Y1 is O, NRd, S, or Se. Rc is a blocking group. Each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Re)2, or —HP(O)(Re). Each instance of Re is independently alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—. Y2 is O, NRd, or S. Each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase. m is an integer of 0 to n−1. n is an integer of 1 to about 200. OA is connected to a trityl moiety, a silyl moiety, an acetyl moiety, an acyl moiety, an aryl acyl moiety, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid. J is O and D is H, or J is S, Se, or BH3 and D is a chiral ligand Ci or a moiety of Formula A.
[0019]  [see pdf for image]
[0020] In Formula A, W1 and W2 are independently NHG5, OH, or SH. A is hydrogen, acyl, aryl, alkyl, aralkyl, or a silyl moiety. G1, G2, G3, G4, and G5 are independently hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, or aryl, or two of G1, G2, G3, G4, and G5 are G6 which taken together form a saturated, partially unsaturated or unsaturated carbocyclic or heteroatom-containing ring of up to about 20 ring atoms which is monocyclic or polycyclic, fused or unfused and wherein no more than four of G1, G2, G3, G4, and G5 are G6.
[0021] In yet other embodiments of the method, the method further comprises providing a condensing reagent CR whereby the molecule comprising an achiral H-phosphonate moiety is activated to react with the chiral reagent to form a chiral intermediate.
[0022] In further embodiments of the method, the condensing reagent CR is Ar3PL2, (ArO)3PL2,
[0023]  [see pdf for image]
[0024] Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9 and Z10 are independently alkyl, aminoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, aryloxy, or heteroaryloxy, or wherein any of Z2 and Z3, Z5 and Z6, Z7 and Z8, Z8 and Z9, Z9 and Z7, or Z7 and Z8 and Z9 are taken together to form a 3 to 20 membered alicyclic or heterocyclic ring. Q is a counter anion, L is a leaving group, and w is an integer of 0 to 3. Ar is aryl, heteroaryl, and/or one of Ar group is attached to the polymer support. In some embodiments of the method, the counter ion of the condensing reagent CR is Cl, Br, BF4, PF6, TfO, Tf2N, AsF6, ClO4, or SbF6, wherein Tf is CF3SO2. In other embodiments of the method, the leaving group of the condensing reagent CR is F, Cl, Br, I, 3-nitro-1,2,4-triazole, imidazole, alkyltriazole, tetrazole, pentafluorobenzene, or 1-hydroxybenzotriazole.
[0025] In some embodiments of the method, the condensing reagent is phosgene, trichloromethyl chloroformate, bis(trichloromethyl)carbonate (BTC), oxalyl chloride, Ph3PCl2, (PhO)3PCl2, N,N′-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BopCl), 1,3-dimethyl-2-(3-nitro-1,2,4-triazol-1-yl)-2-pyrrolidin-1-yl-1,3,2-diazaphospholidinium hexafluorophosphate (MNTP), or 3-nitro-1,2,4-triazol-1-yl-tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyNTP).
[0026]  [see pdf for image]
[0027] In a further embodiment of the method, the method further comprises providing an activating reagent AR. In one embodiment, the activating reagent AR is
[0028]  [see pdf for image]
wherein Z11, Z12, Z13, Z14, Z15, Z16, Z17, Z18, Z19, Z20, and Z21 are independently hydrogen, alkyl, aminoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, aryloxy, or heteroaryloxy, or wherein any of Z11 and Z12, Z11 and Z13, Z11 and Z14, Z12 and Z13, Z12 and Z14, Z13 and Z14, Z15 and Z16, Z15 and Z17, Z16 and Z17, Z18 and Z19, or Z20 and Z21 are taken together to form a 3 to 20 membered alicyclic or heterocyclic ring, or to form 5 or 20 membered aromatic irng; and Q is a counter ion. In an embodiment, the counter ion of the activating reagent AR is Cl, Br, BF4, PF6, TfO, Tf2N, AsF6, ClO4, or SbF6, wherein Tf is CF3SO2. In one embodiment, the activating reagent AR is imidazole, 4,5-dicyanoimidazole (DCI), 4,5-dichloroimidazole, 1-phenylimidazolium triflate (PhIMT), benzimidazolium triflate (BIT), benztriazole, 3-nitro-1,2,4-triazole (NT), tetrazole, 5-ethylthiotetrazole, 5-(4-nitrophenyl)tetrazole, N-cyanomethylpyrrolidinium triflate (CMPT), N-cyanomethylpiperidinium triflate, N-cyanomethyldimethylammonium triflate. In another embodiment, the activating reagent AR is 4,5-dicyanoimidazole (DCI), 1-phenylimidazolium triflate (PhIMT), benzimidazolium triflate (BIT), 3-nitro-1,2,4-triazole (NT), tetrazole, or N-cyanomethylpyrrolidinium triflate (CMPT).
[0029]  [see pdf for image]
In an embodiment, the activating reagent AR is N-cyanomethylpyrrolidinium triflate (CMPT).
[0030] In some embodiments of the method, the reaction is performed in an aprotic organic solvent. In other embodiments of the method, the solvent is acetonitrile, pyridine, tetrahydrofuran, or dichloromethane. In other embodiments of the method, when the aprotic organic solvent is not basic, a base is present in the reacting step. In some embodiments of the method, the base is pyridine, quinoline, or N,N-dimethylaniline. In some embodiments of the method, the base is
[0031]  [see pdf for image]
[0032] wherein Z22 and Z23 are independently alkyl, aminoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, aryloxy, or heteroaryloxy, or wherein any of Z22 and Z23 are taken together to form a 3 to 10 membered alicyclic or heterocyclic ring. In some embodiments of the method, the base is N-cyanomethylpyrrolidine. In some embodiments of the method, the aprotic organic solvent is anhydrous. In other embodiments of the method, the anhydrous aprotic organic solvent is freshly distilled. In yet other embodiments of the method, the freshly distilled anhydrous aprotic organic solvent is pyridine. In another embodiment of the method, the freshly distilled anhydrous aprotic organic solvent is acetonitrile.
[0033] In some embodiments of the method, the step of converting the condensed intermediate to a compound of Formula 1 comprises: modifying the condensed intermediate to produce a compound of Formula 5.
[0034]  [see pdf for image]
[0035] In Formula 5, R1 is —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —HP(O)(Re), —ORa, or —SRc. Y1 is O, NRd, S, or Se. Ra is a blocking moiety. Rc is a blocking group. Each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Re)2, or —HP(O)(Re). Each instance of Re is independently alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—. Y2 is O, NRd, or S. Each instance of R2 is independently hydrogen, —NRdRd, N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, wherein Rb is a blocking moiety. Each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil, or modified nucleobase. Each instance of J is S, Se, or BH3. v is an integer of 1. OA is connected to a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid. A is an acyl, aryl, alkyl, aralkyl, or silyl moiety. G1, G2, G3, G4, and G5 are independently hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, or aryl, or two of G1, G2, G3, G4, and G5 are G6 which taken together form a saturated, partially unsaturated or unsaturated carbocyclic or heteroatom-containing ring of up to about 20 ring atoms which is monocyclic or polycyclic, fused or unfused and wherein no more than four of G1, G2, G3, G4, and G5 are G6.
[0036] In some embodiments of the method, the step of converting the condensed intermediate to a compound of Formula 1 comprises: capping the condensed intermediate and modifying the capped condensed intermediate to produce a compound of Formula 5.
[0037]  [see pdf for image]
[0038] In Formula 5, R1 is —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —HP(O)(Re), —ORa, or —SRc. Y1 is O, NRd, S, or Se. Ra is a blocking moiety. Rc is a blocking group. Each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Re)2, or —HP(O)(Re). Each instance of Re is independently alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—. Y2 is O, NRd, or S. Each instance of R2 is independently hydrogen, —NRdRd, N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRe, wherein Rb is a blocking moiety. Each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil, or modified nucleobase. Each instance of J is S, Se, or BH3. v is an integer of 2 to n−1. OA is connected to a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid. A is an acyl, aryl, alkyl, aralkyl, or silyl moiety. G1, G2, G3, G4, and G5 are independently hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, or aryl, or two of G1, G2, G3, G4, and G5 are G6 which taken together form a saturated, partially unsaturated or unsaturated carbocyclic or heteroatom-containing ring of up to about 20 ring atoms which is monocyclic or polycyclic, fused or unfused and wherein no more than four of G1, G2, G3, G4, and G5 are G6.
[0039] In some embodiments of the method, the method further comprises the steps of: (a) deblocking R1 of the compound of Formula 5 to produce a compound of Formula 4 wherein m is at least 1, J is S, Se, or BH3 and D is a moiety of Formula A; (b) reacting the compound of Formula 4 using the method of claim 10 wherein the step of converting the condensed intermediate comprises capping the condensed intermediate and modifying the capped condensed intermediate to produce a compound of Formula 5 wherein v is greater than 2 and less than about 200; and (c) optionally repeating steps (a) and (b) to form a compound of Formula 5 wherein v is greater than 3 and less than about 200.
[0040] In other embodiments of the method, the method further comprises the step of converting the compound of Formula 5 to the compound of Formula 1 wherein each Ba moiety is unblocked. R1 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —HP(O)(Re), —ORa or —SR. Y1 is O, NRd, S, or Se. Ra is a blocking moiety. Rc is a blocking group. Each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Re)2, or —HP(O)(Re). Each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1. Y2 is O, NRd, or S. Each instance of R2 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, wherein Rb is a blocking moiety. R3 is H. Each instance of X is independently —SZ+, —SeZ+, or —BH3Z+. Z+ is ammonium ion, alkylammonium ion, heteroaromatic iminium ion, or heterocyclic iminium ion, any of which is primary, secondary, tertiary or quaternary, or Z is a monovalent metal ion.
[0041] In some embodiments of the method, the step of converting the condensed intermediate to a compound of Formula 1 comprises acidifying the condensed intermediate to produce a compound of Formula 4, wherein m is at least one, J is O, and D is H. In some embodiments of the method, the condensed intermediate comprises a moiety of Formula A′.
[0042]  [see pdf for image]
[0043] A is hydrogen and G1 and G2 are independently alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, or aryl and G3, G4, and G5 are independently hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, or aryl, or two of G1, G2, G3, G4, and G5 are G6 which taken together form a saturated, partially unsaturated or unsaturated carbocyclic or heteroatom-containing ring of up to about 20 ring atoms which is monocyclic or polycyclic, fused or unfused and wherein no more than four of G1, G2, G3, G4, and G5 are G6.
[0044] In some embodiments of the method, the method further comprises: (a) reacting the compound of Formula 4 wherein m is at least one, J is O, and D is H, using the method of claim 10 wherein the step of converting the condensed intermediate to a compound of Formula 1 comprises acidifying the condensed intermediate to produce a compound of Formula 4 wherein m is at least 2 and less than about 200; J is O, and D is H, and (b) optionally repeating step (a) to produce a compound of Formula 4 wherein m is greater than 2 and less than about 200.
[0045] In some embodiments of the method, the acidifying comprises adding an amount of a Brønsted or Lewis acid effective to convert the condensed intermediate into the compound of Formula 4 without removing purine or pyrimidine moieties from the condensed intermediate. In other embodiments of the method, the acidifying comprises adding 1% trifluoroacetic acid in an organic solvent, 3% dichloroacetic acid in an organic solvent, or 3% trichloroacetic acid in an organic solvent. In yet other embodiments of the method, the acidifying further comprises adding a cation scavenger. In some embodiments of the method, the cation scavenger is triethylsilane or triisopropylsilane.
[0046] In some embodiments of the method, the step of converting the condensed intermediate to a compound of Formula 1 further comprises deblocking R1 prior to the step of acidifying the condensed intermediate.
[0047] In other embodiments of the method, the method further comprises the step of modifying the compound of Formula 4 to introduce an X moiety thereby producing a compound of Formula 1 wherein R3 is a blocking group or a linking moiety connected to a solid support.
[0048] In yet other embodiments of the method, the method further comprises treating an X-modified compound to produce a compound of Formula 1 wherein R1 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —HP(O)(Re), —ORa or —SRc. Y1 is O, NRd, S, or Se. Ra is a blocking moiety. Re is a blocking group. Each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Re)2, or —HP(O)(Re). Each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1. Y2 is O, NRd, or S. Each instance of R2 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, wherein Rb is a blocking moiety. Each Ba moiety is unblocked. R3 is H. Each instance of X is independently alkyl, alkoxy, aryl, alkylthio, acyl, —NRfRf, alkenyloxy, alkynyloxy, alkenylthio, alkynylthio, —SZ+, —SeZ+, or —BH3Z+. Each instance of Rf is independently hydrogen, alkyl, alkenyl, alkynyl, or aryl. Z+ is ammonium ion, alkylammonium ion, heteroaromatic iminium ion, or heterocyclic iminium ion, any of which is primary, secondary, tertiary or quaternary, or Z is a monovalent metal ion. n is greater than 1 and less than about 200.
[0049] In some embodiments of the method, the modifying step is performed using a boronating agent, a sulfur electrophile, or a selenium electrophile.
[0050] In some embodiments of the method, the sulfur electrophile is a compound having one of the following formulas:
          S8  (Formula B),
          Z24—S—S—Z25,
          or
          Z24—S—X—Z25.
[0051] Z24 and Z25 are independently alkyl, aminoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, acyl, amide, imide, or thiocarbonyl, or Z24 and Z25 are taken together to form a 3 to 8 membered alicyclic or heterocyclic ring, which may be substituted or unsubstituted; X is SO2, O, or NRf; and Rf is hydrogen, alkyl, alkenyl, alkynyl, or aryl.
[0052] In some embodiments of the method, the sulfur electrophile is a compound of Formula B, C, D, E, or F:
[0053]  [see pdf for image]
[0054] In some embodiments of the method, the selenium electrophile is a compound having one of the following formulas:
          Se  (Formula G),
          Z26—Se—Se—Z27,
          or
          Z26—Se—X—Z27
[0055] Z26 and Z27 are independently alkyl, aminoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, acyl, amide, imide, or thiocarbonyl, or Z26 and Z27 are taken together to form a 3 to 8 membered alicyclic or heterocyclic ring, which may be substituted or unsubstituted; X is SO2, S, O, or NRf; and Rf is hydrogen, alkyl, alkenyl, alkynyl, or aryl.
[0056] In some embodiments of the method, the selenium electrophile is a compound of Formula G, H, I, J, K, or L.
[0057]  [see pdf for image]
[0058] In some embodiments of the method, the boronating agent is borane-N,N-diisopropylethylamine (BH3.DIPEA), borane-pyridine (BH3.Py), borane-2-chloropyridine (BH3.CPy), borane-aniline (BH3.An), borane-tetrahydrofurane (BH3.THF), or borane-dimethylsulfide (BH3.Me2S).
[0059] In some embodiments of the method, the modifying step is performed using a silylating reagent followed by a sulfur electrophile, a selenium electrophile, a boronating agent, an alkylating agent, an aldehyde, or an acylating agent.
[0060] In some embodiments of the method, the silylating reagent is chlorotrimethylsilane (TMS-Cl), triisopropylsilylchloride (TIPS-Cl), t-butyldimethylsilylchloride (TBDMS-Cl), t-butyldiphenylsilylchloride (TBDPS-Cl), 1,1,1,3,3,3-hexamethyldisilazane (HMDS), N-trimethylsilyldimethylamine (TMSDMA), N-trimethylsilyldiethylamine (TMSDEA), N-trimethylsilylacetamide (TMSA), N,O-bis(trimethylsilyl)acetamide (BSA), or N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA).
[0061] In some embodiments of the method, the sulfur electrophile is a compound having one of the following formulas: S8 (Formula B), Z24—S—S—Z25, or Z24—S—X—Z25, wherein Z24 and Z25 are independently alkyl, aminoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, acyl, amide, imide, or thiocarbonyl, or Z24 and Z25 are taken together to form a 3 to 8 membered alicyclic or heterocyclic ring, which may be substituted or unsubstituted; X is SO2, O, or NRf; and Rf is hydrogen, alkyl, alkenyl, alkynyl, or aryl.
[0062] In some embodiments of the method, the sulfur electrophile is a compound of Formula B, C, D, E, or F:
[0063]  [see pdf for image]
[0064] In some embodiments of the method, the selenium electrophile is a compound having one of the following formulas: Se (Formula G), Z26—Se—Se—Z27, or Z26—Se—X—Z27, wherein Z26 and Z27 are independently alkyl, aminoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, acyl, amide, imide, or thiocarbonyl, or Z26 and Z27 are taken together to form a 3 to 8 membered alicyclic or heterocyclic ring, which may be substituted or unsubstituted; X is SO2, S, O, or NRf; and Rf is hydrogen, alkyl, alkenyl, alkynyl, or aryl.
[0065] In some embodiments of the method, the selenium electrophile is a compound of Formula G, H, I, J, K, or L:
[0066]  [see pdf for image]
[0067] In some embodiments of the method, the boronating agent is borane-N,N-diisopropylethylamine (BH3.DIPEA), borane-pyridine (BH3.Py), borane-2-chloropyridine (BH3.CPy), borane-aniline (BH3.An), borane-tetrahydrofurane (BH3.THF), or borane-dimethylsulfide (BH3.Me2S).
[0068] In some embodiments of the method, the alkylating agent is an alkyl halide, alkenyl halide, alkynyl halide, alkyl sulfonate, alkenyl sulfonate, or alkynyl sulfonate. In other embodiments of the method, the aldehyde is (para)-formaldehyde, alkyl aldehyde, alkenyl aldehyde, alkynyl aldehyde, or aryl aldehyde.
[0069] In some embodiments of the method, the acylating agent is a compound of Formula M or N.
[0070]  [see pdf for image]
[0071] G7 is alkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, aryloxy, or heteroaryloxy; and M is F, Cl, Br, I, 3-nitro-1,2,4-triazole, imidazole, alkyltriazole, tetrazole, pentafluorobenzene, or 1-hydroxybenzotriazole.
[0072] In some embodiments of the method, the modifying step is performed by reacting with a halogenating reagent followed by reacting with a nucleophile. In some embodiments of the method, the halogenating reagent is CCl4, CBr4, Cl2, Br2, I2, sulfuryl chloride (SO2Cl2), phosgene, bis(trichloromethyl)carbonate (BTC), sulfur monochloride, sulfur dichloride, chloramine, CuCl2, N-chlorosuccinimide (NCS), Cl4, N-bromosuccinimide (NBS), or N-iodosuccinimide (NIS). In other embodiments of the method, the nucleophile is NRfRfH, RfOH, or RfSH, wherein Rf is hydrogen, alkyl, alkenyl, alkynyl, or aryl, and at least one of Rf of NRfRfH is not hydrogen.
[0073] In some embodiments of the method, the chiral reagent is the compound of Formula 3 wherein W1 is NHG5 and W2 is OH. In some embodiments of the method, the chiral reagent is Formula O or Formula P.
[0074]  [see pdf for image]
[0075] In some embodiments of the method, the chiral reagent is Formula Q or Formula R.
[0076]  [see pdf for image]
[0077] In some embodiments of the method, Ra is substituted or unsubstituted trityl or substituted silyl. In other embodiments of the method, wherein Ra is substituted or unsubstituted trityl or substituted silyl. In other embodiments of the method, Rb is substituted or unsubstituted trityl, substituted silyl, acetyl, acyl, or substituted methyl ether.
[0078] In some embodiments of the method, R3 is a blocking group which is substituted trityl, acyl, substituted silyl, or substituted benzyl. In other embodiments of the method, R3 is a linking moiety connected to a solid support.
[0079] In some embodiments of the method, the blocking group of the Ba moiety is a benzyl, acyl, formyl, dialkylformamidinyl, isobutyryl, phenoxyacetyl, or trityl moiety, any of which may be unsubstituted or substituted. In some embodiments of the method, R1 is —N3, —NRdRd, alkynyloxy, or —OH. In some embodiments of the method, R1 is —N3, —NRdRd, alkynyloxy, or —OH. In other embodiments of the method, R2 is —NRdRd, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, or heteroaryl-Y1—, and is substituted with fluorescent or biomolecule binding moieties. In yet other embodiments of the method, R2 is —NRdRd, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, or heteroaryl-Y1—, and is substituted with fluorescent or biomolecule binding moieties.
[0080] In some embodiments of the method, the substituent on R2 is a fluorescent moiety. In other embodiments of the method, the substituent on R2 is biotin or avidin. In yet other embodiments of the method, the substituent on R2 is a fluorescent moiety. In some embodiments of the method, the substituent on R2 is biotin or avidin. In other embodiments of the method, R2 is —OH, —N3, hydrogen, halogen, alkoxy, or alkynyloxy. In yet other embodiments of the method, R2 is —OH, —N3, hydrogen, halogen, alkoxy, or alkynyloxy.
[0081] In some embodiments of the method, Ba is 5-bromouracil, 5-iodouracil, or 2,6-diaminopurine. In other embodiments of the method, Ba is modified by substitution with a fluorescent or biomolecule binding moiety. In yet other embodiments of the method, Ba is modified by substitution with a fluorescent or biomolecule binding moiety. In some embodiments of the method, the substituent on Ba is a fluorescent moiety. In other embodiments of the method, the substituent on Ba is biotin or avidin. In yet other embodiments of the method, the substituent on Ba is a fluorescent moiety. In some embodiments of the method, the substituent on Ba is biotin or avidin.
[0082] In some embodiments of the method, Z is pyridinium ion, triethylammonium ion, N,N-diisopropylethylammonium ion, 1,8-diazabicyclo[5.4.0]undec-7-enium ion, sodium ion, or potassium ion. In other embodiments of the method, Z is pyridinium ion, triethylammonium ion, N,N-diisopropylethylammonium ion, 1,8-diazabicyclo[5.4.0]undec-7-enium ion, sodium ion, or potassium ion. In some embodiments of the method, X is alkyl, alkoxy, —NRfRf, —SZ+, or —BH3Z+. In other embodiments of the method, X is alkyl, alkoxy, —NRfRf, —SZ+, or —BH3Z+.
[0083] In an embodiment of the method, the sulfur electrophile is Formula F, Formula E or Formula B. In some embodiments of the method, the sulfur electrophile is Formula F, Formula E or Formula B. In other embodiments of the method, the selenium electrophile is Formula G or Formula L. In yet other embodiments of the method, the selenium electrophile is Formula G or Formula L. In some embodiments of the method, the boronating agent is borane-N,N-diisopropylethylamine (BH3.DIPEA), borane-2-chloropyridine (BH3.CPy), borane-tetrahydrofurane (BH3.THF), or borane-dimethylsulfide (BH3.Me2S). In other embodiments of the method, the halogenating agent is CCl4, CBr4, Cl2, sulfuryl chloride (SO2Cl2), or N-chlorosuccinimide (NCS). In yet other embodiments of the method, the condensing reagent is bis(trichloromethyl)carbonate (BTC), Ph3PCl2, or N,N′-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BopCl).
[0084] In another aspect of the invention, a method is provided of identifying or detecting a target molecule in a sample, the method comprising: contacting a sample suspected of containing a target molecule with a nucleic acid sensor molecule of Formula 1, synthesized according to the methods of the invention, wherein a change in a signal generated by a signal generating unit indicates the presence of said target in said sample. The nucleic acid sensor molecule binds specifically with the target molecule. In some embodiments there is a plurality of nucleic acid sensor molecules. In some embodiments, the plurality of nucleic acid sensor molecules comprises nucleic acid sensor molecules which bind specifically to differing target molecules. In some instances, the method further comprises quantifying the change in signal generated by the signal generating unit to quantify the amount of target molecule in the sample. The signal generating unit detects any sort of signal, including but not limited to fluorescence, surface plasmon resonance, fluorescence quenching, chemiluminescence, interferometry, or refractive index detection.
[0085] The sample to be detected is an environmental sample, biohazard material, organic sample, drug, toxin, flavor, fragrance, or biological sample. The biological sample is a cell, cell extract, cell lysate, tissue, tissue extract, bodily fluid, serum, blood or blood product. In some embodiments of the method, the presence of the target molecule indicates the presence of a pathological condition. In some embodiments of the method, the presence of the target molecule indicates the presence of a desirable molecule.
[0086] In another aspect of the invention, a method is provided of amplifying desired regions of nucleic acid from a nucleic acid template comprising: (a) providing a plurality of first PCR primers having a region of fixed nucleotide sequence complementary to a consensus sequence of interest; (b) providing a plurality of second PCR primers, (c) amplifying the nucleic acid template via the PCR using the plurality of first PCR primers and the plurality of second PCR primers under conditions wherein a subset of the plurality of first primers binds to the consensus sequence of interest substantially wherever it occurs in the template, and a subset of the plurality of second primers binds to the template at locations removed from the first primers such that nucleic acid regions flanked by the first primer and the second primer are specifically amplified, and wherein the plurality of first PCR primers and/or the plurality of second PCT primers are nucleic acid molecules of Formula 1 which are produced according to the methods of the invention.
[0087] In some embodiments, the template is genomic DNA. In some embodiments, the template is eukaryotic genomic DNA. In some embodiments, the template is human genomic DNA. In some embodiments, the template is prokaryotic DNA. In some embodiments, the template is DNA which is a cloned genomic DNA, a subgenomic region of DNA, a chromosome, or a subchromosomal region. In some embodiments, the template is RNA.

INCORPORATION BY REFERENCE

[0088] All publications and patent applications disclosed herein in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0089] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
[0090] FIG. 1. 1H NMR spectrum of (SP)-4tt (CDCl3)
[0091] FIG. 2. 31P NMR spectrum of (SP)-4tt (CDCl3)
[0092] FIG. 3. 1H NMR spectrum of (RP)-4tt (CDCl3)
[0093] FIG. 4. 31P NMR spectrum of (RP)-4tt (CDCl3)
[0094] FIG. 5A. Crude UPLC® profile of (SP)-5tt
[0095] FIG. 5B. Crude UPLC® profile of (SP)-5tt using BTC in place of Ph3PCl2
[0096] FIG. 6A. Crude UPLC® profile of (SP)-5tt
[0097] FIG. 6B. Crude UPLC® profile of (SP)-5tt using BTC in place of PH3PCL2
[0098] FIG. 7A. Crude UPLC® profile of (RP)-5tt
[0099] FIG. 7B. Crude UPLC® profile of (RP)-5tt
[0100] FIG. 8. Crude UPLC® profile of (RP)-5tt
[0101] FIG. 9A. Crude UPLC® profile of (SP)-5ct
[0102] FIG. 9B. Crude UPLC® profile of (SP)-5ct
[0103] FIG. 10A. Crude UPLC® profile of (RP)-5ct
[0104] FIG. 10B. Crude UPLC® profile of (RP)-5ct
[0105] FIG. 11. Crude UPLC® profile of (SP)-5at
[0106] FIG. 12. Crude UPLC® profile of (RP)-5at
[0107] FIG. 13. Crude UPLC® profile of (SP)-5gt
[0108] FIG. 14. Crude UPLC® profile of (RP)-5gt
[0109] FIG. 15A. Crude UPLC® profile of (SP)-5tt
[0110] FIG. 15B. Crude UPLC® profile of (SP)-5tt
[0111] FIG. 16A. Crude UPLC® profile of (SP)-5tt
[0112] FIG. 16B. Crude UPLC® profile of (SP)-5tt
[0113] FIG. 17A. Crude UPLC® profile of (RP)-5tt
[0114] FIG. 17B. Crude UPLC® profile of (RP)-5tt
[0115] FIG. 18. Crude UPLC® profile of (SP)-5ct
[0116] FIG. 19. Crude UPLC® profile of (RP)-5ct.
[0117] FIG. 20A. Crude UPLC® profile of (SP)-5at
[0118] FIG. 20B. Crude UPLC® profile of (SP)-5at
[0119] FIG. 21. Crude UPLC® profile of (SP)-5at
[0120] FIG. 22A. Crude UPLC® profile of (RP)-5at
[0121] FIG. 22B. Crude UPLC® profile of (RP)-5at
[0122] FIG. 23. Crude UPLC® profile of (SP)-5gt
[0123] FIG. 24. Crude UPLC® profile of (RP)-5gt
[0124] FIG. 25. Crude UPLC® profile of (SP)-7tt
[0125] FIG. 26. Crude UPLC® profile of (RP)-7tt
[0126] FIG. 27. Crude UPLC® profile of (SP)-8tt
[0127] FIG. 28. Crude UPLC® profile of (RP)-8tt
[0128] FIG. 29A. Crude UPLC® profile of All-(SP)-[TPS]3T
[0129] FIG. 29B. MALDI TOF-MS spectrum of All-(SP)-[TPS]3T
[0130] FIG. 30A. Crude UPLC® profile of (SP, RP, SP)-[TPS]3T
[0131] FIG. 30B. MALDI TOF-MS spectrum of (SP, RP, SP)-[TPS]3T
[0132] FIG. 31A. Crude UPLC® profile of (RP, SP, RP)-[TPS]3T
[0133] FIG. 31B. MALDI TOF-MS spectrum of (RP, SP, RP)-[TPS]3T
[0134] FIG. 32A. Crude UPLC® profile of All-(RP)-[TPS]3T
[0135] FIG. 32B. MALDI TOF-MS spectrum of All-(RP)-[TPS]3T
[0136] FIG. 33A. Crude UPLC® profile of (SP)-9uMu
[0137] FIG. 33B. MALDI TOF-MS spectrum of (SP)-9uMu
[0138] FIG. 34A. Crude UPLC® profile of (RP)-9uMu
[0139] FIG. 34B. MALDI TOF-MS spectrum of (RP)-9uMu
[0140] FIG. 35A. Crude UPLC® profile of (SP)-10uFu
[0141] FIG. 35B. MALDI TOF-MS spectrum of (SP)-10uFu
[0142] FIG. 36A. Crude UPLC® profile of (RP)-10uFu
[0143] FIG. 36B. MALDI TOF-MS spectrum of (RP)-10uFu
[0144] FIG. 37A. Crude UPLC® profile of (SP)-11nt
[0145] FIG. 37B. MALDI TOF-MS spectrum of (SP)-11nt
[0146] FIG. 38A. Crude UPLC® profile of (RP)-11nt
[0147] FIG. 38B. MALDI TOF-MS spectrum of (RP)-11nt

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0148] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a” “an” and “the” include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. In this application, the use of “or” or “and” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes” and “included” is not limiting.
[0149] The term “nucleic acid” encompasses poly- or oligo-ribonucleotides (RNA) and poly- or oligo-deoxyribonucleotides (DNA); RNA or DNA derived from N-glycosides or C-glycosides of nucleobases and/or modified nucleobases; nucleic acids derived from sugars and/or modified sugars; and nucleic acids derived from phosphate bridges and/or modified phosphorous-atom bridges. The term encompasses nucleic acids containing any combinations of nucleobases, modified nucleobases, sugars, modified sugars, phosphate bridges or modified phosphorous atom bridges. Examples include, and are not limited to, nucleic acids containing ribose moieties, the nucleic acids containing deoxy-ribose moieties, nucleic acids containing both ribose and deoxyribose moieties, nucleic acids containing ribose and modified ribose moieties. The prefix poly- refers to a nucleic acid containing about 1 to about 10,000 nucleotide monomer units and wherein the prefix oligo- refers to a nucleic acid containing about 1 to about 200 nucleotide monomer units.
[0150] The term “nucleobase” refers to the parts of nucleic acids that are involved in the hydrogen-bonding that binds one nucleic acid strand to another complementary strand in a sequence specific manner. The most common naturally-occurring nucleobases are adenine (A), guanine (G), uracil (U), cytosine (C), and thymine (T).
[0151] The term “modified nucleobase” refers to a moiety that can replace a nucleobase. The modified nucleobase mimics the spatial arrangement, electronic properties, or some other physicochemical property of the nucleobase and retains the property of hydrogen-bonding that binds one nucleic acid strand to another in a sequence specific manner. A modified nucleobase can pair with all of the five naturally occurring bases (uracil, thymine, adenine, cytosine, or guanine) without substantially affecting the melting behavior, recognition by intracellular enzymes or activity of the oligonucleotide duplex.
[0152] The term “nucleoside” refers to a moiety wherein a nucleobase or a modified nucleobase is covalently bound to a sugar or modified sugar.
[0153] The term “sugar” refers to a monosaccharide in closed and/or open form. Sugars include, but are not limited to, ribose, deoxyribose, pentofuranose, pentopyranose, and hexopyranose moieties.
[0154] The term “modified sugar” refers to a moiety that can replace a sugar. The modified sugar mimics the spatial arrangement, electronic properties, or some other physicochemical property of a sugar.
[0155] The term “nucleotide” refers to a moiety wherein a nucleobase or a modified nucleobase is covalently linked to a sugar or modified sugar, and the sugar or modified sugar is covalently linked to a phosphate group or a modified phosphorous-atom moiety.
[0156] The term “chiral reagent” refers to a compound that is chiral or enantiopure and can be used for asymmetric induction in nucleic acid synthesis.
[0157] The term “chiral ligand” or “chiral auxiliary” refers to a moiety that is chiral or enantiopure and controls the stereochemical outcome of a reaction.
[0158] In a condensation reaction, the term “condensing reagent” refers to a reagent that activates a less reactive site and renders it more susceptible to attack by a nucleophile.
[0159] The term “blocking moiety” refers to a group that transiently masks the reactivity of a functional group. The functional group can be subsequently unmasked by removal of the blocking moiety.
[0160] The terms “boronating agents”, “sulfur electrophiles”, “selenium electrophiles” refer to compounds that are useful in the modifying step used to introduce BH3, S, and Se groups, respectively, for modification at the phosphorus atom.
[0161] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
[0162] The term “solid support” refers to any support which enables synthetic mass production of nucleic acids and can be reutilized at need. As used herein, the term refers to a polymer that is insoluble in the media employed in the reaction steps performed to synthesize nucleic acids, and is derivatized to comprise reactive groups.
[0163] The term “linking moiety” refers to any moiety optionally positioned between the terminal nucleoside and the solid support or between the terminal nucleoside and another nucleoside, nucleotide, or nucleic acid.
[0164] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
[0165] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
[0166] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a saturated alkyl group (which means that it does not contain any units of unsaturation, e.g. carbon-carbon double bonds or carbon-carbon triple bonds) or the alkyl moiety may be an unsaturated alkyl group (which means that it contains at least one unit of unsaturation). The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or include a cyclic portion. The point of attachment of an alkyl is at a carbon atom that is not part of a ring.
[0167] The “alkyl” moiety may have 1 to 10 carbon atoms (whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). Alkyl includes both branched and straight chain alkyl groups. The alkyl group of the compounds described herein may be designated as “C1-C6 alkyl” or similar designations. By way of example only, “C1-C6 alkyl” indicates that there are one, two, three, four, five, or six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, allyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. In one aspect, an alkyl is a C1-C6 alkyl.
[0168] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings are formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups are a substituted or unsubstituted. In one aspect, an aryl is a phenyl or a naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). In one aspect, an aryl is a C6-C10aryl.
[0169] “Heteroaryl” or alternatively, “heteroaromatic” refers to a 5- to 18-membered aromatic radical (e.g., C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range; e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteraryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), or —S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0170] The term “alicyclic” refers to an all carbon moiety that is both aliphatic and cyclic. Alicyclic groups contain one or more all-carbon rings which may be either saturated or unsaturated, but do not have aromatic character. Alicyclic groups are substituted or unsubstituted and may contain from one to ten carbon atoms. In one aspect, an alicyclic is a monocyclic cycloalkane. In another aspect an alicyclic is a bicyclic cycloalkane.
[0171] The term “aralkyl” refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, all of which may be optionally substituted.
[0172] An “acyl moiety” refers to an alkyl(C═O), aryl(C═O), or aralkyl(C═O) group. An acyl moiety can have an intervening moiety (Y) that is oxy, amino, thio, or seleno between the carbonyl and the hydrocarbon group. For example, an acyl group can be alkyl-Y—(C═O), aryl-Y—(C═O) or aralkyl-Y—(C═O).
[0173] “Alkenyl” groups are straight chain, branch chain, and cyclic hydrocarbon groups containing at least one carbon-carbon double bond. Alkenyl groups can be substituted.
[0174] “Alkynyl” groups are straight chain, branch chain, and cyclic hydrocarbon groups containing at least one carbon-carbon triple bond. Alkynyl groups can be substituted.
[0175] An “alkoxy” group refers to an alkyl group linked to oxygen i.e. (alkyl)-O— group, where alkyl is as defined herein. Examples include methoxy (—OCH3) or ethoxy (—OCH2CH3) groups.
[0176] An “alkenyloxy” group refers to an alkenyl group linked to oxygen i.e. (alkenyl)-O— group, where alkenyl is as defined herein.
[0177] An “alkynyloxy” group refers to an alkynyl group linked to oxygen i.e. (alkynyl)-O— group, where alkynyl is as defined herein.
[0178] An “aryloxy” group refers to to an aryl group linked to oxygen i.e. (aryl)-O— group, where the aryl is as defined herein. An example includes phenoxy (—OC6H5).
[0179] The term “alkylseleno” refers to an alkyl group having a substituted seleno group attached thereto i.e. (alkyl)-Se— group, wherein alkyl is defined herein.
[0180] The term “alkenylseleno” refers to an alkenyl group having a substituted seleno group attached thereto i.e. (alkenyl)-Se— group, wherein alkenyl is defined herein.
[0181] The term “alkynylseleno” refers to an alkynyl group having a substituted seleno group attached thereto i.e. (alkynyl)-Se— group, wherein alkenyl is defined herein.
[0182] The term “alkylthio” refers to an alkyl group attached to a bridging sulfur atom i.e. (alkyl)-S— group, wherein alkyl is defined herein. For example, an alkylthio is a methylthio and the like.
[0183] The term “alkenylthio” refers to an alkenyl group attached to a bridging sulfur atom i.e. (alkenyl)-S— group, wherein alkenyl is defined herein.
[0184] The term “alkynylthio” refers to an alkynyl group attached to a bridging sulfur atom i.e. (alkynyl)-S— group, wherein alkenyl is defined herein.
[0185] The term “alkylamino” refers to an amino group substituted with at least one alkyl group i.e. —NH(alkyl) or —N-(alkyl)2, wherein alkyl is defined herein.
[0186] The term “alkenylamino” refers to an amino group substituted with at least one alkenyl group i.e. —NH(alkenyl) or —N-(alkenyl)2, wherein alkenyl is defined herein.
[0187] The term “alkynylamino” refers to an amino group substituted with at least one alkynyl group i.e. —NH(alkynyl) or —N-(alkynyl)2, wherein alkynyl is defined herein.
[0188] The term “halogen” is intended to include fluorine, chlorine, bromine and iodine.
[0189] A “fluorescent group” refers to a molecule that, when excited with light having a selected wavelength, emits light of a different wavelength. Fluorescent groups include, but are not limited to, indole groups, fluorescein, tetramethylrhodamine, Texas Red, BODIPY, 5-[(2-aminoethyl)amino]napthalene-1-sulfonic acid (EDANS), coumarin and Lucifer yellow.
[0190] An “ammonium ion” is a positively charged polyatomic cation of the chemical formula NH4+.
[0191] An “alkylammonium ion” is an ammonium ion that has at least one of its hydrogen atoms replaced by an alkyl group, wherein alkyl is defined herein. Examples include triethylammonium ion, N,N-diisopropylethylammonium ion.
[0192] An “iminium ion” has the general structure R2C═NR2+. The R groups refer to alkyl, alkenyl, alkynyl, aryl groups as defined herein. A “heteroaromatic iminium ion” refers to an imminium ion where the nitrogen and its attached R groups form a heteroaromatic ring. A “heterocyclic iminium ion” refers to an imminium ion where the nitrogen and its attached R groups form a heterocyclic ring.
[0193] The terms “amino” or “amine” refers to a —N(Rh)2 radical group, where each Rh is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a —N(Rf)2 group has two Rf other than hydrogen they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —N(Rf)2 is meant to include, but not