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2.  Enantio- and Diastereoselective Synthesis of syn-β-Hydroxy-α-Vinyl Carboxylic Esters via Reductive Aldol Reactions of Ethyl Allenecarboxylate with 10-TMS-9-Borabicyclo[3.3.2]decane and DFT Analysis of the Hydroboration Pathway 
Organic letters  2013;15(21):10.1021/ol4025277.
An enantio- and diastereoselective synthesis of syn-β-hydroxy-α-vinyl carboxylate esters 3 via the reductive aldol reaction of ethyl allenecarboxylate (2) with 10-trimethylsilyl-9-borabicyclo[3.3.2]decane (1R, Soderquist’s borane) has been developed. Density functional theory calculations suggest that the allene hydroboration involves the 1,4-reduction of 2 with the chiral borane 1R, leading directly to dienolborinate Z-(O)-8a.
PMCID: PMC3849616  PMID: 24138187
3.  Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-Chagas agents 
Journal of medicinal chemistry  2013;56(19):10.1021/jm401067s.
A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 of 0.65 µM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, that have low nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14–18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6 and 3A4 (<50% inhibition at 1 µM). A rationale for the improvement of microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the T. brucei CYP51 (TbCYP51) ortholog has been characterized by x-ray structure analysis.
PMCID: PMC3864028  PMID: 24079662
Chagas disease; non-azole CYP51 inhibitors; structure guided drug design; structure activity and property relationships; x-ray structure
4.  Enantiodivergent hydroboration reactions of a racemic allenylsilane with diisopinocampheylborane and Curtin–Hammett controlled double asymmetric crotylboration reactions of (S)-E-αphenyldimethylsilyl(ddiisopinocampheyl)-crotylborane 
Tetrahedron  2013;69(36):7551-7558.
The enantiodivergent hydroboration reactions of racemic allenylsilane (±)-4 with (dIpc)2BH and subsequent crotylboration of achiral aldehydes with the product crotylborane (S)-E-5 at −78 °C provide (E)-δ-silyl-anti-homoallylic alcohols 6 in 71–89% yield and with 93–96% ee. Intriguingly, mismatched double asymmetric crotylboration reactions of enantioenriched chiral aldehydes 20 with (S)-E-5 proceed under Curtin–Hammett control to give anti-β-hydroxylcrotylsilanes 24 as the only products.
PMCID: PMC3779609  PMID: 24068848
Enantiodivergent hydroboration; Mismatched double asymmetric; crotylboration; Curtin–Hammett control
5.  (Diisopinocampheyl)borane-Mediated Reductive Aldol Reactions: Highly Enantio and Diastereoselective Synthesis of Syn-Aldols from N-Acryloylmorpholine** 
Angewandte Chemie (International ed. in English)  2013;52(33):10.1002/anie.201302535.
An efficient and highly enantio- and diastereoselective synthesis of syn propionamide aldols is described. Formation of the Z-enolborinate via the hydroboration of 4-acryloylmorpholine with (diisopinocampheyl)borane followed by aldol reactions with representative achiral and chiral aldehydes provided syn-α-methyl-β-hydroxy morpholine carboxamides with excellent enantio- and diastereoselectivity (96–98% ee and d.r. >20:1).
PMCID: PMC3813003  PMID: 23818095
Diisopinocampheylborinate; aldol; enantioselective; diastereoselective; morpholine amide
6.  (Diisopinocampheyl)borane-Mediated Reductive Aldol Reactions of Acrylate Esters: Enantioselective Synthesis of Anti-Aldols 
Organic letters  2013;15(15):3922-3925.
The (diisopinocampheyl)borane promoted reductive aldol reaction of acrylate esters 4 is described. Isomerization of the kinetically formed Z(O)-enolborinate 5Z to the thermodynamic E(O)-enolborinate 5E via 1,3-boratropic shifts, followed by treatment with representative achiral aldehydes, leads to anti-α-methyl-β-hydroxy esters 9 or 10 with excellent diastereo- (up to ≥20:1 dr) and enantioselectivity (up to 87% ee). Results of double asymmetric reactions of 5E with several chiral aldehydes are also presented.
PMCID: PMC3773495  PMID: 23885946
7.  Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties 
The development of a series of potent and highly selective casein kinase 1δ/ε (CK1δ/ε) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC50 ≤ 50 nM versus CK1δ. The two lead compounds have ≤ 100 nM EC50 values in MTT assays against the human A375 melanoma cell line and have physical, in vitro and in vivo PK properties suitable for use in proof of principle animal xenograft studies against human cancer cell lines.
PMCID: PMC3783656  PMID: 23787102
Casein kinase 1δ/ε inhibitor; Selective CK1δ/ε inhibitor; Purine scaffold kinase inhibitor; Antiproliferative agent; Potent growth inhibitor of A375 melanoma; cell line
8.  Enantiodivergent Hydroboration Reactions of a Racemic Allenylsilane with Diisopinocampheylborane and Curtin-Hammett Controlled Double Asymmetric Crotylboration Reactions of (S)-E-α-phenyldimethylsilyl(ddiisopinocampheyl)-crotylborane 
Tetrahedron  2013;69(26):5468-5475.
The enantiodivergent hydroboration reactions of racemic allenylsilane (±)-4 with (dIpc)2BH and subsequent crotylboration of achiral aldehydes with the product crotylborane (S)-E-5 at −78 °C provide (E)-δ-silyl-anti-homoallylic alcohols 6 in 71–89% yield and with 93–96% ee. Intriguingly, mismatched double asymmetric crotylboration reactions of enantioenriched chiral aldehydes 20 with (S)-E-5 proceed under Curtin-Hammett control to give anti-3-hydroxylcrotylsilanes 24 as the only products.
PMCID: PMC3768161  PMID: 24039304
Enantiodivergent hydroboration; Mismatched double asymmetric crotylboration; Curtin-Hammett control
9.  Enantioselective Synthesis of (Z)-2-Methyl-1,5-anti- and (E)-2-Methyl-1,5-anti-Pentenediols Via an Allene Hydroboration-Double Allylboration Reaction Sequence 
Kinetic controlled hydroboration of allenylboronate 5 followed by double allylboration with resulting allylborane (Z)-7 gave (Z)-2-methyl-1,5-anti-pentenediols 6 in good yield and high enantioselectivity in the presence of 10% BF3•OEt2 as the catalyst in the second allylboration step. Under thermodynamically controlled isomerization conditions, (Z)-7 can readily isomerize to (E)-7. Double allylboration of representative aldehydes with allylborane (E)-7 gave (E)-2-methyl-1,5-anti-pentenediols 4 in good yield and high enantioselectivity without requiring use of the BF3•OEt2 catalyst. Thus, 2-methyl-1,5-anti-pentenediols with either olefin geometry can be synthesized from the same allenylboronate precursor 5. Furthermore, 1,5-pentenediols 4 and 6 can be easily converted to 1,3,5-triols with excellent diastereoselectivity in one step.
PMCID: PMC3733567  PMID: 23758559
10.  Small-molecule inhibitors of acetyltransferase p300 identified by high-throughput screening are potent anticancer agents 
Molecular cancer therapeutics  2013;12(5):610-620.
Acetyltransferase p300 (KAT3B) plays key roles in signaling cascades that support cancer cell survival and sustained proliferation. Thus, p300 represents a potential anticancer therapeutic target. To discover novel anticancer agents that target p300, we conducted a high-throughput screening campaign. A library of 622,079 compounds was assayed for cytotoxicity to the triple-negative breast cancer (TNBC) cell line MDA-MB-231 but not to the human mammary epithelial cells. The resulting compounds were tested in a biochemical assay for inhibiting the enzymatic activity of p300. One compound (L002, NSC764414) displayed an IC50 of 1.98 μM against p300 in vitro, inhibited acetylation of histones and p53, and suppressed STAT3 activation in cell-based assays. L002 could be docked to the active site of the p300 catalytic domain. Biochemical tests of a series of related compounds revealed functional groups that may impact inhibitory potency of L002 against p300. Interestingly, these analogs showed inhibitory activities against CBP (the cellular paralog of p300), PCAF and GCN5, but not to other acetyltransferases (KAT5, KAT6B and KAT7), histone deacetylases (HDACs) and histone methyltransferases. Among the NCI-60 panel of cancer cell lines, leukemia and lymphoma cell lines were extremely sensitive to L002, whereas it is toxic to only a limited number of cell lines derived from solid tumors. Notably, breast cancer cell lines, especially those derived from TNBC, were highly susceptible to L002. In vivo, it potently suppressed tumor growth and histone acetylation of MDA-MB-468 xenografts. Thus, these new acetyltransferase inhibitors are potential anticancer therapeutics.
PMCID: PMC3651759  PMID: 23625935
11.  Enantio- and Diastereoselective Synthesis of N-Acetyl Dihydrotetrafibricin Methyl Ester 
A highly diastereoselective synthesis of N-acetyl dihydrotetrafibricin methyl ester (34) is described. The synthesis features three enantioselective double allylboration reactions, an intramolecular hydrosilylation/Tamao-Fleming oxidation sequence to establish seven of the hydroxy-bearing stereocenters of 34. Especially noteworthy is the fragment assembly double allyboration reaction of 2 and 7 with reagent 3 that provides the advanced intermediate 6 with >20:1 diastereoselectivity.
PMCID: PMC3679187  PMID: 23530855
12.  Chiral Brønsted Acid Catalyzed Enantioselective Synthesis of anti-Homopropargyl Alcohols via Kinetic Resolution-Aldehyde Allenylboration Using Racemic Allenylboronates 
Organic letters  2013;15(7):1568-1571.
A chiral phosphoric acid catalyzed kinetic resolution/allenylboration of racemic allenylboronates with aldehydes is described. Allenylboration of aldehydes with 2.8 equivalents of allenylboronate (±)-1 in the presence of 10 mol% of catalyst (R)-2 provided anti-homopropargyl alcohols 3 in 83–93% yield with 9:1 to 20:1 diastereoselectivity and 73–95% e.e. The catalyst enables the kinetic resolution of the racemic allenylboronate (±)-1 to set the methyl stereocenter and biases the facial attack of the aldehyde to set the stereochemistry of the hydroxyl group in 3.
PMCID: PMC3640598  PMID: 23484801
13.  Enantioselective Synthesis of (E)-δ-Silyl-anti-Homoallylic Alcohols Via An Enantiodivergent Hydroboration-Crotylboration Reaction of a Racemic Allenylsilane 
Organic letters  2013;15(7):1662-1665.
The enantioselective hydroboration of racemic allenylsilane (±)-4 with (dIpc)2BH proceeds via enantiodivergent pathways to give vinylborane 11 and crotylborane intermediate (S)-E-5. Subsequent crotylboration of aldehyde substrates with (S)-E-5 at −78 °C provides (E)-δ-silyl-anti-homoallylic alcohols in 71–89% yield and with 93–96% ee.
PMCID: PMC3663895  PMID: 23534391
14.  Crotylboron-Based Synthesis of the Polypropionate Units of Chaxamycins A/D, Salinisporamycin, and Rifamycin S 
Syntheses of the C(15)–C(27) fragments of chaxamycins A/D, rifamycin S, and the C(12)–C(24) fragment of salinisporamycin have been accomplished in ten steps from commercially available starting materials. Three crotylboron reagents were utilized to construct the seven contiguous stereocenters in these fragments with excellent stereoselectivity.
Aldehyde allylboration, synthesis of propionate fragments of chaxamycins A and D, rifamycin S and salinisporamycin
PMCID: PMC3465507  PMID: 22703288
15.  Stereoselective Synthesis of the Disaccharide Unit of Incednine 
Organic letters  2012;15(1):62-64.
A stereoselective synthesis of a fully protected version of the disaccharide unit (2) of incednine (1) is described. The synthesis of 2 proceeds in 4.7% overall yield from commercially available allyl α-D-galactopyranoside over the longest linear sequence.
PMCID: PMC3537911  PMID: 23249392
16.  Enantioselective Synthesis of the C(1)–C(11) Fragment of Tedanolide C 
Organic letters  2012;15(1):58-61.
A convergent synthesis of the protected C(1)–C(11) fragment 6 of the targeted enantiomer of tedanolide C is described. The key step of the synthesis is the Felkin-Ahn addition of vinyl iodide 7 to aldehyde 8 that proceeds in 80% yield with 4:1 diastereoselectivity.
PMCID: PMC3539184  PMID: 23249423
Journal of chemical ecology  2009;35(8):861-870.
Phyllium westwoodii is a species of phasmid insect (Order Phasmatodea) in the more specific group known as leaf insects (Family Phylliidae). These rather large and ornate creatures are known for their morphological resemblance to plant leaves for camouflage. Pyrazines are a common class of compounds used or produced by a wide variety of organisms, even humans. When an individual of P. westwoodii is disturbed, it sprays an opaque liquid from a pair of prothoracic glands which are utilized by other phasmid species for defense. The current study has found that this liquid contains glucose and a mixture of 3-isobutyl-2,5-dimethylpyrazine, 2,5-dimethyl-3-(2-methylbutyl)pyrazine, and 2,5-dimethyl-3-(3-methylbutyl)pyrazine. This is the first report of pyrazines found in the defensive gland spray of phasmid insects and the first chemical analysis of glandular material from family Phylliidae.
PMCID: PMC3787517  PMID: 19685263
Insect; Phyllium westwoodii; Phasmatodea; Phasmid; Phylliidae; Chemical ecology; Defense; Dimethyl alkylpyrazine; 3-Isobutyl-2,5-dimethylpyrazine; 2,5-Dimethyl-3-(2-methylbutyl)pyrazine; 2,5-Dimethyl-3-(3-methylbutyl)pyrazine; Glucose
Journal of chemical ecology  2012;38(9):1105-1115.
Insects are the largest and most diverse group of organisms on earth, with over 1,000,000 species identified to date. Stick insects (“walkingsticks” or “phasmids”, Order Phasmatodea) are well known for and name derived from their uncanny stereotypical use of camouflage as a primary line of defense from predation. However, many species also possess a potent chemical defense spray. Recently we discovered that the defensive spray of Asceles glaber contains spiroketals (confirmed major component: (2S,6R)-(−)(E)-2-methyl-1,7-dioxaspiro[5.5]undecane and tentative minor component: 2-ethyl-1,6-dioxaspiro[4.5]decane) and glucose. In this paper we 1) illustrate the identification of spiroketals and glucose in the defense spray of A. glaber using Nuclear Magnetic Resonance (NMR), Gas Chromatography/Mass Spectrometry (GC/MS), and comparison with a synthetic reference sample, 2) provide the elucidation of the absolute configuration of the major spiroketal in that defense spray and 3) demonstrate the effect of this compound and its enantiomer on both fire ants (Solenopsis invicta) and mosquitoes (Aedes aegypti).
PMCID: PMC3473114  PMID: 22976590
Spiroketal; Phasmatodea; Asceles glaber; Solenopsis invicta; Aedes aegypti; Defense
19.  Enantioselective Synthesis of anti- and syn-homopropargyl alcohols via Chiral Brønsted Acid Catalyzed asymmetric Allenylboration reactions 
Journal of the American Chemical Society  2012;134(26):10947-10952.
Chiral Brønsted acid catalyzed asymmetric allenylboration reactions are described. Under optimized conditions, anti-homopropargyl alcohols 2 are obtained in high yields with excellent diastereo- and enantioselectivities from stereochemically matched aldehyde allenylboration reactions with (M)-1 catalyzed by the chiral phosphoric acid (S)-4. The syn-isomers 3 can also be obtained in good diastereoselectivities and excellent enantioselectivities from the mismatched allenylboration reactions of aromatic aldehydes using (M)-1 in the presence of the enantiomeric phosphoric acid (R)-4. The stereochemistry of the methyl group introduced into 2 and 3 is controlled by the chirality of the allenylboronate (M)-1, whereas the configuration of the new hydroxyl stereocenter is controlled by the enantioselectivity of the chiral phosphoric acid catalyst used in these reactions. The synthetic utility of this methodology was further demonstrated in triple asymmetric syntheses of a variety of anti,anti-stereotriads, the direct synthesis of which has constituted a significant challenge using previous generations of aldol and crotylmetal reagents.
PMCID: PMC3474359  PMID: 22731887
20.  Diastereo- and Enantioselective Synthesis of (E)-2-Methyl-1,2 -syn- and (E)-2-Methyl-1,2 -anti-3-pentenediols via Allenylboronate Kinetic Resolution with (dIpc)2BH and Aldehyde Allylboration 
Organic letters  2012;14(12):3028-3031.
Enantioselective hydroboration of racemic allenylboronate (±)-1 with 0.48 equiv of (dIpc)2BH at −25 °C proceeds with efficient kinetic resolution and provides allylborane (R)-Z-4. When heated to 95 °C, allylborane (R)-Z-4 isomerizes to the thermodynamically more stable allylborane isomer (S)-E-7. Subsequent allylboration of aldehydes with (R)-Z-4 or (S)-E-7 at −78 °C followed by oxidative workup provides 1,2-syn- or 1,2-anti-diols, 2 or 3, respectively, in 87–94% ee.
PMCID: PMC3426628  PMID: 22646839
22.  Enantioselective Synthesis of (+)-Crocacin C. An Example of A Highly Challenging Mismatched Double Asymmetric δ-Stannylcrotylboration Reaction 
Organic Letters  2012;14(7):1880-1883.
A concise, enantioselective synthesis of (+)-crocacin C is described, featuring a highly diastereoselective mismatched double asymmetric δ-stannylcrotylboration of the stereochemically demanding chiral aldehyde 9 with the bifunctional crotylborane reagent (S)-E-10. The total synthesis of (+)-crocacin C was accomplished in seven steps (longest linear sequence) starting from commercially available precursors.
PMCID: PMC3321065  PMID: 22409510
23.  Enantioselective Synthesis of (−)-Basiliskamide A 
Organic Letters  2012;14(6):1556-1559.
Basiliskamide A is an antifungal polyketide natural product isolated by Andersen and co-workers from a Bacillus laterosporus isolate, PNG-276. A nine-step enantioselective synthesis of basiliskamide A is reported, starting from commercially available β-hydroxy ester 7. The synthesis features a highly diastereoselective mismatched double asymmetric δ-stannylallylboration reaction of aldehyde 5 with the bifunctional allylborane reagent 4.
PMCID: PMC3306514  PMID: 22372693
24.  Highly Stereoselective Synthesis of Anti, Anti-Dipropionate Stereotriads: A Solution to the Long-Standing Problem of Challenging Mismatched Double Asymmetric Crotylboration Reactions# 
The stereocontrolled synthesis of the β-branched anti, anti-dipropionate stereotriad 4 via aldol or crotylmetal chemistry represents a historical challenge to the organic synthesis community. Here we describe a general solution to the long-standing problem associated with the synthesis of 4 by utilizing mismatched double asymmetric crotylboration reactions of enantioenriched α-methyl substituted aldehydes with the chiral, nonracemic crotylborane reagent (S)-(E)-22 (or its enantiomer). This method not only provides direct access to anti, anti-dipropionate stereotriads 24 [a synthetic equivalent of 4] with very good (5-8:1) if not excellent (≥15:1) diastereoselectivity from β-branched chiral aldehydes with ≤50:1 intrinsic diastereofacial selectivity preferences, but also provides a vinylstannane unit in the products that is properly functionalized for use in subsequent C-C bond forming events. We anticipate that this method will be widely applicable and will lead to substantial simplification of strategies for synthesis of polyketide natural products.
PMCID: PMC3292054  PMID: 22332989
25.  Structure Guided Development of Novel Thymidine Mimetics targeting Pseudomonas aeruginosa Thymidylate Kinase: from Hit to Lead Generation 
Journal of Medicinal Chemistry  2012;55(2):852-870.
Thymidylate kinase (TMK) is a potential chemotherapeutic target because it is directly involved in the synthesis of an essential component, thymidine triphosphate, in DNA replication. All reported TMK inhibitors are thymidine analogs, which might retard their development as potent therapeutics due to cell permeability and off-target activity against human TMK. A small molecule hit (1, IC50 = 58 μM), which has reasonable inhibition potency against Pseudomonas aeruginosa TMK (PaTMK), was identified by the analysis of the binding mode of thymidine or TP5A in a PaTMK homology model. This hit (1) was co-crystallized with PaTMK, and several potent PaTMK inhibitors (leads, 46, 47, 48, and 56, IC50 = 100–200 nM) were synthesized using computer aided design approaches including virtual synthesis/screening, which was used to guide the design of inhibitors. The binding mode of the optimized leads in PaTMK overlaps with that of other bacterial TMKs, but not with human TMK which shares few common features with the bacterial enzymes. Therefore, the optimized TMK inhibitors described here should be useful for the development of antibacterial agents targeting TMK without undesired off-target effects. In addition, an inhibition mechanism associated with the LID loop, which mimics the process of phosphate transfer from ATP to dTMP, was proposed based on X-ray co-crystal structures, homology models, and SAR results.
PMCID: PMC3306445  PMID: 22243413

Results 1-25 (75)