Directing Stem Cell Fate: The Synthetic Natural Product Connection

Review pubs.acs.org/CR

Directing Stem Cell Fate: The Synthetic Natural Product Connection Trevor C. Johnson†,§ and Dionicio Siegel*,‡ †

Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, United States

‡

ABSTRACT: Stem cells possess remarkable potential for the treatment of a broad array of diseases including many that lack therapeutic options. However, the use of cell-based products derived from stem cells as therapeutics has limitations including rejection, sufficient availability, and lack of appropriate engraftment. Chemical control of stem cells provides potential solutions for overcoming many of the current limitations in cell-based therapeutics. The development of exogenous molecules to control stem cell self-renewal or differentiation has arrived at natural product-based agents as an important class of modulators. The ex vivo production of cryopreserved cellular products for use in tissue repair is a relatively new area of medicine in which the conventional hurdles to implementing chemicals to effect human health are changed. Translational challenges centered on chemistry, such as pharmacokinetics, are reduced. Importantly, in many cases the desired human tissues can be evaluated against new chemicals, and approaches to cellular regulation can be validated in the clinically applicable system. As a result linking new and existing laboratory syntheses of natural products with findings of the compounds’ unique abilities to regulate stem cell fate provides opportunities for developing improved methods for tissue manufacture, accessing probe compounds, and generating new leads that yield manufactured cells with improved properties. This review provides a summary of natural products that have shown promise in controlling stem cell fate and which have also been fully synthesized thereby providing chemistry platforms for further development.

CONTENTS 1. Introduction 2. Chemical Control of Stem Cell Fate 2.1. Natural Product Control of Stem Cell Fate 3. Embryonic Stem Cell Regulators 3.1. Compounds Promoting Self-Renewal of Embryonic Stem Cells 3.1.1. Doxycycline 3.1.2. Forskolin 3.1.3. Okadaic Acid 3.2. Differentiation of Embryonic Stem Cells 3.2.1. Cyclopamine 3.2.2. Cyclosporin A 3.2.3. Indolactam V 3.2.4. Quinidine Derivatives 3.2.5. Stauprimide 4. Hematopoietic Stem Cell Regulators 4.1. Expansion (Self-Renewal) of Hematopoietic Stem and Progenitor Cells 4.1.1. Eupalinilide E 4.1.2. Garcinol 4.1.3. Prostaglandin E2 4.1.4. Chlaydocin, Trichostatin A, and Trapoxin B 4.2. Differentiation of Hematopoietic Stem Cells 4.2.1. Euphohelioscopin A 4.2.2. Phorbol Esters 4.2.3. Placotylene A 5. Neural Stem Cell Regulators 5.1. Expansion of Neural Stem Cells © 2017 American Chemical Society

5.1.1. Huperazine 5.1.2. HU210 5.1.3. Alstoscholarisine A 5.2. Differentiation of Neural Stem Cells 5.2.1. Apicidin 6. Mesenchymal Stem Cells 6.1. Differentiation 6.1.1. FK506 6.1.2. Wedelolactone 7. Concluding Remarks Author Information Corresponding Author ORCID Present Address Notes Biographies Acknowledgments References

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1. INTRODUCTION Stem cells have significant potential for the development of new cell-based treatments for degenerative diseases and tissue repair.1 Stem cells give rise to all of the cells in adult organisms providing the basis for the organs that make up humans and animals.2

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Special Issue: Natural Product Synthesis Received: January 9, 2017 Published: August 3, 2017 12052

DOI: 10.1021/acs.chemrev.7b00015 Chem. Rev. 2017, 117, 12052−12086

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Figure 1. Natural products regulating stem cell self-renewal and differentiation.

These early cells also function as a reserve providing an essentially limitless supply of new cells to replenish lost or injured tissues throughout an organism’s lifetime.3 However, later stage, adult stem cells only proliferate a limited number of times and are less sensitive to external guidance cues. When stem cells are appropriately activated they can either increase their number through cellular division (self-renewal) or change (differentiate) into a cell type with a more specific physiological function. Depending on the organ, stem cells can continually undergo expansion and differentiation. Bone, for example,

undergoes remodeling with replacement of 10% of the skeleton per year, while in other organs, such as the heart, stem cells remain dormant waiting for events that cause specific signaling to reactivate leading the cells to undergo self-renewal and differentiation. Stem cells can be categorized as embryonic or tissue-specific stem cells. Embryonic stem cells, which can persist in an undifferentiated state, can differentiate into all tissuespecific stem cells. Of stem cells used, embryonic stem cells are associated with ethical debates due to their isolation from the early embryo while tissue-specific stem cells are typically free 12053


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provide, in theory, a quicker entry into advanced preclinical testing. The connection of stem cells and cancer has provided evidence that treatment of cancer cells with stem-cell-like characteristics that include self-renewal and survival mechanisms drive the growth and survival of these cancers.12 Approaches to treating these cells provide a promising strategy for the treatment, and possibly the complete eradication of cancer.13 In addition to functioning as selective cytotoxic agents, natural products can also be used to selectivity promote the differentiation of cancer stem cells, thereby removing the source of new cancer cells. While this review focuses on regenerative science, previous reviews that discuss natural product approaches to selectively kill cancer stem cells can provide an overview of this field.14,15

from these concerns. The ability to generate induced pluripotent stem cells from adult cells has provided an alternative to embryonic stem cells providing access to cells with the ability to indefinitely self-renew and differentiate into tissue-specific cell types similar to embryonic stem cells.4−6 In contrast, tissuespecific stems cells have a limited ability to produce other cell types, for example hematopoietic stem cells can generate red or white blood cells and platelets but not liver cells. Self-renewal, the process where a stem cell divides to produce more of the same cells, occurs over an organism’s lifetime. This requires the cell to remain multipotent or pluripotent, depending on the cell type and block differentiation. If differentiation occurs stem cells lose their ability to self-renew depending on the type of cell. In this process the intrinsic regulatory elements that induce self-renewal are balanced by tumor suppressors limiting renewal and maintaining genomic consistency. Through self-renewal, proliferating cells can maintain their multipotency or pluripotency while blocking cell death and differentiation. Extrinsic signaling regulate stem cell activation in response to physiological changes ensuring tissue homeostasis and appropriate development. These extrinsic signaling events are produced from the microenvironment surrounding the cells, the niche, providing appropriate cues. In differentiation these include signaling factors, released from proximal cells, that activate genes to produce proteins needed for the correct formation of the terminal cell type. Given that all differentiated cells are produced by this process (there are approximately 220 cell types in humans) tight regulation is required to ensure the correct cells are generated and in an appropriate number. For example if an embryonic stem cell is transplanted indiscriminately into a host it will develop into a teratoma, a cells mass composed of different tissue types due to the lack of appropriate guidance cues.

2.1. Natural Product Control of Stem Cell Fate

Through phenotypic screens, natural product and their derivatives have emerged as important regulators of stem cell fate. In addition to new natural products uncovered through screening, existing compounds with established mechanisms of action have been used to validate hypotheses on pathways that are relevant to self-renewal and differentiation. The FDA approval process for the use of stem-cell-based products16 derived through ex vivo techniques requires the cells generated by treatment with compound(s) to go through approval rather than the compound (this process is being refined at the time of this review). Importantly, the opportunity in ex vivo production of cells overcomes one of the major challenges in advancing natural products (and most drugs) through preclinical development: pharmacokinetic properties. The study of natural products that control stem cell fate is initiated by screening against different stem cell types focusing on self-renewal or differentiation that are monitored for by determining the new cell types produced by specific cell surface markers. Three major types of stem cells have been the focus of the majority for these studies: embryonic, hematopoietic, and neural stem cells. Within these three classes there are natural products that promote self-renewal or differentiation. With syntheses of a number of the compounds that proceeded the discovery of the compounds’ effects on stem cells the laboratory approaches provide chemistry platforms to further develop new chemicals to enhance the effects, clarify/identify mechanisms of action, or provide new leads with marketable potential. In many cases, new synthetic compounds can be directly studied in human tissues providing a clear connection to therapeutic potential. The list of natural products covered is outlined in Figure 1 with structural formulas, stem cell type regulated, and effect of the compound on self-renewal/differentiation.

2. CHEMICAL CONTROL OF STEM CELL FATE The external control of stem cell fate has led to the artificial directing of self-renewal and differentiation.7−9 By controlling the environment surrounding stem cells and activating specific signaling pathways access to different cell types starting from stem cells has been made possible.10 Given the specificity requirements many of the strategies use in drug development can be applied in the exogenous control of stem cells. Small molecules provide precise control over biological functions and can be made reversible by removal of the chemical. Phenotypic screens have provided the basis for discovery of the majority of chemical stem cell regulators. From these discoveries the mechanisms of action of the compounds can be determined providing biological targets. With identified targets, structure guided optimization can be achieved as well as the development of high throughput assays to identify additional regulators of the newly discovered enzyme, messenger, and/or pathway. Many of the compounds discovered to regulate stem cells closely resemble the compounds identified in the initial chemical screens used and in many cases are the same chemical. This is possible as studies controlling stem cells can be achieved ex vivo, with tissues and cells derived from organisms studied outside their host. With a major focus of stem-cell-based therapies on regenerative science there is an effort to develop a cost-effective, cryopreserved supply of different cell types that can be used in the health setting for tissue repair.11 Growth of large numbers of homogeneous cell starting from isolated (donated) cells provides this desirable resource. Through ex vivo chemically directed production of cells many of the pharmacokinetic requirements are relaxed, compared to conventional drug development, and

3. EMBRYONIC STEM CELL REGULATORS Embryonic stem cells give rise to the approximately 220 cell types in the adult human. Embryonic stem cells, relative to adult stem cells which are multipotent, are the most versatile. High

Figure 2. Structure of doxycycline (1). 12054


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Scheme 1. Myers Synthesis of Doxycycline (1)

3.1.1. Doxycycline. The tetracycline derivative doxycycline (1; Figure 2) when added as a supplement to expansion culture, a chemically defined medium, significantly improves the viability and self-renewal of human embryonic stem cells (as well as induced pluripotent stem cells).18 The effects on self-renewal of treated cells persisted for long time periods. The activity of doxycycline was not associated with the compound’s clinically related antibiotic effects but rather the compound’s direct activation of a PI3K-AKT signaling pathway. The syntheses of the tetracycline related compounds have witnessed numerous achievements including the Shemyakin synthesis of (±)-12α-deoxy-5a,6-anhydrotetracycline,19 Woodward’s synthesis of (±)-6-deoxy-6-demethyltetracycline,20 Muxfeldt’s synthesis of the first complete tetracycline natural product (±)-terramycin,21 Stork’s synthesis of (±)-12a-deoxytetracycline,22 and Tatsuta’s synthesis of (−)-tetracycline.23 While these syntheses provided access to the targeted compounds, or related subtargets, the routes could not directly be utilized for accessing derivatives. The Myers’ general synthesis of tetracyclines not only solved this but provided laboratory access to doxycycline in 2005.24,25 Early introduction of the 12a-hydroxyl group using a microbial, enantioselective dihydroxylation reaction of benzoic acid (24) followed from difficulties encountered in previous synthetic approaches (Scheme 1).26 Transformation of diol 25 enabled access of main fragment 28, which was used for syntheses of the terramycin series of compounds. For the synthesis of doxycycline (1), the enone fragment 28 was made to react with the anion of ester 29 that generated protected doxycycline 30 through a Michael/Dieckmann sequence. Deprotection of pentacycle 30 with liberation of the vinylogous carbamic acid generated doxycycline (1). 3.1.2. Forskolin. The adenylate cyclase agonist forskolin (2; Figure 3) is effective at rescuing mouse embryonic stem cells from differentiation.27 Treatment of stem cells with the natural product retinoic acid, a compound that induces differentiation of stem cells,28 and forskolin (which effectively blocked differentiation) led to an overall self-renewal. The change in the cAMP levels, by forskolin, is proposed to be the basis for this activity.29

Figure 3. Structure of forskolin (2).

versatility and a limitless capability to self-renew have placed a significant focus on embryonic stem cells for the treatment of degenerative diseases, injury, and tissue loss.17 However, as embryonic stem cells are derived from the inner cell mass of early stage embryos and stem cell removal results in nonviable blastocysts, there are ethical concerns related to isolation. The production of induced pluripotent stem cells prepared by dedifferentiation of existing fully differentiated cells through the delivery of multiple genes provides an attractive alternative to the use embryonic stem cells. 3.1. Compounds Promoting Self-Renewal of Embryonic Stem Cells

The process where stem cells divide to make more of the same stem cells is termed self-renewal. A fundamental attribute of selfrenewal is that the newly produced cells maintain their undifferentiated state while possessing the capacity for selfrenewal or differentiation when directed to do so. This process is carefully orchestrated with the drive for self-renewal balanced by gate-keeping suppressors appropriately limiting growth and ensuring genomic copy quality. The intrinsic mechanisms are further regulated by the external regulatory environment of the stem cell niche which provides cues for growth and dormancy. Treatment of isolated cells, ex vivo, with chemicals that can promote self-renewal can generate a larger population of stem cells that can be cryopreserved and used when needed. Through this process it is important that differentiation is blocked to prevent the stem cell loss. 12055


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Scheme 2. Ziegler Synthesis of Forskolin (2)

Scheme 3. Corey Synthesis of Forskolin (2)

been previously derived through degradation34 of forskolin and had been transformed back to the natural product. The completed, fully synthetic route to forskolin (2) by Corey started form alcohol 31 which was transformed, proceeding through the Ziegler intermediate, into enol-acetate 39 (Scheme 3).35 Irradiation of enol-acetate 39 in an oxygen saturated solution with 2% methylene blue led to photocyclization formation of pyran 40 that once generated underwent a cycloaddition with singlet oxygen generating an endoperoxide 41. Elimination and peroxide reduction generated enone 42 that

As a synthetic target the natural product of forskolin has engendered significant interest.30 Three of the four completed syntheses have utilized a key lactonic intermediate arrived at in the first synthesis by Ziegler, a synthesis that employed a relay synthesis strategy (Scheme 2).31−33 In this synthesis, esterification of allylic alcohol 31 followed by a thermal, intramolecular Diels−Alder reaction formed the A/B ring system (34) of forskolin. Conversion of aldehyde 34 to lactone 35 then arrived at the “Ziegler intermediate” which could be transformed over several steps to the racemic enone 37, a compound that had 12056


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thiophenol to form 45. Dihydroxylation by osmium, forming diol 46, followed by Parikh-modified Moffat oxidation with a subsequent [2,3] sigmatropic of an intermediate enol-sulfur ylide formed diketone 47. Conversion of diketone 47 to forskolin then proceeded through the Ziegler intermediate. Lett and co-workers completed the synthesis of forskolin (2) starting from allylic alcohol 31 (Scheme 5).38−40 Esterification of alcohol 31 followed by an intramolecular Diels−Alder reaction generated diene 50 forming the A/B ring system. This reaction was reported to require careful experimental setup due to the sensitivity of both the product and starting material. Reductive, oxidative, and protecting group installation reactions arrived at epoxy-carbamate 51. Intramolecular opening of the epoxide mediated by BF3·OEt2 then generated the correct alcohol stereochemistry in diol 52. This compound was further elaborated to provide forskolin (2). 3.1.3. Okadaic Acid. Protein serine/threonine phosphatase 2A (PP2A) was investigated as a regulator of hESC self-renewal as it was previously determined that PP2A activity increases as hESC differentiate. Okadaic acid, as a potent inhibitor of PP2A, was examined, and in the absence of basic fibroblast growth factor (bFGF), hESCs treated with okadaic acid produced cells that maintained pluripotency markers and the hESCs produced under the control of okadaic acid could differentiate appropriately (Figure 4).41 This provided evidence of the importance of PP2A to self-renewal as well as a novel strategy for self-renewal of hSPCs in a simplified media regimen. Interestingly, a derivative of okadaic acid, methyl 27-deoxy-27-oxookadaate, was found to be a selective agent that killed hESC and induced pluripotent stem cells.42 The Isobe synthesis of okadaic acid utilized the addition of sulfone anions into aldehydes (including Julia−Lythgoe reactions) to bring multiple fragments together (Scheme 6).43−46 Peterson olefination of the advanced aldehyde 54 generated vinyl sulfone 55. Diastereoselective conjugate addition in turn provided the correct configuration of the newly formed stereocenter within alkyl sulfone 56. Coupling of alkyl sulfone 56 with aldehyde 57 generated alcohol 58. Transformation of alcohol 58 into aldehyde 59 over several steps provided a coupling partner for the anion of sulfone 60. The resulting adduct, alcohol 61, was converted to okadaic acid (3) following protecting group removal, oxidation, and reductive elimination. The synthesis of okadaic acid (3) by the Forsyth group targeted bond disconnections through the addition of carbanions, stabilized or alkyl, into aldehydes (Scheme 7).47,48 Combination of the advanced organolithium 63 and CeCl3 proved optimal for the addition reaction of the anion into the uconjugated aldehyde 62 to generate the desired adduct 65 as a mixture of diastereomers (the undesired isomer 64 could be readily transformed through oxidation/diastereoselective reduction to the desired alcohol 65). Elaboration of alcohol 65 to the keto phosphonate 66 enabled the combination of the remaining two fragments 66 and aldehyde 67 to form enone 68. Catalyst controlled diastereoselective carbonyl reduction using the CBS catalyst49 provided the final stereogenic center that, following treatment with acid, generated okadaic acid in protected form 69. Subsequent removal of the protecting groups yielded okadaic acid (3). The synthesis of okadaic acid (3) by Ley employed coupling of three fragments (Scheme 8).50 Displacement of the pyranyl sulfone in 70 under Lewis acidic conditions by the acetylide anion of 71, formed in the presence of dimethyl aluminum chloride, provided disubstituted alkyne 72. Elaboration of alkyne

Scheme 4. Ikegami Synthesis of Forskolin (2)

Scheme 5. Lett Synthesis of Forskolin (2)

Figure 4. Structure of okadaic acid (1) and methyl 27-deoxy-27oxookadate (53).

was converted to forskolin. Corey also developed a nonracemic synthesis of the Ziegler intermediate accessing allylic alcohol 31 in 90% enantiomeric excess using an enantioselective CBS reduction.36 The Ikegami synthesis, reported alongside the Corey synthesis of forskolin, utilized a different intramolecular Diels−Alder reaction to construct the A/B ring system (Scheme 4).37 Butenolide 44, accessed from aldehyde 43, underwent a thermal Diels−Alder reaction when conducted in the presence of 1% 12057


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Scheme 6. Isobe Synthesis of Okadaic Acid (3)

The synthesis of cyclopamine by Giannis was initiated by the protection of the secondary hydroxyl of dehydroepiandrosterone and formation of a 2-picolylimine to provided a substrate, imine 79, for a directed C−H oxidation reaction (Scheme 9).54 The reaction of imine 79 with tetrakis(acetonitrile)copper(I) hexafluorophosphate and molecular oxygen resulted in the selective introduction of a 12β-hydroxyl group forming alcohol 80.55 Elaboration of alcohol 80 by installing a lactone in the D ring provided a substrate, androsterone 81, for a rearrangement reaction that would transform the C and D rings. Combination of androsterone 81 and trifluoromethanesulfonic anhydride in pryridine with heating induced a Wagner−Meerwein-type skeletal rearrangement forming the C-nor-D-homo ring system56 of cyclopamine with olefin 82 as the major isomer. With the correctly modified and substituted A−E ring system established additional transformation assembled the last F ring with appropriate substitution providing cyclopamine (4). 3.2.2. Cyclosporin A. The loss of heart muscle with age or injury, also known as cardiomyopathy, leads to loss of heart function and decreased circulation. As adult heart tissue lacks significant regenerative capacity, a heart transplant is currently the sole option when this occurs. To provide a resource of cardiac progenitor cells that could be used for cardiac regeneration, methods57 are being developed starting from either embryonic or induced embryonic stem cells. Cyclosporin (Figure 6), the

72 into aldehyde 73 provided a key coupling fragment for a Julia−Kocienski olefination reaction. The vinyl anion of dihydropyran 74 was generated in a two step sequence was combined with γ-butyrolactone 75 to form ketone 76. Transformation of ketone 76 to benzothiazol-2-yl sulfone 77 occurred over multiple steps. Benzothiazol-2-yl sulfone 77 was made to react with NaHMDS and the resulting anion combined with aldehyde 73 to form the required E-olefin present in protected okadaic acid 78. Two step deprotection then yielded okadaic acid (3). 3.2. Differentiation of Embryonic Stem Cells

3.2.1. Cyclopamine. The hedgehog signaling pathway regulates the development of embryos and the production of new cells in adults.51 The hedgehog signaling inhibitor cyclopamine52 (Figure 5) promotes the differentiation of human embryonic stem cells (hESC) into astrocytes expressing nestin and glial fibrillary acidic protein (GFAP).53 The natural product inhibits the signaling pathway by binding and inducing a structural change to the membrane protein. Treatment of hESC with cyclopmaine in human astrocycte medium led to neuroectodermal stem cell marker (nestin) expression in cells at the edges of hESC colonies; nestin is markers for neural stem/ progenitor cells. Incubation of these cyclopamine treated cells in human astrocyte medium led to the production of cells that presented the astrocyte marker GFAP. 12058


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Scheme 7. Forsyth Synthesis of Okadaic Acid (3)

indole 94 was achieved by use of a transient N-trimethylsilyl group forming the 3-(2-nitroethyl)indole derivative 95. Nondiastereoselective introduction and protection of a hydroxymethyl followed by nitro reduction and saponification yielded salt 97. Macrocyclization by amide bond formation yielded the nine membered ring which at this point allowed separation of the diastereomers and pure lactam 98 that could be further elaborated to indolactam V (6). Garg, starting from indole 99 (generated in seven steps from 5benzyloxyindole), used a distortion-controlled indolyne reaction that drove the formation of the requisite C4-N bond yielding indole 101 (Scheme 12).73,76 The placement of bromine as an inductively withdrawing substituent enabled the aryne distortion and correct indolyne regiochemical reactivity. Debromination and dehydration yielded the dehydroalanine containing derivative 102 that successfully underwent ZrCl4-mediated cyclization to generate the nine-membered lactam 103. Epimerization and reduction of lactam 103 yielded indolactam V (6). 3.2.4. Quinidine Derivatives. To identify compounds that lead to the differentiation of ESC to cardiomyocytes, an assay was developed that utilized transgenic mouse embryonic stem cells (mESC) bearing enhanced green fluorescent protein on a region controlled by α-myosine heavy chain.77 Through this assay Nalkylated quinidine derivatives were identified and partial structure activity relationships were performed (Figure 8). The synthesis of quinidine by Uskoković was developed over two routes that also accessed the related cinchona alkaloid quinine (Scheme 13).78−80 Toluyl metalation of 105 using LDA followed by addition to ester 106 generated ketone 107. Bromination followed by reduction formed epoxides 108 as a mixture of diastereomers. Cleavage of the benzoyl group and thermolysis of the resulting amino epoxide led to cyclization forming the 1-azabicyclo[2.2.2] octane core yielding quinidine

immunosuppressive natural product, increases the production of cardiomyoctes from mouse ESC. Starting from a single mESC, ∼200 cardiomyocytes can be produced by this method.58 Cells produced by this method were then used for heart repair in a rodent model of myocardial infarction.58 The chemically produced cells were incorporated into the scar tissue as would be predicted for native cardiomyocytes. The Danishefsky synthesis of cyclosporine A59 used isonitriles and thioacids for iterative formation of amide bonds (Scheme 10). Following from the first synthesis of cyclosporine by Wenger,60 the leucine and D-alanine-derived thioacids 83 and 86 were coupled with valine and leucine isonitriles, 84 and 87, respectively, by combination of the thioacids and isonitriles in chloroform. Reduction of the resulting N-thioformyl amides with Bu3SnH and AIBN yielded the N-methyl dipeptides 85 and 88. An alternative coupling using a “sacrificial isonitrile” to generate a formimidate (thio)carboxylate mixed anhydride of thioacid 90 was made to react with amine 91 to generate the hexapeptide 92. Convergent coupling for multiple fragments that were generated using the isonitrile coupling technology yielded cyclosporine (5). 3.2.3. Indolactam V. The delivery of exogenous insulin secreting beta cells would provide a potentially transformative approach for the treatment of diabetes.61 Additionally, understanding the process wherein embryonic stem cells undergo the carefully orchestrated steps to arrive at beta cells could provide insight into how to treat patients. Indolactam V (Figure 7) was identified through a large chemical screen as being capable of transforming human ESC into cells expressing insulin promoter factor 1 (Pdx1), a cell surface marker on pancreatic progenitor cells.62 Pancreatic progenitor cells in turn produce all of the cell types of the pancreas. Ley reported the first synthesis of (±)-indolactam V63 (Scheme 11) with many other groups also successfully synthesizing the natural product.63−76 After generating valineindole adduct 94 from 4-aminoindole, reaction at C-3 of the 12059


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Scheme 8. Ley Synthesis of Okadaic Acid (3)

benzoyl group and thermal cyclization then generated quinidine 104. The enantioselective synthesis of quinidine (and quinine) was achieved by Jacobsen through a sequence that proceeded from an initial stereogenic center established within 115 by the asymmetric conjugate addition of methyl cyanoacetate into unsaturated imide 113 catalyzed by (salen)Al complex 114

(104) as the major isomer formed along with the three other isomers. The enantioselective synthesis of quinidine 104 (and quinine) by Kobayashi was achieved starting with the chiral alcohol 109 (Scheme 14).81 Catalyst controlled diastereoselective, chemoselective dihydroxylation generated the diol 111 that was stereospecifically converted to epoxide 112. Cleavage of the 12060


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Figure 7. Structure of indolactam (6).

Figure 5. Structure of cyclopamine (4).

Scheme 9. Giannis Synthesis of Cyclopamine (4)

Figure 8. Structure of quinidine (104).

Figure 9. Structure of stauprimide (7).

Figure 10. Structure of eupalinilide E (8).

endoderm is the basis for endodermal organs including intestines, liver, pancreas, thyroid, and lungs. While stauprimide is a semisynthetic compound, the precursor has been synthesized by Danishefsky en route to staurosporine (Scheme 16).85 Coupling of the bis(indole) maleimide 118 (aglycon acceptor) with the glycosyl donor epoxide 119 generated the indole glycoside 120. Elaboration of indole glycoside 120 to the exo-glycan 121 provided a precursor for a second glycosylation reaction forming iodine 122. Transformation of iodide 122 to 7-oxostaurosporine 123 provided the precursor for the synthesis of stauprimide (achieved by Nbenzoylation). The final synthetic target of these efforts staurosporine (127) was also synthesized by Wood employing a noteworthy ring expansion (Scheme 17).86,87 This chemistry provided a platform for the synthesis of related natural products

Figure 6. Structure of cyclosporine (5).

(Scheme 15).82 Stereochemistry relayed to the other stereogenic center within styrene 116 that was converted to quinidine through the intermediate epoxide 117. 3.2.5. Stauprimide. Stauprimide (Figure 9), identified by Schultz and co-workers, increased the efficiency of both human and mouse ESC in directed differentiation.83,84 This effect was found to be manifested through altering c-Myc expression interacting with nonmetastatic cells, protein expressed in-2 (NME2). Treatment of hESC with stauprimide followed by activin A led to the induction of definitive endoderm.84 Definitive 12061


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Scheme 10. Danishefsky Synthesis of Cyclosporine A (5)

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Scheme 11. Ley Synthesis of Indolactam V (6)

Scheme 12. Garg Synthesis of Indolactam V (6)

4.1. Expansion (Self-Renewal) of Hematopoietic Stem and Progenitor Cells

including (+)-RK286c, (+)-MLR-52, and (−)-TAN-1030a. These compounds or related analogues could provide new chemicals for the directed differentiation of ESCs.

4.1.1. Eupalinilide E. The Schultz laboratory through screening Norvartis’ collection of natural products discovered eupalinilide E96 (Figure 10) as a new agent capable of expanding HSPCs.97 HSPC expansion was possible using either human mobilized peripheral blood or CB. In the first week of treatment of cells with eupalinilide E there was a 2-fold increase in the number of THY1+ cells and a 50% increase in the percentage of CD34+ cells where TYY1+ and CD34+ immunophenotypes on the cell surface of undifferentiated cells identify them as HSPCs. This effect, after 45 days, was increased and there was a 45-fold increase in the number of cells when compared to controls using vehicle (DMSO). Eupalinilde E’s effects were found to be a result of the natural product inhibiting differentiation and driving expansion. The effects are reversible, and after transferring the treated cells to fresh media, the cells chemically expanded demonstrate a native potential for differentiation, proliferation, and expansion. The synthesis of eupalinilide E by Siegel, starting from carvone, used Favorskii rearrangement98 to access lactone 129 on a large scale (Scheme 18).99 Elaboration of lactone 129 to trieneyne 130 provided a system that was poised for a diastereoselective borylative eneyne cyclization100 to generated

4. HEMATOPOIETIC STEM CELL REGULATORS Following the first human cord blood (CB) transplant in 1988,88 the world established banks for the storage of CB. From these repositories an estimated 30 000 units of CB are distributed yearly to patients with hematological diseases.89 The use of CB as a source of hematopoietic stem and progenitor cells (HSPCs) has increased due to reduced immune reactivity and proliferative advantages compared to HSPCs derived from either bone marrow or peripheral blood.90,91 The reduced number of starting cells in CB samples, however, is a major limitation as the number of cells used in transplants has been found to be one of the most important factors for patient recovery. The use of two units of CB, recently developed for transplants has improved the oucomes92−95 while at the same time creating a larger burden on CB bank repositories. With the survival outcomes being correlated to the number of cells transplanted the development of a cost-effective, cryopreserved product is needed to ensure that the world will have access to an abundant source of HSPCs in the future. 12063


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prostaglandin E2 increased HSPC number while compounds that inhibited prostaglandin E2 synthesis decreased stem cell numbers. In addition to leading to HSPC expansion, pulse treatment with PGE2 leads to cells with improved survival and homing capabilities. Stem cell homing, in the case of HSPC, is where once transplanted the cells seek and engraft into bone marrow providing the correct environment. Competition of PGE2 treated HSPC and untreated cells demonstrates the PGE2 cells possessed superior properties.109 The derivative of PGE2, 16,16-dimethyl prostaglandin E2, has entered and passed through phase 1 clinical trials.110 As synthetic targets with tremendous biological activity, significant efforts have been committed to the syntheses of the prostaglandin class of compounds.111,112 The synthesis of PGE2 by Corey, reported in 1969, continued to be refined over the years as the group developed new chemical transformations to solve synthetic problems. The synthetic route developed is used on an industrial scale for the manufacture of Scheme 14. Kobayashi Synthesis of Quinidine (104)

vinyl silane 131. Conversion of vinyl silane 131 to the tricyclic system within 132 then provided a substrate for a double allylic oxidation to generate butenolide 133 that underwent three more transformations to yield eupalinildie E (8). 4.1.2. Garcinol. The plant derived histone acetyltransferase inhibitor garcinol101 (Figure 11) was identified through a screen of natural products to find compounds that promote the expansion of human CB derived HSPC.102 Garcinol along with stem cell factor and thrombopoietin increased the production of cells that were CD34+CD38− by 4.5 fold, and the related natural product isogarcinol increased the growth by 7.4 fold. The activity of the compounds was found to be correlated with their ability to function as histone acetyltransferase inhibitors. The polycyclic polyprenylated acylphloroglucinols (PPAPs), of which garcinol is a member, have engendered significant interest from the synthetic community.103−105 The synthesis of garcinol has been achieved by Plietker, and starting from acetylacetone, the intermediate cyclohexenone 134 was prepared in four steps (Scheme 19).106 Further modification of cyclohexenone 134 by installing additional carbons and activating the system for an allylation reaction arrived at a mixture of allyl carbonates 135 and 136.107 This mixture underwent a diastereoselective allylation, installing an allyl group on the same face as the acetoxylated prenyl-type side chain forming 137. This product 137 in turn provided a substrate for a Pd-catalyzed allyl−allyl cross coupling employing allylpinacolborane. With optimization β-hydride elimination was minimized, and the desired diastereomer 138 was formed with no evidence of the alternative isomer. The highly modified cyclohexanone 138 was then transformed to (±)-garcinol (9) completing the synthesis in 13 steps. 4.1.3. Prostaglandin E2. A chemical screen in zebrafish identified prostaglandin E2 (10; Figure 12) as a modulator of HSPC homeostasis and formation.108 In addition, compounds that promote the production of prostaglandin E2 as well as administration of the more stable derivative 16,16-dimethyl Scheme 13. Uskoković Synthesis of Quinidine (104)

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Scheme 15. Jacobsen Synthesis of Quinidine (104)

Scheme 16. Danishefsky Synthesis of Desbenzoyl Stauprimide (123)

the related compound latanoprost.113 Starting from methyl ester 139 (prepared in one step from cyclopentadiene) a Diels−Alder reaction with 2-chloro-acrylonitrile using copper catalysis led to a mixture of exoendo products that were both converted to ketone 140 with potassium hydroxide (Scheme 20).114 Bayer−Villager oxidation provided oxygen at the appropriate position of the cyclopentene yielding lactone 141. This compound, 141, was transformed over four steps to the Corey lactone (142) a pivotal

intermediate in the syntheses of prostaglandin derivatives including PGE2 (10) which was accessed from this intermediate. The concise synthesis of PGF2α by Aggarwal was initiated by an optimized aldol cascade reaction of the highly reactive substrate succinaldehyde (143) using proline organcataysis, accessing enal 144 with an enantiomeric ratio of 99:1 and amenable to generating 15 g of 144 (Scheme 21).115 Enal 144, possessing correct stereochemistry and functionalization, could 12065


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Thy-1 were increased 7-fold after 5 days of culturing cells with HDAC inhibitors. Cells produced by the use of HDAC inhibitors were also found to have a 4-fold improvement in engrafting ability over control cells.116 The Schmidt synthesis of chlamydocin119 (Figure 13) sought to address the previous challenges for incorporation of the epoxide bearing side chain with the appropriate steochemistry, a challenge that had been encountered in previous syntheses.120,121 Using the resident steochemistry in tartaric acid, the dehydroamino acid 148 was prepared as an inconsequencial mixture of olefin isomers (Scheme 22). Homogenous hydrogenation using the Monsanto catalyst [Rh(cod)(dipamp)]+BF4− provided the correct (S)-amino acid stereochemistry, and heterogeneous hydrogenation saturated the remaining alkene and cleaved the benzyloxycarbonyl protecting group forming amino ester 149. This compound was elaborated to the cyclization precursor 150 that self-condensed after cleavage of a similar benzyloxycarbonyl protecting group. This generated an amine that reacted internally with the activated pentafluorophenyl ester forming cyclopeptide 151. The cyclic peptide 151 was transformed into chlamydocin (12) in three steps. In the synthesis of chlamydocin by Baldwin, the stereospecific incorporation of the epoxide bearing side chain was achieved by an alternative late-stage reaction carbon−carbon bond forming strategy (Scheme 23).122 Proceeding through the protected chloroamino acid 152 the cyclization precursor was assembled. Cyclization was triggered by cleavage of the benzyloxycarbonyl protecting group under hydrogenation, and primary chloride was converted to an iodide by Finklestein halogen exchange generating iodide 154. Installation of iodine prior to cyclization proved incompatible. Iodide 154 was subjected to free radical homologation by reaction with silylepoxyenone 155, tributyltin hydride, and azobis(isobutyronitrile) to generate the epoxy

Scheme 17. Wood Synthesis of Straurosporine (127)

be directly made to react with mixed cuprate 145 to generate the silyl enol ether 146 which was transformed over three steps to PGF2α (147). 4.1.4. Chlaydocin, Trichostatin A, and Trapoxin B. Rodent HSPCs treated with natural products that function as histone deacetylase (HDAC) inhibitors increased the expansion of HSPCs.116−118 Similarly, human HSPCs bearing the marker Scheme 18. Siegel Synthesis of Eupalinilide E (8)

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ketone bearing cyclic peptide 156 that after silicon cleavage formed chlamydocin (12). The synthesis of trichostatin A by Fleming was achieved multiple ways including γ-alkylation of a silyl dienol ether 158, accessed from aldehyde 157 (Scheme 24).123 Under the influence of TiCl4 the acetal 159 and silyl dienol ether 158 underwent a vinylogous Mukaiyama aldol to form methyl ether 160. Over three steps this intermediate was transformed to (±)-trichostatin A (13). With numerous strategies for the synthesis of trichostatin A,124 Helquist also created an enanatioselective approach125 that was developed employing an enantioselective Marshall propargylation reaction126 using the nonracemic (S)-mesylate 162 and aldehyde 161 to form alcohol 163 as a mixture of syn and anti isomers at the benzylic center (Scheme 25). Protection of the benzylic alcohol and methylation of the alkyne generated ether 164. This compound was transformed over three steps to methyl ester 166 that converted to (R)-trichostatin A in 81% ee. Additional syntheses of trichostatin (13) include those by Koseki127 and Wang.128 The synthesis of trapoxin B by Schreiber (Scheme 26) used a related strategy to Schmidt for the incorporation of the epoxide bearing side chain but assembled the amino acid precursor through an alternative strategy (Scheme 25).129 Generation of the Grignard of bromide 167 followed by the addition of catalytic copper(I) bromide dimethyl sulfide complex and β-lactone

Figure 11. Structure of garcinol (9).

Figure 12. Structure of prostaglandin E2 (10).

Scheme 19. Plietker Synthesis of Garcinol (9)

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Scheme 20. Corey Synthesis of Prostaglandin E2 (10)

Scheme 21. Aggarwal Synthesis of Prostaglandin F2 (147)

Figure 13. Structures of chlamydocin (12), trichostatin A (13), and trapoxin B (14). 12068


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Scheme 22. Schmidt Synthesis of Chlamydocin (12)

Scheme 23. Baldwin Synthesis of Chlamydocin (12)

generated the desired amino acid derivative.130 This acid was converted to the cyclization precursor 170 that after optimization was cyclized using benzotriazol-1-yloxytris(dimethylamino)-

phosphonium hexafluorophosphate and dimethylamino pyridine to yield cyclic peptide 171. This compound could be elaborated to trapoxin B and, importantly, paved the way for the syntheses of 12069


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Scheme 24. Fleming Synthesis of Trichostatin A (13)

Scheme 25. Helquist Synthesis of Trichostatin A (13)

Figure 16. Structure of placotylene (17). Figure 14. Structure of euphohelioscopin (15).

Figure 15. Structure of phorbol 12-myristate 13-acetate (16). Figure 17. Structure of huperzine A (18). 12070


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Scheme 26. Schreiber Synthesis of Trapoxin B (14)

Scheme 27. Wender Synthesis of Phorbol (177)

probe compounds that allowed for the description of trapoxin’s mechanism of action.

was found to decrease the percentage of CD34+ cells from 29% in control to 13% while increasing the number of total nucleated cells 2-fold. The cell surface marker CD45ra+ was increased to 79% versus controls possessing 50%. The marker CD45ra+ is indicative of GM lineage. Mechanistically euphohelioscopin functions as a protein kinase C (PKC) activator and produced a similar cell population as know PKC agonist phorbol 12myristate 13-acetate. No synthesis of euphohelioscopic has been achieved to date.

4.2. Differentiation of Hematopoietic Stem Cells

4.2.1. Euphohelioscopin A. The plant derived natural product euphohelioscopin A (Figure 14)131 was identified through a screen using human CD34+ cells monitoring for the ability of compounds to promote differentiation to the granulocyte/monocytic (GM) lineage.132 The natural product 12071


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Scheme 28. Baran Synthesis of Phorbol (177)

Scheme 29. Parker Synthesis of Placotylene (17)

Scheme 30. Kozikowski Synthesis of Huperzine A (18)

4.2.2. Phorbol Esters. The tumor-promoting esters of phorbol (Figure 15), but not the parent compound phorbol, were shown to possess the ability to drive the proliferation of mouse HSPCs.133,134 The compound phorbol 12-myristate 13acetate (PMA) supported the survival of day 11 colony-forming units-spleen (CFU-S). This effect was similar to the lymphokine interleukin 3 (IL 3) which promotes the ex vivo growth of HSPCs. Short exposure of CFU-S (1 h) was sufficient to synergize the effects of IL 3 on HSPC survival. Chemical activation of PKC has been a focus for the development of

chemotherapeutics, as the compounds can promote the differentiation of malignant myeloid precursors; however, the tumor promoting activities of phorbol esters have limited their development. Other natural products such as bryostatins and ingenol derivatives with different PKC hour profiles have been advanced, and as a result of these effects and their remarkable chemical structures, complete syntheses of bryostatins135−138 and ingenol139−141 have been achieved. The synthesis of phorbol (177) by Wender was initiated starting from furfuryl alcohol (172) to generate a precursor for a 12072


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Scheme 31. Azadi−Ardakani Synthesis of Huperzine A (18)

Scheme 32. Herzon Synthesis of Huperzine A (18)

the tissues and minerals to the blood, is dictated by the actions of bone forming osteoblasts and bone break down by osteoclasts.146 Homeostasis between the two processes is needed for preservation of appropriate bone mass with an estimated 10% of the total bone content in the adult skeleton being replaced every year.147 Excess activity of osteoclasts leads to degenerative bone diseases including osteoporosis. With the goal of favorably controlling the equilibrium, selective removal of osteoclasts would provide a method for the strengthening of degraded bone tissue.148 Blocking the production of osetoclasts, generated from the monocyte/macrophage lineage cells which arise from HSPCs, would provide a balance. The receptor activator of nuclear factor-κB ligand (RANKL) is an inducer of osteoclast differentiation.149 An inhibitor of RANKL was identified from marine natural products, plactotylene A (Figure 16).150 Interestingly, the olefin isomer, placotylene B, lacks RANKL inhibitory activity. En route to the synthesis of phosphoiodyn A, Parker accomplished the synthesis of the novel diyne-containing natural product placotylene A (Scheme 29).151 Generation of 4-bromo3-butyn-1-ol (183) (from 3-butyn-1-ol) provides a partner for a Cadiot-Chadkiewicz coupling152 using excess 1,9-decadiyne (184) to form triynol 185. Reaction with Schwartz reagent followed by iodine generated placotylene A (17). While a synthetic intermediate toward the related compound phos-

oxidopyrylium-alkene cycloaddition, enone 173 (Scheme 27).142,143 Upon treatment of enone 173 with DBU, cyclization of the tethered alkene with the resulting oxidopyrylium proceeded with selectivity generating cycloadduct 174. Cycloadduct 174 was elaborated further to aldehyde 175 that underwent a second cycloaddition reaction, a 1,3-dipolar cycloaddition of a nitrile oxide and alkene, forming isoxazoline 176. This intermediate was transformed to a central compound with application to the syntheses of tiglianes, daphnanes, and ingenanes. In this instance application of this approach achieved the synthesis of the tigliane phorbol 177. The synthesis of phorbol by Baran employed the group’s twophase terpene synthesis strategy, carbocycle formation followed by oxidation (Scheme 28).144 Six step synthesis of the polycyclic intermediate 179, previously used in the synthesis of (−)-ingenol,145 provided the platform for selective oxidation reactions. The chemoselective reaction of one of the C−H bonds at C12 proceeded by treatment with methyl(trifluoromethyl)dioxirane generating alcohol 180. Conversion of alcohol 180 to diketone 181 provided a precursor for a cyclization to reinstate the cyclopropane with the requisite oxidation within tetracycle 182. The synthesis was achieved with an overall step count of 19 steps from (+)-3-carene (178). 4.2.3. Placotylene A. The balance between the formation of bone and the resorption, the break down of bone tissue releasing 12073


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Figure 18. Structure of HU210 (19) and tetrahydrocannabinol (196).

Figure 21. Structure of FK506 (22).

Figure 19. Structure of alstoscholarisine A (20).

Figure 22. Structure of wedelolactone (23).

phoiodyn A, the natural product placotylene A was discovered contemporaneously with the synthetic efforts.

5. NEURAL STEM CELL REGULATORS 5.1. Expansion of Neural Stem Cells

Neural stem cells can differentiate into neurons, oligodendrocytes, and astrocytes which are present throughout the central nervous system (CNS). Neural stem cells can self-renew providing cells for CNS tissue repair following disease or injury,

Figure 20. Structure of apicidin (21).

Scheme 33. Mechoulam Synthesis of HU210 (19)

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Scheme 34. Yang Synthesis of Alstoscholarisine A (20)

Scheme 35. Bihelovic Ferjancic Synthesis of Alstoscholarisine A (20)

Scheme 36. Singh Synthesis of Apicidin (21)

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Scheme 37. Kitahara Synthesis of Apicidin (21)

allyl palladium chloride dimer, and 1,3-diacetoxy-2-methylenepropane (192) to form the bicyclo[3.3.1] system of ketoester 194. Selective olefin isomerization was achieved using trifluoromethanesulfonic acid forming alkene 195 and this intermediate was converted to huperazine A (18). The Herzon synthesis of huperzine A used an alternative strategy initiated by the conjugate addition of lithium dimethylphenylsilylcuprate into (R)-4-methyl-cyclohex-2-ene1-one 196, followed by alkylation of the resulting enolate with 3bromo-2-(bromomethyl)-6-methoxypyridine 197 to generate cyclohexanone 198 (Scheme 32).166 Kinetic enolate formation and reaction with p-toluenesulfonyl cyanide generated an inconsequential mixture of isomers represented by β-ketonitrile 199. Optimization of a palladium-catalyzed intramolecular arylation171 arrived at the use of bis(trit-butyl-phosphine) palladium in combination with sodium t-butoxide for the formation of nitrile 200. Following formation of the bicyclo[3.3.1] system, a telescoped sequence arrived at huperzine A (18) providing 1.6 g of the natural product in a single pass. 5.1.2. HU210. The therapeutic potent synthetic cannabinoid HU210 (19; Figure 18), related to tetrahydrocannabinol (196), was examined on adult rat hippocampal neural stem and progenitor cells as they were found to possess CB1 cannabinoid receptors. Through this HU210 was found to promote neurogenesis but not differentiation of embryonic hippocampal neural stem and progenitor cells.172 This activity arises from the activation of CB1 receptors Gi/o proteins and extracellular signalregulated kinase signaling. Chronic exposure to HU210 was required for enhanced neurogenesis in adult rodents. The synthesis and study of 1,1-dimethylheptyl homologues of 7-hydroxy-Δ6-tetrahydrocannabinol as single isomers was achieved by Mechoulam starting from [1S, 5R]-myrtenol (202) which was protected, oxidized, and reduced to generate an allylic alcohol 203 as a mixture of diastereomers (Scheme 33). 173 This was made to react directly with 5-(1,1dimethylheptyl)-resorcinol 204 and boron trifluoride diethyl ether complex generating HU210 in protected form 205.174 Ester cleavage generates free HU210 (19) which can be

potentially providing treatments for neurodegenerative diseases and CNS injuries, including spinal cord injury and traumatic brain injury. As there is a reduced capacity for stem cell proliferation with age, the system does not maintain the balance of cell death and birth later in life.153 Methods to both promote neurogenesis in vivo as well as generate large pools of cells ex vivo that can be cryopreserved and used for tissue repair could provide new avenues for the treatment of diseases and injury states that currently lack therapeutic options. 5.1.1. Huperazine. Due to its established activities for the treatment of degenerative neurological diseases,154,155 the lycopodium alkaloid huperzine A (Figure 17) has been an attractive target for chemical synthesis.156−169 In addition, following from the characterization of its activity, the natural product was also found to increase the proliferation of mousederived embryonic hippocampal neural stem cells.170 A dose dependent response has been established for these effects which has been proposed to occur through activation of the mitogenactivated protein kinase/extracellular signal-regulayted kinase (MAPK/ERK) pathway.170 The synthesis of huperazine A by Kozikowski employed a tandem Michael-aldol sequence to construct the bicyclo[3.3.1] core (Scheme 30).162 Starting from the monoethylene ketal of 1,4-cyclohexanedione 186, the β-ketoester 187 was prepared in six steps. Reaction of β-ketoester 187 with methacrolein (188) and tetramethylguanidine formed an isomeric mixture of bicyclo[3.3.1] alcohols 189. Dehydration and Wittig olefination generated alkene 190 with the incorrect Z olefin configuration as the major isomer that was isomerized to the E isomer using thiophenol and azobis(isobutyronitrile) yielding diene 191. Conversion of diene 191 to huperzine A (18) required a Curtius rearrangement to install the bridgehead nitrogen and methyl ether cleavage. A scaled synthesis of huperazine (275 g) by Azadi−Ardakani utilized previous syntheses as well as employed an enantioselective, palladium catalyzed bicycloannulation reaction (Scheme 31).164 Using β-ketoester 187 an asymmetric bicycloannulation reaction158 was optimized using chiral ligand SL-T002-1 (193), 12076


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Scheme 38. Schreiber Synthesis of FK506 (22)

generated lactam 209 in 99% e.e. This system was elaborated to form the unsaturated tricyclic amide 210 that in turn underwent a sequential vinyl Grignard conjugate addition followed by aldol reaction with acetaldehyde to form alcohol 211. Through a series of oxidation and reduction reactions proceeding from 211, the remaining two rings were generated forming alstoscholarisine A (20). The Bihelovic Ferjancic synthesis of (±)-alstoscholarisine A was started by elaboration of ester 212 to provide amine 213 (Scheme 35).178 Reaction of amine 213 with selenoaldehyde 214 induced, after enamine formation, a cascade reaction forming all but one of the rings for alstoscholarisine A (followed by treatment with DBU to form the thermodynamic isomeric product) within tetracycle 215. Oxidative and reductive manipulation of tetracycle 215 provided aldehyde 216 that was

repeatedly recrystallized to generate material with an enantiomeric excess higher than 99.8%. 5.1.3. Alstoscholarisine A. Alstoscholarisine A (Figure 19) promotes the proliferation of adult neuronal stem cells derived from mice.175 The natural product did not affect the growth of neuroblastoma cells. Alstoscholarisine A enhanced neural stem cell sphere formation and differentiation by activation of the Wnt signaling pathway. Related natural products alstoscholarisine B− E also possessed the ability to enhance neurogenesis, although they possessed diminished activity relative to alstoscholarisine A. The Yang synthesis of alstoscholarisine was initiated by the acylation of 3-methylindole 206 with 4-vinylbutyrolactone 207 using trimethylaluminum (Scheme 34).176 An enantioselective, intramolecular Friedel−Crafts alkylation was achieved next and using [Ir(cod)Cl]2, a Carreira ligand,177 and Sc(OTf)3. The alkylative cyclization, starting with racemic allylic alcohol, 12077


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Scheme 39. Merck Synthesis of FK506 (22)

The Singh synthesis of apicidin A hindged on the successful synthesis of (S)-2-amino-8-oxodecanoic acid in protected form 221 (Scheme 36).181 Starting from monomethylester, Ncarboxybenyl L-glutamic acid 218, primary iodide 219 was generated. Photolysis of iodine 219 in the presence of ethyl vinyl ketone and tributyltin hydride generated ketone 221. Coupling ketone 221 with the remaining amino acids followed by macrocyclization yielded apicidin 21. The Kitahara synthesis of apicidin was initiated by the synthesis of 2-amino-8-protected hydroxydecanoic acid 223 (Scheme 37).182 The Grignard generated from bromide 222 was combined with β-lactone 168 in the presence of copper(I) bromide dimethylsulfide complex to yield 2-amino-8-protected hydroxydecanoic acid 223.130 The acid 223 was coupled with the oxidized methylated tryptophan 224 to yield amide 225. The

epimerized forming hemiacetal 217 which was converted to alstoscholarisine A (20). 5.2. Differentiation of Neural Stem Cells

5.2.1. Apicidin. The histone deacetylase inhibitor apicidin (Figure 20) has the ability to prime lineage-committed oligodendrocyte precursor cells for developmental plasticity expanding the cells differentiation potential.179 It had been previously established that multipotent neural stem-like cells that can produce glia and neurons and can be generated from lineagecommitted oligodendrocyte precursor cells following treatment with bone morphogenic proteins.180 The effects achieve by treatment with apicidin HDAC inhibition where in part attributed to the reactivation of sox2 and silencing a set of oligodendrocyte lineage-specific genes. 12078


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Scheme 40. Ireland Synthesis of FK506 (22)

transformed to the aldehyde 231, a partner for an olefination reaction. The strategy to the synthesis of the next fragment used a class C two-directional chain synthesis strategy.187 Diepoxide 232, generated from arabitol, was treated with an excess of the lithium anion of ethoxyacetylene and boron trifluoride diethyl ether complex and directly treated under acidic conditions to generate the double lactone containing compound 233. This, and the continued use of this strategy, greatly simplified the synthesis of phosphonamide 234. Coupling of aldehyde 231 and the anion of phosphonamide 234, following separation and elimination, generated the trisubstituted olefin 235 that was elaborated to provide FK506 (22). The Merck synthesis of FK506 starting from quinic acid (236) generated aldehyde 237 that was made to undergo an Evans aldol reaction188 with imide 238 providing alcohol 239 (Scheme 39).189 Alcohol 239 was converted to aldehyde 240, a partner for an olefination reaction. Phosphine oxide 242 (prepared from the chiral epoxy alcohol 241) was deprotonated and combined with aldehyde 240, and the resulting diastereomers were separated and treated with KHMDS to provide alkene 243 that was further transformed to FK506 (22). The Ireland synthesis of FK506 utilized a diastereoselective conjugate addition reaction for the union of the major fragments (Scheme 40).190 Starting from bromide 244 that underwent

dipeptide was iteratively coupled, deprotected, and oxidized to generate apicidin 21.

6. MESENCHYMAL STEM CELLS 6.1. Differentiation

6.1.1. FK506. The immunosuppressive agent FK506 (Figure 21), a long-standing synthetic target,183 was found to enhance osteoblastic differentiation and enhance bone morphogenetic protein induced osteoblastic differentiation.184 However, the related natural product rapamycin had a dose dependent inhibitory effect on proliferation. The advancement of an immunosuppressive agent that can simultaneously increase osteoblastic differentiation would be useful for bone tissue transplantation. The Schreiber synthesis of FK506 and probe compounds was approached by the syntheses of multiple fragments that were then coupled (Scheme 38).185 Starting from the achiral divinylcarbinol 226, the vinyl bromide 227 was synthesized in optically active form utilizing a Sharpless directed epoxidation186 to generate nonracemic material. Lithium-halogen exchange with t-butyllithium and sequential treatment with magnesium bromide and aldehyde 229 (arrived at from β-keto ester 228) formed alcohol 230 as the major isomer. The alcohol 230 was 12079


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Scheme 41. Yang Synthesis of Wedelolactone (23)

Scheme 42. Lee Synthesis of Wedelolactone (23)

6.1.2. Wedelolactone. Wedelolactone (Figure 22) possesses the ability to increase bone formation while simultaneously reducing bone resorption.191 In this study mouse bone marrow derived mesenchymal stem cells treated with wedelolactone underwent increased osteoblast differentiation inhibiting GSK3β activity driving the translocation of β-catenin and runx2 increasing osteoblastogensis markers. Interestingly, in the same investigation the natural product conversely inhibited osteoclastic activity reducing osteoclastogenesis markers c-src, c-fos, and cathepsin K. In the rodent model for postmenopausal bone

lithium-halogen exchange and reaction with aldehyde 245, the allylic alcohol 246 was generated. Transformation of alcohol 246 to enone 247 over several steps provided one of the two major fragments in the synthesis. Vinyl iodide 249, generated from diol 248, underwent lithium-halogen exchange and transfer to copper, following combination with hexynylcopper bis-HMPA complex, to provide a mixed cuprate that added to enone 247 and proved to be a reliable method for the generation of ketone 250. Transformation of ketone 250, which possessed all of the required carbons, to FK506 (22) was successfully achieved. 12080


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human tissues and validated. Indeed, the identification of new natural products that regulate stem cell fate, syntheses of these exciting compounds, and the application of these synthetic routes to developing new approaches to direct stem cells have made, and will continue to make, an impact on a nascent field of medicine.

loss, administration of wedelolactone prevented ovariectomy related bone loss.192 The Yang synthesis of wedelolactone (23), proceeding from alkyne 251 and iodide 252, employed a Sonogashira reaction to generate biaryl alkyne 253 (Scheme 41).193 Acetate cleavage from 253 liberated a single phenol and provided a substrate, alkyne 254, for a carbonylative annulation reaction. Treatment of phenol with palladium(II) iodide, thiourea, carbon tetrabromide, cesium carbonate, and carbon monoxide in methanol generated benzofuran 255. Further elaboration of benzofuran 255 to wedelolactone (23) was accomplished over two steps. The Lee synthesis of wedelolactone began with a Stille reaction of bromocoumarin 256 and stannane 257, yielding arylcoumarin 258 (Scheme 42).194 Selective cleavage of the single benzyl protecting group of arylcoumarin 258 formed phenol 259. Once liberated the phenol of 259 was primed for oxidative cyclization using iodine and pyridine to generate coumestan 260. Three steps, two of which were deprotection steps, transformed coumestan 260 to wedelolactone (23).

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Dionicio Siegel: 0000-0003-4674-9554 Present Address §

Gilead Sciences, Inc., Foster City, California 94404, United States. Notes

The authors declare no competing financial interest.

7. CONCLUDING REMARKS In the ongoing effort to develop new stem-cell-based treatments for diseases, including a large number that lack therapeutic options, it has become increasingly apparent that chemical control over stem cell fate will provide the required methods for the regulated production of specific cell types. The analysis of ex vivo produced cells relies on the characterization of cell surface markers, and while this provides an indication of cells’ potential type, it does not fully capture the cells’ likelihood of undergoing rejection, proliferative ability, or engraftment potential. As ex vivo produced cells proceed through preclinical testing and clinical trials, these attributes of laboratory-produced cells are pivotal for the success of the cell-based products. The continued discovery and development of chemical modulators of stem cells will provide an increased likelihood of these products reaching the clinic and providing the outcomes that have been envisioned by the stem cell community. The use of synthetic natural products to regulate stem cell fate provides new and relatively untapped opportunities for developing improved methods for the ex vivo production of tissues. As with most lines of research that involve natural products and biology, the synthetic community is reliant on isolation chemists to adapt their screening technologies to include stem cells. With wider access to a variety of cell types and improvements in methods for characterizing cells that are chemically produced, there is hope that new regulators of stem cell fate will be discovered. With the synthetic routes that have been established to natural products identified through previous phenotypic screens, the opportunity for probe compounds development can be used to identify targets, potentially new, that regulate self-renewal or differentiation of stem cells. These derivatives include tool compounds that allow enrichment of the target either through covalent or noncovalent interactions. The identification of new targets through these tailor-made chemicals can have a tremendous impact on human health, even potentially more significant that advancing a single compound through preclinical development. Given the variable nature of ex vivo, chemically produced cells, synthetic derivatives can be prepared with the goal of fine-tuning the natural product leads by enhancing or even reducing activities that lead to cells with improved characteristics. From the standpoint of a chemist working in the area of stem cells, it can be immediately gratifying to witness one’s compounds tested directly against relevant

Biographies Trevor C. Johnson received his B.S. in Biochemistry and Molecular Biology in 2012 from the University of California, Santa Cruz under the advisement of Professor Needhi Bhalla. He began his graduate career under the direction of Professor Dionicio Siegel in 2012 and earned his Ph.D. in Chemistry from the University of California, San Diego in 2016. His graduate work focused on the total synthesis of eupalinilide E, a small molecule regulator of hematopoietic stem cell expansion, and on the total synthesis of the thiopeptide antibiotic lactocillin. Dionicio Siegel, born in 1974 in Truchas, New Mexico, studied chemistry at Reed College and earned his Ph.D. in Chemistry with Andy Myers at Harvard University. Postdoctoral work with Samuel Danishefsky at the Memorial Sloan-Kettering Cancer Center was followed, from 2007 to 2014, with a faculty position at The University of Texas at Austin. In 2014 he moved on to continue his work at the University of California, San Diego in the Skaggs School of Pharmacy and Pharmaceutical Sciences. His research interests focus on synthetic organic chemistry and the application of natural products in drug development.

ACKNOWLEDGMENTS This work was supported by grants from the National Science Foundation (CHE-1151708) and the California Institute for Regenerative Medicine (DISC1-08737). REFERENCES (1) Calegari, F.; Waskow, C. Stem Cells: From Basic Research to Therapy; CRC Press: New York, 2014. (2) Slack, J. M. W. Stem Cells: A Very Short Introduction; Oxford University Press: Oxford, U.K., 2012. (3) Mattson, M. P.; Van Zant, G. Stem Cells: A Cellular Fountain of Youth; Elsevier: Amsterdam, The Netherlands, 2002. (4) Okita, K.; Ichisaka, T.; Yamanaka, S. Generation of GermlineCompetent Induced Pluripotent Stem Cells. Nature 2007, 448, 313− 317. (5) Takahashi, K.; Yamanaka, S. Induction of Pluripotent Stem Cells From Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 2006, 126, 663−676. (6) Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. Induction of Pluripotent Stem Cells From Adult Human Fibroblasts by Defined Factors. Cell 2007, 131, 861−872. (7) Ding, S.; Schultz, P. G. A Role For Chemistry in Stem Cell Biology. Nat. Biotechnol. 2004, 22, 833−840. 12081


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