Organic Cumulative Exam November 12, 2015

Answer only three of the six questions. No more than three question answers will be graded and any work not to be considered must be marked as such. Clearly indicate which questions are to be graded on the front of your answer booklet.

1. (33 points) Jia and co-workers recently disclosed the total synthesis of (–)-pallavicinin and (+)-neopallavicinin.

Angew. Chem., Int. Ed. 2015, 54, 13599-13603.

(a) Please provide reagents and conditions for the conversion of racemic 1 into enantioenriched bicycle 2.

(b) Provide reagents and conditions for the conversion of bicycle 2 into epoxide 3.

(c) The authors notice an interesting temperature dependence when compound 3 is treated with Super Hydride (LiBHEt3). Provide a mechanistic explanation for the formation of both compounds 4 and 5 - including any stereogenic centers which are formed or changed.

(d) The authors complete the synthesis by the conversion of compound 5 over a series of steps into natural products 6 and 7. Provide reagents and conditions for the construction of 6 and/or 7.

(e) This synthesis is referred to by the authors as a "protecting group free" synthesis. Would you agree with that description? Why or why not?

Ot-Bu

O

O

OO

Mesteps

O

MeMe

Me

OOH

OTMS

steps

(±)-1 (+)-2 3

O

MeMe

Me

OOH

OTMS

3

LiBHEt3, THF

60°C, 84%

MeMe

MeO

TMS

5

OOHH

HMeMe

MeO

TMS

4

LiBHEt3, THF

0°C, 90%OHOOH

H

MeMe

MeO

TMS

5

OOHH H

MeMeMe

O

(–)-pallavicinin (6)

H

O O

Me

O

steps

H

MeMeMe

(+)-neopallavicinin (7)

H

O O

Me

O

HH

O

2. (33 points) The following potential energy surface was calculated for a molecule as a means of probing processes involved in formation of fullerene molecules.

Esselman et al. J. Org. Chem. 2015, ASAP. DOI: 10.1021/acs.joc.5b01864

Relative energy (kcal/mol; ZPVE not included) CCSD(T)/cc-pVTZ//MP2/cc-pVTZ (B3LYP/6-31G(d) in parentheses), reported in kcal/mol.

(a) Based on the way the calculations are reported, describe how the geometries were identified for each species and how each energy was determined.

(b) Describe the origin of the following energy barriers:

– between 1a and 1b – between 2 and 3 – between 4 and 3

(HINT: examine each in terms of geometric and hybridization changes, as well as overall bond reorganization).

(c) You will note that the chart also includes results calculated at the B3LYP/6-31G(d) level. Are the differences significant? Explain (including which is the “better” method in the specific context of the kinds of species shown).

(d) How would you set about providing experimental support for these computational results? Specifically address the likely stability of any compound you propose using, and the impact any stabilizing structural feature might have on the significance of your findings.

3. (33 points) Two reactions of sulfinimines are shown and referenced below. (a) The addition of organometallic reagents to tert-butylsulfinimines was developed and

popularized by Ellman and coworkers. Show the product and mechanism of this transformation, and show any relevant stereochemical models to explain the stereochemistry.

"N-tert-Butanesulfinyl Imides: Versatile Intermediates for the Asymmetric Synthesis of Amines”

Acc. Chem. Res. 2002, 35, 984-995.

(b) Show how the enantiopure tert-buylsulfinimine above is made from achiral starting materials. (c) Recently, a reaction was reported by McGlacken and coworkers. Show the mechanism of

this transformation, and any relevant stereochemical models to explain the stereochemistry.

"Asymmetric Aldol-Tischencko Reaction of Sulfinimines" Org. Lett. 2015, ASAP. DOI: 10.1021/acs.orglett/5b02919

(d) The product of the reaction in part (c) above displays a 1,3-N,O relationship. This chemical relationship is often made using the Mannich reaction. Could the molecule below be made using the Mannich reaction? If you answer “yes”, then show conditions and starting materials. If you answer “no”, then describe why not.

SO

N

H

PhMgBrEt2O, CH2Cl2

?

NSO

i) LDA, 0 oC, 1 h 2.2 equiv PhCHO –78 to –20 oCii) KOH, MeOH

NHSO OH

Ph87%, dr 86:14

NH2 OH

Ph

4. The following questions are based on the previously distributed paper referenced below. Be brief – less than 5 sentences for each of the responses.

"Conformations of Cycloheptadecane. A Comparison of Methods for Conformational Searching"

Houk et al. J. Am. Chem. Soc. 1990, 112, 1419-1427.

(a) Which is more efficient and effective for conformational searches – Cartesian coordinate search or internal coordinate search? Define these terms and explain why which is better.

(5 points)

(b) Which is more efficient and effective for conformational searches – tree search or Monte Carlo search? Define these terms and explain why which is better.

(5 points)

(c) Why was molecular dynamics a particularly poor method for conformational search? (5 points)

(d) What is the SHAKE algorithm and why would this method be useful? (3 points)

(e) Why is the conformational search of cycloheptadecane a complicated problem? Why is it harder than cyclooctadecane?

(5 points)

(f) Consider a complex macrocycle natural product such as Mandelalide or Ionomycin. Is this a “harder” conformational search problem than cycloheptadecane? Why or why not? Justify.

(10 points)

5. Glycation is a post-translational modification of proteins that involves non-enzymatic conjugation of protein side-chains with an open chain tautomer of a carbohydrate. Spiegel and coworkers recently reported the synthesis of the protein-free form of glucosepane: a particularly stable glycation linkage formed from the condensation of lysine and arginine side-chains within two separate proteins with a molecule of glucose.

Science 2015, 350, 294-298.

(a) Glucosepane is present in long-lived proteins such as collagen and lens crystallin. How are proteins more commonly covalently cross-linked? What advantage(s) might a glucosepane linkage offer to stabilize proteins that must survive long periods of time? (5 points)

(b) The central 2,5-diaminoimidazolium unit of glucosepane favors the non-aromatic 4H-tautomer (as illustrated). Draw the aromatic 1H-imidazolium form of glucosepane and suggest why the 4H-tautomer is thermodynamically more stable. (6 points)

(c) Initial attempts to prepare glucosepane in a biomimetic fashion failed, instead the route below was devised to access a protected protein-free form of this adduct (5).

i. Give reagents and conditions for the multi-step conversion of diacetone-D-glucose and the benzyl ester of N-Cbz lysine into amino alcohol 2. (7 points)

ii. Formulate detailed mechanisms for the conversion of 2 to 3 and 3 + 4 to glucosepane adduct 5. (15 points)

NH

O

N

protein

protein

NH

N

N N

H

OHOH

NproteinHN

Oprotein

protein bound glucosepane

H

OHOHO

OH

OH

OH

glucose

NH

NH2

NH2arginine side-chain

NH2 lysine side-chain

= R= R´

HR

R´

H

OO O

O

O

diacetone- D-glucose (1)

O

O

O

HN

OHsteps?

= R''

N

O

R''

OO

aq. AcOH, 65 °Cthen,

Me2C(OMe)2PPTS

PhMe, 90 °C2 3

H2N NH

NH

NH

NHCbz

CO2H

NHCbz

CO2Bn

4

N

R''

HOHO

N

N

H

HN

H NHCbz

CO2H

(a)

(b) Me3SiCl, CHCl3Cl–

5

6. Linington et al. recently disclosed the new polyene macrolactams lobosamides A-C, one of the first complete absolute stereochemical assignments in this compound class.

ACS Chem. Biol. 2015, 10, 2373-2381.

Biosynthesis:

(a) What biosynthetic pathway is responsible of producing lobosamides? (2 points)

(b) Identify the starter unit and propose a mechanism to form the starter unit. (4 points)

(c) How many enzymatic modules are used to form the 26-membered macrolactam? (3 points)

(d) How is the final biosynthesis product released from the enzyme? (2 points)

Structure elucidation:

(e) Acetonide formation was used to elucidate the relative configuration of the C9 and C11 hydroxyl groups to each other. Explain briefly how to perform the chemical derivatization and what information can be gained. (7 points)

(f) J-based method analysis was applied using ROESY NMR experiments supported by DFT molecular modeling. For C8-C9 and C9-C10 draw possible Newman projections that represent lobosamide A and estimate coupling constants. (6 points)

(g) Why are polyene marcolactams hard to work with? (3 points)

Genome analysis: (h) The authors sequenced the genome of the producer of lobosamides, a bacterium belonging

to Micromonospora sp. How can you use this information to identify more producers of this rare class of compounds? (4 points)

(i) How can knowledge of the enzymes involved in the biosynthesis help with the absolute stereochemical assignment? (2 points)

important compounds, such as salinosporamide A, which iscurrently in late-phase clinical trials for multiple myeloma.11 Inaddition to many other biological activities, marine naturalproducts are an important source of lead compounds for globalhealth targets. Representatives of multiple classes of marinenatural products have shown activity against T. brucei parasitesincluding polyketides,12 alkaloids,13,14 diketopiperazines,15

peptides,16 and others.8

As part of our ongoing program to discover new leadcompounds for NTDs, we have screened our bacterially derivedmarine natural products library against T. brucei (T. b.)subspecies T. b. brucei Lister 427. Herein, we report a familyof structurally novel polyene macrolactams, lobosamides A−C(1−3, Figure 1), which are produced by a marine sediment-derived Micromonospora sp., with lobosamide A exhibitingsubmicromolar antitrypanosomal activity. To date, thesemolecules represent the first polyene macrolactams withreported activity against T. brucei parasites. In order to confirmthe structures and deduce the full absolute configurations forthese new molecules, we sequenced the genome of theproducing Micromonospora sp. and identified the biosyntheticgene cluster (BGC) responsible for their production. Using acombination of detailed spectroscopic and genome sequenceanalyses, we assigned the full absolute configurations of thelobosamides, providing a rare example of the complete absoluteconfigurational assignment for a member of this compoundclass.The increased availability of bacterial genomes and BGCs has

the potential to change the way natural products discovery isconducted.17 In this study, we have implemented a “molecules-to-genes-to-molecules” approach by using the newly elucidatedlobosamide structure and assembled BGC as a query sequence

to identify similar BGCs in other organisms that have not yetbeen chemically annotated. This genome mining strategy,which uses the genetic information found in biosynthetic geneclusters to predict molecular frameworks, is gaining importancein natural product discovery platforms.18,19 Using thisapproach, we identified a homologous BGC in the full genomesequence of a distantly related actinobacterium, Actinosynnemamirum (ATCC 29888), which we predicted to produce arelated macrocyclic lactam.20 Using the predicted structure toguide the isolation, we identified two additional 26-memberedmacrolactams, which provided structure−activity relationship(SAR) information about the features necessary for anti-trypanosomal activity. The success of this strategy providesfurther support for the parallel implementation of molecularbiology and analytical chemistry techniques for the discovery ofnatural products with unique chemical and biological features.

■ RESULTS AND DISCUSSIONIdentification and Structure Elucidation of Lobosa-

mides A−C. Initial screening of our marine bacterially derivednatural product library against axenic T. b. brucei parasitesrevealed a prefraction that exhibited significant trypanocidalactivity and no measurable cytoxicity toward mammalian cellsin our phenotypic assay.21 This prefraction was produced byMicromonospora sp. RL09-050-HVF-A isolated from a marinesediment sample collected from Point Lobos in the MontereyBay, CA. Secondary screening of a one-compound, one-well“peak library” (Supporting Information) identified two relatedcompounds in the trace as responsible for the biologicalactivity. Isolation by reversed-phase (RP)-HPLC led to thediscovery of lobosamides A and B (Figure 1). Analysis of the(+)-HRESIFTMS (obsd. [M + Na]+ at m/z 506.2882) and

Figure 1. Structures of the lobosamides and related polyene macrolactams.

ACS Chemical Biology Articles

DOI: 10.1021/acschembio.5b00308ACS Chem. Biol. 2015, 10, 2373−2381

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