Organic Cumulative Exam January 21, 2016

LPSC 239 and LPSC 259 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 clearly marked as such. Clearly indicate which questions are to be graded on the front of your answer booklet. Good luck! !

1. Fu and coworkers: J. Am. Chem. Soc. 2005, 127, 4594

a. Draw the complete mechanism of the above reaction. What is the rate determining step? Stereodetermining?

b. What are the origins of stereoselectivity? Draw the key transition structure(s) and explain.

c. Is it a kinetic resolution, a dynamic kinetic resolution, or neither? Why? d. Ni is not the most obvious choice for a cross-coupling metal catalyst. Explain

why this strategy may be necessary. (Hint: What are the challenges associated with developing an enantioselective cross-coupling reaction using Pd chemistry? How does the use of the Ni circumvent these issues?)

e. Why might enantioselective cross-coupling of sp3 hybridized carbons be of value? Consider academic importance as well as practical importance as it relates to industry or other fields of science.

Asymmetric Nickel-Catalyzed Negishi Cross-Couplings of Secondaryr-Bromo Amides with Organozinc Reagents

Christian Fischer and Gregory C. Fu*Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Received February 1, 2005; E-mail: gcf@mit.edu

Recently, considerable progress has been described in the questfor catalysts that can cross-couple alkyl electrophiles.1 Althoughmost investigations have focused on reactions of primary electro-philes, there have also been noteworthy advances in the develop-ment of catalysts that achieve couplings of secondary alkylelectrophiles.2,3For cross-couplings of unsymmetrical secondary electrophiles,

a stereocenter may be produced at the carbon that bears the leavinggroup. This stereochemical aspect adds an important new dimensionto these carbon-carbon bond-forming processes, control of whichwould greatly increase their utility. In this report, we describe thefirst catalytic enantioselective cross-couplings of secondary alkylelectrophiles (eq 1; DMI ) 1,3-dimethyl-2-imidazolidinone).4

In 2003, we reported that Ni(cod)2/(s-Bu)-Pybox catalyzesNegishi reactions of secondary alkyl bromides and iodides.3a Ourobservation that the cross-couplings proceed particularly well inthe presence of (s-Bu)-Pybox clearly opened the door to thepossibility of achieving an asymmetric variant.5 Upon exploringseveral different families of secondary alkyl electrophiles, weobtained promising results with R-bromo amides (for some illustra-tive data, see eqs 2 and 3). Optimization of the reaction conditionsled to a catalyst system that furnishes the desired product in bothhigh enantiomeric excess and yield (eq 4).6 This method has proved to be general for catalytic asymmetric

Negishi cross-couplings of a range of R-bromo amides with an arrayof organozinc reagents (Table 1).7 Not only unfunctionalized (entries1-7) but also functionalized (entries 8-12) organozincs serve asuseful coupling partners, affording the target compounds in verygood enantiomeric excess. Thus, asymmetric carbon-carbon bondformation proceeds smoothly in the presence of groups such as anolefin (entry 8), a benzyl ether (entry 9), an acetal (entry 10), animide (entry 11), and a nitrile (entry 12).8Several other observations are worthy of note. First, this catalyst

system is highly selective for coupling an R-bromo amide in thepresence of either an unactivated primary or secondary alkylbromide (eq 5). Second, there is no evidence for kinetic resolutionduring the catalytic asymmetric cross-coupling (eq 6). Third, theamide can be converted into other useful functional groups (eq 7).We have not yet had the opportunity to systematically investigate

the mechanism(s) of the nickel-based catalysts that we havedescribed for cross-coupling alkyl electrophiles.3 Recently, Vicicsuggested that, for Negishi reactions, carbon-carbon bond forma-

Table 1. Asymmetric Negishi Cross-Couplings of SecondaryR-Bromo Amides with Organozinc Reagents (eq 1; all data are theaverage of two experiments)

a Isolated yield. b The coupling was conducted at room temperature. c Forthe second run (data given in parentheses), the product was recrystallized,which leads to an enrichment of the enantiomeric excess of the product.

Published on Web 03/12/2005

4594 9 J. AM. CHEM. SOC. 2005, 127, 4594-4595 10.1021/ja0506509 CCC: $30.25 © 2005 American Chemical Society

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Asymmetric Nickel-Catalyzed Negishi Cross-Couplings of Secondaryr-Bromo Amides with Organozinc Reagents

Christian Fischer and Gregory C. Fu*Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Received February 1, 2005; E-mail: gcf@mit.edu

Recently, considerable progress has been described in the questfor catalysts that can cross-couple alkyl electrophiles.1 Althoughmost investigations have focused on reactions of primary electro-philes, there have also been noteworthy advances in the develop-ment of catalysts that achieve couplings of secondary alkylelectrophiles.2,3For cross-couplings of unsymmetrical secondary electrophiles,

a stereocenter may be produced at the carbon that bears the leavinggroup. This stereochemical aspect adds an important new dimensionto these carbon-carbon bond-forming processes, control of whichwould greatly increase their utility. In this report, we describe thefirst catalytic enantioselective cross-couplings of secondary alkylelectrophiles (eq 1; DMI ) 1,3-dimethyl-2-imidazolidinone).4

In 2003, we reported that Ni(cod)2/(s-Bu)-Pybox catalyzesNegishi reactions of secondary alkyl bromides and iodides.3a Ourobservation that the cross-couplings proceed particularly well inthe presence of (s-Bu)-Pybox clearly opened the door to thepossibility of achieving an asymmetric variant.5 Upon exploringseveral different families of secondary alkyl electrophiles, weobtained promising results with R-bromo amides (for some illustra-tive data, see eqs 2 and 3). Optimization of the reaction conditionsled to a catalyst system that furnishes the desired product in bothhigh enantiomeric excess and yield (eq 4).6 This method has proved to be general for catalytic asymmetric

Negishi cross-couplings of a range of R-bromo amides with an arrayof organozinc reagents (Table 1).7 Not only unfunctionalized (entries1-7) but also functionalized (entries 8-12) organozincs serve asuseful coupling partners, affording the target compounds in verygood enantiomeric excess. Thus, asymmetric carbon-carbon bondformation proceeds smoothly in the presence of groups such as anolefin (entry 8), a benzyl ether (entry 9), an acetal (entry 10), animide (entry 11), and a nitrile (entry 12).8Several other observations are worthy of note. First, this catalyst

system is highly selective for coupling an R-bromo amide in thepresence of either an unactivated primary or secondary alkylbromide (eq 5). Second, there is no evidence for kinetic resolutionduring the catalytic asymmetric cross-coupling (eq 6). Third, theamide can be converted into other useful functional groups (eq 7).We have not yet had the opportunity to systematically investigate

the mechanism(s) of the nickel-based catalysts that we havedescribed for cross-coupling alkyl electrophiles.3 Recently, Vicicsuggested that, for Negishi reactions, carbon-carbon bond forma-

Table 1. Asymmetric Negishi Cross-Couplings of SecondaryR-Bromo Amides with Organozinc Reagents (eq 1; all data are theaverage of two experiments)

a Isolated yield. b The coupling was conducted at room temperature. c Forthe second run (data given in parentheses), the product was recrystallized,which leads to an enrichment of the enantiomeric excess of the product.

Published on Web 03/12/2005

4594 9 J. AM. CHEM. SOC. 2005, 127, 4594-4595 10.1021/ja0506509 CCC: $30.25 © 2005 American Chemical Society

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2. Over a decade of experimental work from Sutherland et al. has provided support to a plausible hypothesis explaining how RNA could have arisen spontaneously on the prebiotic Earth. A central tenet of the Sutherland hypothesis is that the ribose unit and nuclear base are formed in concert (e.g., as below) and not in separate events as conventional thinking had long suggested.

Angew. Chem., Int. Ed. 2016, 55, 104.

(a) Formulate a detailed mechanism to show how β-cytidine-2´,3´-cyclic phosphate (5) can arise from D-glyceraldehyde (1), 2-aminooxazole (2), cyanoacetylene (4), and phosphate. In the process, identify the structure of bicyclic intermediate 3.

(15 points)

(b) Glyceraldehyde (1) arises from an aldol reaction between glycolaldehyde (6) and formaldehyde. Further reactions involving formaldehyde lead not only to the formation of higher sugars but also to an amplification in the quantity of 6. Show how the reaction of 1 and HCHO can produce two molecules of 6.

(8 points)

(c) Suggest how 6 and thence 2 could be formed from extremely simple molecules likely to be plentiful on a young Earth. Consider any combination of HCHO, HCN, NH3, and H2O and allow for redox processes ([O] or [H]) to occur.

(6 points)

(d) According to the 'RNA world' hypothesis, RNA was the primordial molecule required for the later emergence of all life as we know it today. What is your understanding of the 'RNA world' hypothesis and in the light of it, briefly comment on the significance of the spontaneous chemistry highlighted above.

(4 points)

OHO

N N

NH2

OOPO

O O 5O

NNH2

CN

H2PO4–

CHO

OHHO

+

1

2 3

4C6H10N2O4

structure?

O

base CHO

OHHO

1

HCHO

base

HCHO

6 6 6

HOO

HOO

HO+

3. (33 points) Organocatalysis offers a powerful route to complex molecules because of the ability to induce electronic and steric preorganization prior to the desired transition state. A recent example with fairly broad scope was reported by a Danish group:

Yields are high (usually >95%), and ee's are usually 76-81% but occasionally better.

A. Provide a thorough mechanism for the reaction that explains the function of all components.

B. Explain the regioselectivity of the reaction, based on your mechanism.

C. Provide a predictive model for the enantioselectivity of the reaction.

D. Provide a concise synthesis of organocatalyst 3c, and explain how you would ensure access to both enantiomers.

Ref.: Li, Y. et al. Angew. Chem., Int. Ed. 2016, 55, 1020.

4) 33Pts. Tsukamoto and co-workers recently isolated and characterized taichunamides A-D, chemical unique fungal metabolites produced by several fungi of the genus Aspergillus.

Angew. Chem. Int. Ed. 2015, 54, 1-6.

A) Taichunamides are biosynthetically derived from Notoamide S (1), shown below. 1) What biosynthetic building blocks can you recognize in the

shown diketopiperazine? 2) What biosynthetic pathway is responsible for the side

chains on the indole? Name the pre-cursor and show how both side chains are derived from the same starting material.

B) Starting from Notoamide S (1), show a mechanism for the chemical formation of the

bicyclo[2.2.2]diazaoctane core in taichunamides. 1) Can you name that type of reaction? 2) Two fungi produce the syn-bicyclo[2.2.2]diazactane, while the taichunamide

producer forms the anti- bicyclo[2.2.2]diazaoctane. Draw a transition state for both cases and explain the stereoselectivity.

C) Taichunamides show very unusual structural features: 1) Taichunamide A contains an azetidine moiety. How can you prove its structure?

Name four techniques/experiments to support the identify of the natural product. 2) Taichunamide C exhibits a N-linked peroxide bridge. Name three spectroscopic

techniques that could help you verify this moiety. Bonus: Do you know any other peroxide containing natural products?

3) Taichunamide D has a N-methyl sulfonyl group that is useful in medicinal chemistry to modulate pharmacokinetics and physical properties. Explain why.

CommunicationsNatural Products

I. Kagiyama, H. Kato, T. Nehira,J. C. Frisvad, D. H. Sherman,R. M. Williams,S. Tsukamoto* &&&&—&&&&

Taichunamides: Prenylated IndoleAlkaloids from Aspergillus taichungensis(IBT 19404)

Magnificent seven : Seven new prenylatedindole alkaloids were isolated from A.taichungensis. This fungus produces alka-loids containing an anti-bicyclo-[2.2.2]diazaoctane core, whereas A. pro-tuberus and A. amoenus produce deriva-

tives with a syn-bicyclo core. The struc-tural diversity of tryptophan-derived sec-ondary metabolites reveals unusuallydiverse stereochemical and structuralsecondary metabolite tailoring functionsin these orthologous fungi.

.AngewandteCommunications

6 www.angewandte.org ! 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2015, 54, 1 – 6! !

These are not the final page numbers!

hexanone ring fused with a A unit was indicated by thepresence of a ketone carbon atom [dC = 190.7 ppm (C2)] andtwo methyl groups [dH = 1.35 ppm, dC = 19.7 ppm (C23); dH =1.21 ppm, dC = 27.2 ppm (C24)], along with the HMBCcorrelations H323/C2, C21, C22, and C24, H210/C2, C3, C11,C12, and C21, and H21/C22. The direct connection betweenC9 in the B unit and the quaternary C3 was shown by theHMBC correlations H4/C3 and H10/C9. The chemical shiftsof C3 (dC = 81.3 ppm) and C8 (dC = 147.9 ppm) revealed thatthe two carbon atoms were linked through the remainingportion NH, and resulted in the formation of an azetidinering. Two exchangeable hydrogen signals were observed atd = 6.29 (s) and 7.54 ppm (s). The latter signal showed HMBCcorrelations with C11, C12, and C17, thus indicating that thesignal was H19, and the former signal was that of H1. Therelative configuration of 1 was established by the NOEcorrelations H1/H323 (d = 1.35 ppm), H323/H19, and H21/H10 (d = 1.71 ppm), which showed that H1, H10 (d =2.63 ppm), H19, and H323 (d = 1.35 ppm) were on the sameside and H21 and H10 (d = 1.71 ppm) were located on theopposite side (see Figure 2b and Figure S1). The Cottoneffect at l = 225–250 nm arises from an n–p* transition of thedioxopiperazine moiety, and is diagnostic of the bicyclo-[2.2.2]diazaoctane dioxopiperazine core.[6] The ECD spectraof 1 showed a positive Cotton effect around l = 225 nm, andthus the absolute configuration of 1 was assigned as3S,11S,17S,21R.

Taichunamide B (2) showed a protonated molecular ion atm/z 446.2064, which indicated a molecular formulaC26H27N3O4. The 1H NMR spectrum in [D6]DMSO (seeTable S2) indicated that 2 was an equilibrium mixture of

two entities in the ratio of 3:1. An analysis of two-dimensional(2D) NMR spectra revealed that 2 contained a 5,6-disubsti-tuted 2,2-dimethyl-2H-chromene and bicyclo-[2.2.2]diazaoctane moieties as observed in 1. The HMBCcorrelations H4 (dH = 7.92 ppm)/C3 (dC = 172.8 ppm), H1(dH = 10.42 ppm)/C8 (dC = 135.7 ppm), C9 (dC = 121.1 ppm),C10 (dC = 119.9 ppm), and C22 (dC = 43.7 ppm), H324 (dH =1.41 ppm)/C2 (dC = 164.1 ppm) and C21 (dC = 53.5 ppm), andH19 (dH = 8.47 ppm)/C10, revealed that the major tautomerof 2 comprised a 4-pyridone ring (Figure 3). In contrast, theHMBC correlations 3OH (dH = 11.27 ppm)/C3 (dC =157.3 ppm), C9 (dC = 114.4 ppm), and C10 (dC = 107.4 ppm),H4 (dH = 7.96 ppm)/C3, and H19 (dH = 8.93 ppm)/C10, H324(dH = 1.30 ppm) and H21 (dH = 2.15 ppm)/C2 (dC =174.2 ppm), secured the presence of a 4-pyridol ring as theminor tautomer (Figure 3). Thus, 2 exists as an equilibriummixture of keto–enol tautomers in [D6]DMSO. Curiously, theratio of the keto and enol forms is highly solvent-dependent.A single keto form is evident in CD3OD and a single enolform is apparent in [D6]acetone (see Table S3). The NOEcorrelations H21/H324 and H19/H323 in the keto form(Figure 3, see Figure S1), and the ECD spectrum establishedthe 11R,17S,21R configuration.

The molecular formula of taichunamide C (3) was estab-lished by HRESIMS to be C27H31N3O6, thus indicating onemore CH3O3 unit more than that of 13. Analysis of the 2DNMR spectra (see Table S4) indicated that the structure of 3was similar to that of 13. Carbon chemical shifts of C2 (d =107.2 ppm) and C3 (d = 73.2 ppm) suggested that the olefiniccarbon atoms, C2 and C3, in 13 were replaced with oxygen-bearing carbon atoms in 3. The presence of a hydroxy group at

Scheme 1. Proposed facial specificities of IMDA reactions for metabolites in A. protuberus (circles), A. amoenus (triangles), and A. taichungensis(squares). Major and minor metabolites in each fungus are represented with large and small symbols, respectively.

.AngewandteCommunications

2 www.angewandte.org ! 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2015, 54, 1 – 6! !

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1

5.### i.#(11#pts.)#Over#the#past#several#years,#there#has#been#intense#interest#in#the#

generation#of#quaternary#carbon#stereocenters#(see#Quasdorf,#K.#W.;#Overman,#L.#E.#Nature#2015,&516,+181.)##Show#two#distinct#general#methods#for#constructing#molecules#with#such#stereocenters#as#single#enantiomers.#

#

##

# ii.##(11#pts.)#There#has#also#been#increasing#interest#in#the#stereoselective#formation#of#

αHtertiary#amines#(see#Hager,#A.;#Vrielink,#N.;#Hager,#D.;#Lefranc,#J.;#Trauner,#D.#Nat.+Prod.+Rep.+2016,&Advance#Article)#.##Show#two#distinct#general#methods#for#constructing#molecules#with#such#stereocenters#as#single#enantiomers.#

#

# iii.##(11#pts.)#Show#two#distinct#general#methods#for#constructing#tertiary#alcohols#as#single#enantiomers.#

#

#

R1

R2

R3R4

quaternary carbon stereocenter

R1

N

R2R3

α-tertiary amine stereocenter

R5R4

R1

OH

R2R3

tertiary alcohol stereocenter

In Johnson and co-workers recent publication on paspaline (JOC 2015, 80, 9740-9766), they disclose the following interesting sequence.

(a) Provide the products A-C including stereochemistry.

(B) Provide a mechanism for the conversion of compound C into alcohol 4. Rationalize and stereochemical or regiochemical outcomes in the processs.

I

O CO2EtCO2Me

CO2Me

Cs2CO3DMF

rt

99%, >20:1 dr

O

CO2Me

Compound AC16H24O7

DIBAL-HTHF72%;

Ph3P, I2imid

Ph3P, I2imid

Compound BC14H21IO5

O

O

Cs2CO3DMF, 65°C

34%

Compound CC21H30O7

O OH

H H

NaCl, DMSO

150°C, 43%

1 2

3

4Unfortunately, alcohol 4 contains the wrong stereochemistry alpha to the ketone. In a revised route, they are able to access oxime 5.

(c) Provide a viable sequence to convert oxime 5 into ketone 6.

(d) Provide a viable sequence to convert ketone 6 into paspaline (7).

OH H5

OTBS

NOBn

OH H6

OTBS

H

O

steps

OH H

paspaline (7)

OH

H

NH

steps