synthetic approaches to pyrroloindoline … approaches to pyrroloindoline containing natural...

Synthetic Approaches to Pyrroloindoline Containing Natural Products

MacMillan Group MeetingJoe Carpenter

February 18, 2009

Synthetic Approaches to Pyrroloindoline Natural ProductsPresentation outline

■ Introduction to pyrroloindolines

■ Methods to construct the pyrroloindoline core

● Biomimetic approach

i. Raceimc methods ii. Synthesis from chiral pool iii. Enantioselective synthesis

● "Oxoindole" approach

● Other methods

■ Conclusions

Synthetic Approaches to Pyrroloindoline Natural ProductsIntroduction

■ Diverse biological activity of pyrroloindolines

calabar alkaloidsAlzheimer's

anticholinergicorganophosphate poisoning

flustramines and pseudophyrnaminesanticancer activitymuscle relaxant

cholecystokinin antagonist

calycanthaceous alkaloidsanalgesic

antibacterialsomatostatin agoinst

echitamine alkaloidsanticancer

■ Pyrroloindolines are isolated from amphibians, marine organisms and plant sources

ardeemins and amaurominereverse multi-drug resistance in cancer cells

vasodilator

HNMeN R

RCO2MeR

Synthetic Approaches to Pyrroloindoline Natural ProductsIntroduction

■ Substitution pattern around central pyrroloindoline varies greatly

calabar alkaloidsesermethole R = Me

physostigmine R = CONMephenserine R = CONPh

flustramines and pseudophyrnamines calycanthaceous alkaloidschimonanthine R = H

echitamine alkaloidsechitaminevincorine

ardeemins and amauromine

HNMeN R

RCO2MeR

Synthetic Approaches to Pyrroloindoline Natural ProductsBiomimetic Approach

■ Perceived to arise via electrophilic attack at indole C-3 position of tryptophan or tryptamine

■ Alkylative cyclization allows rapid access to racemic flustramines

Tan, G. H.; Zhu, X.; Ganesan, A. Org. Lett. 2003, 5, 1801.

tryptamine

Zn(OTf)2, i-Pr2NEt

Bu4NIToluene, r.t.

Red-Al

Toluene96 %

(±) debromoflustramine B

■ Perceived to arise via electrophilic attack at indole C-3 position of tryptophan or tryptamine

■ Alkylative cyclization allows rapid access to racemic flustramines

Tan, G. H.; Zhu, X.; Ganesan, A. Org. Lett. 2003, 5, 1801.

tryptamine

Zn(OTf)2, i-Pr2NEt

Bu4NIToluene, r.t.

Red-Al

Toluene96 %

(±) debromoflustramine B

■ Menéndez used a similar strategy to access the flustramine core

López-Alvarado, P.; Caballero, E.; Avendaño, C.; Menéndez, C. J. Org. Lett. 2006, 8, 4303.

i. ICH2TMS, Et3Nii. LiHMDSiii. prenyl bromide

one-pot 86%

LiOTMS

OEtN N

■ Tryptophan derivitaves give rise to possible diastereomers

Crich, D.; Huang, X. J. Org. Chem. 1999, 64, 7218.

ECO2Me

CO2Me CO2Me

E CO2Me

exo(kinetic)

endo(thermodynamic)

Combined Yield (%)

8565768340310

electrophile

HPhthSePhPhthSePhPhthSePhPhthSePhPhthSePhPhthSePh

CO2BnCO2MeSO2Ph

SO2PMPH

CO2MeBoc

CO2MeCO2MeCO2MeCO2MeCO2Me

endo:exo

9:11:91:121:11

<2:98<2:98

■ Application in Danishefsky's synthesis of amauromine and acetylardeemin

CO2MePhth SePh

pTSA, Na2SO4

CH2Cl278 %

PhSe CO2Me

9:1 d.r.

1. MeOTf, prenyl Bu3Sn

2. NaOH3. TMSI N

BOP-Cl NBoc

TMSINH

amauromine

1. D-Ala-OMe•HCl

2. TMSI NH

1. KHMDS

2. PBu33. LDA, AcCl

5-N-acetylardeemin

Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143.

CO2MePhth SePh

pTSA, Na2SO4

CH2Cl278 %

PhSe CO2Me

9:1 d.r.

2. NaOH3. TMSI N

BOP-Cl NBoc

TMSINH

amauromine

1. D-Ala-OMe•HCl

2. TMSI NH

1. KHMDS

2. PBu33. LDA, AcCl

5-N-acetylardeemin

CO2MePhth SePh

pTSA, Na2SO4

CH2Cl278 %

PhSe CO2Me

9:1 d.r.

2. NaOH3. TMSI N

BOP-Cl NBoc

TMSINH

amauromine

1. D-Ala-OMe•HCl

2. TMSI NH

1. KHMDS

2. PBu33. LDA, AcCl

5-N-acetylardeemin

■ The Joullié group synthesis of roquefortine C uses the same strategy as Danishefsky

1. HATU, i-Pr2NEt

2. EDC CuCl2 (syn elim)3. TMSI, MeCN4. NH3•H2O

roquefortine C

isoroquefortine C

more stable by 14kJ/molnot found in nature

■ Other electrophiles are also competent for pyrroloindoline formation

Shangguan, N.; Hehre, W. J.; Ohlinger, W. S.; Beavers, M. P. Joullié, M. M. J. Am. Chem. Soc. 2008, 130, 6281.

NHCO2Me

i-Pr2NEt, CH2Cl292 %

NCO2Me

CO2MeMeO

SMe1. Raney Ni, HCHOaq2. Red-Al

3. i. Swern ii. NH2SO3H iii. NaBH4

(–)-esermethole

Kawahara, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 675.

1:1 d.r.

■ The Joullié group synthesis of roquefortine C uses the same strategy as Danishefsky

1. HATU, i-Pr2NEt

2. EDC CuCl2 (syn elim)3. TMSI, MeCN4. NH3•H2O

roquefortine C

isoroquefortine C

more stable by 14kJ/molnot found in nature

■ Other electrophiles are also competent for pyrroloindoline formation

Shangguan, N.; Hehre, W. J.; Ohlinger, W. S.; Beavers, M. P. Joullié, M. M. J. Am. Chem. Soc. 2008, 130, 6281.

NHCO2Me

i-Pr2NEt, CH2Cl292 %

NCO2Me

CO2MeMeO

SMe1. Raney Ni, HCHOaq2. Red-Al

3. i. Swern ii. NH2SO3H iii. NaBH4

(–)-esermethole

Kawahara, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 675.

1:1 d.r.

■ Danishefsky used a slight variation to construct the Himastatin core

Kamanecka, T. M.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1998, 37, 2993 and 2995.

NHSO2anth

CO2tBu

NBS, Et3N DMDO

NHSO2anth

CO2tBu

NaBH4 75 % N

NHSO2anth

CO2tBuHO

CO2tBuTBSO

Me3Sn1. i. Al(Hg) ii. CbzCl iii. TBSCl

2. ICl3. Sn2Me6 Pd(PPh3)4

Pd2dba3AsPh3

CO2tBuTBSO

ButO2C OTBS

himastatin

■ Danishefsky used a slight variation to construct the Himastatin core

Kamanecka, T. M.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1998, 37, 2993 and 2995.

NHSO2anth

CO2tBu

NBS, Et3N DMDO

NHSO2anth

CO2tBu

NaBH4 75 % N

NHSO2anth

CO2tBuHO

CO2tBuTBSO

Me3Sn1. i. Al(Hg) ii. CbzCl iii. TBSCl

2. ICl3. Sn2Me6 Pd(PPh3)4

Pd2dba3AsPh3

CO2tBuTBSO

ButO2C OTBS

himastatin

■ Electophilic sources of nitrogen have also been shown to work efficiently

Newhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 10886.

NHCO2Me

NIS, Et3N

NH267% N

NCO2Me

(±)-psychotrimine

Also works with tryptophan derivatives (45%)

NHCO2Me

Pd(OAc)2

NCO2Me

NHCO2Me

CuI, K2CO3

NHCO2Me

NCO2Me

NHCO2Me

MeO2CHN

Red-Al

■ Electophilic sources of nitrogen have also been shown to work efficiently

Newhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 10886.

NHCO2Me

NIS, Et3N

NH267% N

NCO2Me

(±)-psychotrimine

Also works with tryptophan derivatives (45%)

NHCO2Me

Pd(OAc)2

NCO2Me

NHCO2Me

CuI, K2CO3

NHCO2Me

NCO2Me

NHCO2Me

MeO2CHN

Red-Al

■ Dimerization of benzylic radicals allows access to dimeric structures

Movassaghi, M.; Schmidt, M. A. Angew. Chem. Int. Ed. 2007, 46, 3725.

NSO2Ph

NCO2Me

CO2MeH

cyclized with H3PO4

NSO2Ph

NCO2Me

CO2MeBr[CoCl(PPh3)3]

NSO2Ph

NCO2Me

SO2PhN

MeO2CN

4 steps to (+)-chimonanthine

(+)-chimonanthine

(+)-folicanthine(–)-calycanthine

HCOHaqNaBH(OAc)3

■ Dimerization of benzylic radicals allows access to dimeric structures

Movassaghi, M.; Schmidt, M. A. Angew. Chem. Int. Ed. 2007, 46, 3725.

NSO2Ph

NCO2Me

CO2MeH

cyclized with H3PO4

NSO2Ph

NCO2Me

CO2MeBr[CoCl(PPh3)3]

NSO2Ph

NCO2Me

SO2PhN

MeO2CN

4 steps to (+)-chimonanthine

(+)-chimonanthine

(+)-folicanthine(–)-calycanthine

HCOHaqNaBH(OAc)3

■ Tryptophan derivatives will react with carbenes to give the pyrroloindoline core upon cyclization

He, B.; Song, H.; Du, Y.; Qin, Y. J. Org. Chem. 2009, 74, 298.Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem. Int. Ed. 2008, 47, 3618.

Cu(OTf) NMe

87%, 16:1 dr (–30 °C) 73%, 1.6:1 dr (r.t.)

15 steps

O (–)-ardeemin, R = H

(–)-acetylardeemin R = AcH

■ Qin uses a tethered carbene to access the fully substituted C-3 of Minfiensine

(10 steps)

9 steps

(±)-minfiensine

■ Tryptophan derivatives will react with carbenes to give the pyrroloindoline core upon cyclization

He, B.; Song, H.; Du, Y.; Qin, Y. J. Org. Chem. 2009, 74, 298.Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem. Int. Ed. 2008, 47, 3618.

Cu(OTf) NMe

87%, 16:1 dr (–30 °C) 73%, 1.6:1 dr (r.t.)

15 steps

O (–)-ardeemin, R = H

(–)-acetylardeemin R = AcH

■ Qin uses a tethered carbene to access the fully substituted C-3 of Minfiensine

(10 steps)

9 steps

(±)-minfiensine

Austin, J. F.; Kim, S-G.; Sinz, C. J.; Xiao, W-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. 2004, 101, 5482.

■ Catalytic asymmetric approach to the flustramines by the MacMillan group

enantioinrichedpyrroloindoline

Austin, J. F.; Kim, S-G.; Sinz, C. J.; Xiao, W-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. 2004, 101, 5482.

enantioinrichedpyrroloindoline N

20 mol %

2. NaBH4

• p-TSA

78% yield 90% ee

1. MsCl

2. NO2PhSeCN H2O2 89%

NBocGrubbs

metathesis94%

NBoc 1. TMSI

2. (CHO)n NaBH4 89%

(–)-flustramine B

Synthetic Approaches to Pyrroloindoline Natural ProductsThe 2-Oxoindole Approach

■ The pyrroloindoline core can also readily be attained through a suitable 2-oxoindole

generic 2-oxoindole

alkylation

amination

reduction NH

■ Similarities to biomimetic approach but different oxidation state utilized

NsNBS, tBuOH

THF, H2O83%

Cs2CO3

2. Cs2CO3, PhSH NBr

Oalane

Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677.

(±)-flustramine A

Julian, P. L.; Pikl. J.; Boggess. D. J. Am. Chem. Soc. 1934, 56, 1797.

■ The pyrroloindoline core can also readily be attained through a suitable 2-oxoindole

generic 2-oxoindole

alkylation

amination

reduction NH

■ Similarities to biomimetic approach but different oxidation state utilized

NsNBS, tBuOH

THF, H2O83%

Cs2CO3

2. Cs2CO3, PhSH NBr

Oalane

(±)-flustramine A

Julian, P. L.; Pikl. J.; Boggess. D. J. Am. Chem. Soc. 1934, 56, 1797.

■ Evidence for the indole-2-one intermediate

Cs2CO3

■ Dalko invokes the same intermediate in the synthesis of meso-chimonanthine

Cs2CO3

NHCO2Me

NCO2Me

Red-Al

NCHO2Me

Menozzi, C.; Dalko, P. I.; Cossy, J. Chem. Commun. 2006, 4638.

desmethyl-meso-chemonanthine

75% 95:5 d.r. 57%

■ Evidence for the indole-2-one intermediate

Cs2CO3

■ Dalko invokes the same intermediate in the synthesis of meso-chimonanthine

Cs2CO3

NHCO2Me

NCO2Me

Red-Al

NCHO2Me

Menozzi, C.; Dalko, P. I.; Cossy, J. Chem. Commun. 2006, 4638.

desmethyl-meso-chemonanthine

75% 95:5 d.r. 57%

■ Radical cyclization to provide the oxoindole by Ishibashi

Ishibashi, H.; Kobayashi, T.; Machida, N.; Tamura, O. Tetrahedron 2000, 56, 1469.

MeO BrO

CNmix E/Z3 steps

BuSn3HAIBN

MeCN LAH

HCOH NaBH4

NMe (±)-esermethole(formal synthesis)

72% 98%

■ Fujisawa pharmaceuticals thio-Claisen route to flustramine C core

Takase, S.; Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron 1986, 42, 5879.

(±)-debromo-8,8a-dihydroflustramine C

PS5, pyr

K2CO3, MeI

not isolatedNH

4 steps

2 steps

■ Domino olefination/isomerization/Claisen rearrangement sequence to flustramines A and B

Kawasaki, T.; Shinada, M.; Kamimura, D.; Ohzono, M.; Ogawa, A. Chem. Commun. 2006, 420.

HHex CNP

EtOEtO

70% yield98% ee

O3, PPh3then Ph3PCMe2

54%NHBr

(–)-flustramine B

EtOEtO

70% yield98% ee N

7 stepsN

(–)-flustramine A

5 steps

■ Domino olefination/isomerization/Claisen rearrangement sequence to flustramines A and B

Kawasaki, T.; Shinada, M.; Kamimura, D.; Ohzono, M.; Ogawa, A. Chem. Commun. 2006, 420.

HHex CNP

EtOEtO

70% yield98% ee

O3, PPh3then Ph3PCMe2

54%NHBr

(–)-flustramine B

EtOEtO

70% yield98% ee N

7 stepsN

(–)-flustramine A

5 steps

■ Overman uses two basic strategies to access the pyrroloindoline core

Strategy 1:Intramolecular Heck reaction

Pd(II) Ligand

reduction

Strategy 2:oxoindole alkylation

OTfRN NR

R 1. H+

2. NaIO4

3. NH2R LAH N

d.r. depends on R groups, base, additives

solvent and temp

■ Overman uses two basic strategies to access the pyrroloindoline core

Strategy 1:Intramolecular Heck reaction

Pd(II) Ligand

reduction

Strategy 2:oxoindole alkylation

OTfRN NR

R 1. H+

2. NaIO4

3. NH2R LAH N

d.r. depends on R groups, base, additives

solvent and temp

TfO RN

TfO NR

Si face alkylationfavored

Re facealkylation

■ Possible alkylation transition states proposed by Overman

Open transition states using Li or K enolates with THF/DMPU

RN NROO OO

major C2 C1 minor C2

Huang, A.; Kodanko, J. J.; Overman, L. E.J. Am. Chem. Soc. 2004, 126, 14043.

■ Bisalkylation strategy in the synthesis of (–)-phenserine

OTfMeN NMe

1. p-TSA

2. NaIO4 92%

OMeO CHOMe

72%89:11:<1

major C2

OMeO CHOMe

PhNHCO2

MeNH2•HClLiAlH4

MgSO490%

1. BBr3

2. PHNCO75%

(–)-phenserine

Huang, A.; Kodanko, J. J.; Overman, L. E.J. Am. Chem. Soc. 2004, 126, 14043.

■ Heck cascade to chimonanthine

Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem. Soc. 1999, 121, 7702.

OBnBnO

MeO2C CO2Me

OBnBnO

MeO2CCO2Me

LDA, I233%

OBnBnO

ONHI I

iodoanaline92%

1. NaH, BnBr2. BCl3

3. 2,2-DMP, CSA49%

ONBnI I

OO(PH3P)2PdCl2

90% BnN

OOCSA, NaBH4

Pb(OAc)4NaBH488%

6 steps

(–)-chimonanthine (+)-calycanthine

■ Combination of alkylation and Heck reaction in Overman synthesis of idiospermuline

MeN NBn

LHMDS75%

10 steps

4 steps

5 steps Pd(OAc)2

(S)-Tol-BINAP97%, 6:1 d.r.

1. H2, Pd(OH)2

2. Red-Al then NaNH3

ONMeTs

idiospermuline

Overman, L. E.; Peterson, E. A. Angew. Chem. Int. Ed. 2003, 42, 2525.

■ Zhu uses a domino Heck-cyanation sequence to obtain the oxoindole

Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961.

Pd(OAc)2

Pd0LnNMe

MePdLnCN

base L

2 steps

MeOO [Pd(dba)2]

(S)-DIFLUORPHOS78% yield, 72%ee

NMeMeO1. LAH

2. HCHO, NaBH460%

esermethole

(S)-DIFLUORPHOS

2 steps

MeOO [Pd(dba)2]

(S)-DIFLUORPHOS78% yield, 72%ee

NMeMeO1. LAH

2. HCHO, NaBH460%

esermethole

(S)-DIFLUORPHOS

NMeMeO

esermethole

1. HBr

NMeMeNCO2

physostigmineN

■ Trost asymmetric allylation in the synthesis of (–)-physostigmine

Trost. B. M. Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.

NH HNOO

Mo(0), Base

allyl carbonate NO

92-99% yield74-95% ee

■ Proposed model for enantiodescrimination

MoON CO

N R2R1

MoON CO

N R1R2

favored disfavored

■ Trost asymmetric allylation in the synthesis of (–)-esermethole and (–)-physostigmine

Trost. B. M. Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.

MeMeO MeOMo(C7H8)(CO)3, L*

LiOtBu

THF98% yield82% ee

OsO4, NMO

Me OMeO

NaIO492%

recrystallize to 99% ee

Me OMeO MeNH2, Et3NLiAlH4

(–)-esermethole

MePhHNCO2

(–)-physostigmine

2 steps

Synthetic Approaches to Pyrroloindoline Natural ProductsOther Methods

■ Bis-enamine rearrangement to pyrroloindoline core of calabar alkaloids

MeN CO2Me N

MeHO2C

H200 °C

Santos. P. F.; Srinivasan, N.; Almeida, P. S.; Lobo, A. M.; Prabhakar, S. Tetrahedron 2005, 61, 9147.

■ Dimethallyl rearrangement to flustramine C

Lindel, T.; Bräuchle, L.; Golz, G.; Böhrer, P. Org. Lett. 2007, 9, 283.

NBS, r.t.

(±)-flustramine C

N [1,5]MeH

■ Bis-enamine rearrangement to pyrroloindoline core of calabar alkaloids

MeN CO2Me N

MeHO2C

H200 °C

Santos. P. F.; Srinivasan, N.; Almeida, P. S.; Lobo, A. M.; Prabhakar, S. Tetrahedron 2005, 61, 9147.

■ Dimethallyl rearrangement to flustramine C

Lindel, T.; Bräuchle, L.; Golz, G.; Böhrer, P. Org. Lett. 2007, 9, 283.

NBS, r.t.

(±)-flustramine C

N [1,5]MeH

■ [4+1] cyclization of a bis(alkylthio)carbene and indole isocyanate

Rigby, J. H.; Sidique, S. Org. Lett. 2007, 9, 1219.

■ Aza-Pauson-Khand-type reaction of alkynecarbodiimides

Aburano, D.; Yoshida, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72, 6878.

PhCl, reflux

then LAH72%

SPrPrS

MePrS SPr

TMSO NaCNBH3

Co2(CO)8TMTU

MeO MeO

3 steps

3 steps to esermethole

■ [4+1] cyclization of a bis(alkylthio)carbene and indole isocyanate

Rigby, J. H.; Sidique, S. Org. Lett. 2007, 9, 1219.

■ Aza-Pauson-Khand-type reaction of alkynecarbodiimides

Aburano, D.; Yoshida, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72, 6878.

PhCl, reflux

then LAH72%

SPrPrS

MePrS SPr

TMSO NaCNBH3

Co2(CO)8TMTU

MeO MeO

3 steps

3 steps to esermethole

■ Asymmetric synthesis of calabar alkaloids by Ogasawara

Tanaka, K.; Taniguchi, T.; Ogasawara, K. Tetrahedron Letters 2001, 42, 1049.

NHNH2 O

OMeMeO

HCl, HCOHaqNaBH(OAc)3

NaIO452% (one pot) N

MeMeOMeNH2•HCl

LiAlH454%

(–)-esermethole

3 steps

■ Overman synthesis of (+)-minfiensine

Dounay, A. B.; Humphreys, P. G.; Overman. L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368.

OTfNCO2Me

Pd(OAc)2, L*

85% yield99% ee

NCO2Me

NHBocTFA

PPh2 N

N NBoc

■ Overman synthesis of (+)-minfiensine

Dounay, A. B.; Humphreys, P. G.; Overman. L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368.

OTfNCO2Me

Pd(OAc)2, L*

85% yield99% ee

NCO2Me

NHBocTFA

PPh2 N

N NBoc

1. 9-BBN H2O2, NaOH

2. TPAP, NMO63%

25% isomer

O1. TFA

2. N N

PdCl2(dppf)

MeOH74%

MeO2CNH

(+)-minfiensine

1. NaHMDS Comins' reagent

2. Pd(OAc)2, PPh3 CO, MeOH

CO2Me1. LiAlH4

2. NaOH

Conclusions

■ Each method has its strengths and weaknesses

■ Biomimetic approach is rapid and tryptophan is an abundant source of chiral material

■ Few enantioselective methods for pyrroloindoline construction have been developed

■ Efficiently obtaining fully-substituted vicinal stereocenters of the pyrroloindoline core remains a challenge

synthetic approaches to pyrroloindoline … approaches to pyrroloindoline containing natural...

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