Chemical Synthesis and Self-Assembly of a Ladderane Phospholipidf !

Mercer, J. A. M.; Cohen, C. M.; Shuken, S. R.; Wagner, A. M.; Smith, M. W.; Moss, F. R.; Smith, M.D.;!Vahala, R.; Gonzalez-Martinez, A.; Boxer, S.G.; Burns, N. Z. J. Am. Chem. Soc. 2016, 138, 15854.

!Michael Houghton

Wipf Group12/24/16

1

O

O

O

OPOMe3N+ O

O-

H H

H

H

HH

H H

HH H H

H H

H

H

Michael Houghton@ Wipf Group Page 1 of 12 12/25/2016

2

General Uses and Types of Lipids

-  Lipids are used to provide and store energy, absorb vitamins, cell membrane and general cell health, signaling, and numerous other biological activities.

HO

H

H

H

HO

H

HH

OH

HO

O

O

O

O

OO

O

HO

O

Cholesterol Testosterone

Linoleic acid

Triglceride(coconut oil)

Elaidic acidMichael Houghton@ Wipf Group Page 2 of 12 12/25/2016

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Ladderane Phospholipid is Found in Anammox Bacteria

-  Anammox- Anaerobic Ammonium Oxidizing

-  These bacteria convert ammonia and nitrite into dinitrogen and water -  This process takes place in a unique organelle, the anammoxosome, which is composed of ~ 90 % ladderane phospholipds. -  These densely packed phospholipds are believed to keep hydrazine and hydroxylamine waste products from damaging the rest of the cell. -  There are five types of known anammox bacteria: Brocadia, Keunenia, Anammoxoglobus, Jettenia and Scalindua. -  Anammox bacteria are used industrially to purify ammonia rich, contaminated water.

-  Purification difficulties have prohibited the isolation of pure material and useful quantities of material.

1. Reimann, J.; Jetten, M. S.; Keltjens, Jan T. Metal Ions in Life Sciences. 15. Springer. 257-313. 2. Strous, M. et al. Nature. 1999, 400, 446-449. 3. Kartal, B.; Keunen, J. G.; Van Loosdrecht, M. C. Science. 2010, 328, 702-703. Michael Houghton@ Wipf Group Page 3 of 12 12/25/2016

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Previous Synthetic Efforts – Racemic

Mascitti, V., E. J. Corey. JACS, 2004, 126, 15664-15665.

CbzN

CbzN

BrBr

1. H2, PtO2, NaNO2,EtOH/THF, 23 oC

2. Zn, AcOH, 95 oC

CbzNNCbz

(80 %, 2 steps)

1. hv, 2-cyclopenten-1-one,MeCN, 23 oC (40 % b.s.m.)

1. H2, Pd–C, EtOH, 23 oCthen O2, 23 oC (76 %)

NN

O

1. HC(OMe)3, PTSAMeOH, 40 oC (91 %)

1. hv, MeCN, 50 oCthen AcOH/H2O, 23 oC(6 %)

O

1. HCO2Et, PhH, MeONa, 23 oC

1. TsN3, Et3N, CH2Cl2 23 oC (80 %, 2 steps)

O

N2

1.hv, MeOH, Et3N, 23 oC (72 %)

CHO

1.LDA, (Br,Ph3P(CH2)6CO2H)THF, –78 to 23 oC (67 %)

2. NH2NH2, CuSO4, O2,EtOH/H2O, 23 oC (88 %)3. CH2N2, Et2O, 0 oC (95 %)

OMe

O

“The recent report of the remarkable pentacyclic C20-fatty acid methyl ester from the anammoxic microbe Candidatus Brocadia anammoxidans opens a fascinating new chaper in the field of natural products.” - E. J. Corey

Michael Houghton@ Wipf Group Page 4 of 12 12/25/2016

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Previous Synthetic Efforts – Enantioselective

+

Ohv, MeCN

–15 oC (78 %)O

1. NaHMDS, HCO2Et, THF, –30 oC to 0 oC

1. TsN3, Et3N, CH2Cl2 23 oC (62 %, 2 steps)

O

N2

1.hv, MeOH, Et3N, 23 oC

2. LiOH, H2O/THF, 23 oC (86 %, 2 steps)

CO2H

1.(COCl)2, DMF, DMF, 23 oC

2.

1.hv,

MeCN, 23 oC (50 %) O

Me2PhSi

1.NaHMDS, THF, –78 oCthen TMSCl, –78 to 0 oC

2.NBS, THF, –50 to –30 0C3. TBAF, THF, 23 oC(53 %, 3 steps)

ONaHTe, EtOH, 23 oC

79 %O

N SONa

BrCCl3,DMAP, 75 oC,15 min;

hv, 10 oC, 10 min (79 %)3. t-BuOK, DMSO50 oC (84 %)

O

SiPhMe2

O

TBSO THF, –50 to 0 oC 71 %

(PhMe2Si)2Cu/(CN)Li2

O

TBSOSiPhMe2

MeCN, 23 oC 80 %

HF (aq)O

HOSiPhMe2

C5H5N, –20 oCDBU 86 %

(CF3CO)2O

O

SiPhMe2

Mascitti, V., E. J. Corey. JACS, 2006, 128, 3118-3119.

OMe

O

Michael Houghton@ Wipf Group Page 5 of 12 12/25/2016

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Retrosynthetic Analysis

O

O

O

OPOMe3N+ O

O-

H H

H

H

HH

H H

HH H H

H H

H

H

HO

O H H

H

H

HH

H H

H

H

H

H

HH

H H

H

Natural Ladderane Phospholipid

[5]-ladderanoic acid

HO H H H

H H

H

H

[3]-ladderanol

H

HH

H

+

H H

H H

H

H

O

O

x

H

H

O

O

x +

Michael Houghton@ Wipf Group Page 6 of 12 12/25/2016

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Route to [5]-Ladderanoic Acid

H

H

HOHO 2. Na2S

H2O2 (93 %)3. SO2Cl2 (89 %)

1. MsCl (94 %)H

H

SO

Cl

DMSO(49 %)

H

H

KOt-Bu

hv = 254 nmPhH, –4 oC

(42 %)

CuOTfH

H

H

HH

H H

H> 10 g

Confirmed by X-ray

Michael Houghton@ Wipf Group Page 7 of 12 12/25/2016

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Route to [5]-Ladderanoic Acid

2. KOt-Bu (91 %) KOt -B

1. Mn(TMP)ClNaOCl (40 %) H

H

H

HH

H H

H(95 %, 90 % ee)

Cu(MeCN)4PF6(R)-DM-SEGPHOS

B2pin2, NaOt-Bu H

H

H

HH

H H

H

HBpin

OTBSLi

6

NBS, NaOMe

H

H

H

HH

H H

H

HHO

1.

2. HF-pyr(88 %, 2 steps)

1. H2, Ra-Ni

2. CrO3/H2SO4(86 %, 2 steps)

H

H

H

HH

H H

H

HHO

O

> 600 mg synthesized

Michael Houghton@ Wipf Group Page 8 of 12 12/25/2016

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Route to [3]-Ladderanol

OH

OH

Br

Br

1. CrO3, H2SO4

(82 %)

O

O

Br

Br

hv = 350 nm0 oC

(82 %)H

H

O

O

Br

Br

H

H

H

H

H

H

pyridine

(73 %, 2 steps)

O

OBr

H

H

H

H

H

H

OPMBZnI

8

(78 %)

O

O

H

H

H

H

H

H

PMBO 8

Michael Houghton@ Wipf Group Page 9 of 12 12/25/2016

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Route to [3]-Ladderanol

O

O

H

H

H

H

H

H

PMBO 8

N

N

H

H

H

H

H

H

PMBO 8

(78 %)

NH2NH2

NH2

H2N

(78 %, 2 steps)

Cu - TMEDAH

H

H

H

H

H

PMBO 8

1. Crabtree'scat., H2 (99 %)

2. DDQ (89 %)

H

H

H

H

H

H

HO

> 600 mg synthesized

Michael Houghton@ Wipf Group Page 10 of 12 12/25/2016

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Final Route to Ladderane Phosopholipid

PMBO OH H

H

H

H

H

H

Oi-PrNEt2, DMF

(74 %)

EDC, HOBt [5]-ladderanoic acid

PMBO

O

O

O

H H

H

H

HH

H H

HH H H

H H

H

H

CH2Cl2/H2O(89 %)

DDQ

PMBO OTrOH (60 %)

NaH/DMF, then [3]-ladderanol-OMs PMBO OTr H

H

H

H

H

H

OCH2Cl2/MeOH

(86 %)

HCl

HO

O

O

O

H H

H

H

HH

H H

HH H H

H H

H

H

1.O O

PO

Cl

2. Me3N, MeCN75 oC

(50 %, 2 steps)

Me3N O

O

O

OPOMe3N+ O

O-

H H

H

H

HH

H H

HH H H

H H

H

H

Michael Houghton@ Wipf Group Page 11 of 12 12/25/2016

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Conclusions

§  Successfully completed first enantioselective selectivesynthesis of a complete ladderane phospholipid

§  Provided first proof of absolute configuration of naturalladderane.

§  Developed novel dimerization of bicyclohex[2.2.0]eneto form the fused pentacyclobutane core.

§  Confirmed Wipf et al computations on sign of Trans-(R)-ladderane

Zuber, G.; M.-R.; Beratan, D. N.; Wipf, P. Chirality 2005, 17, 507-510. Michael Houghton@ Wipf Group Page 12 of 12 12/25/2016