The Denmark Group Molecule of the Month

Forazoline A
Angewandte Chemie, Int. Ed. 2014, 53, 11583

TEAM B
Scott Barraza, Hyung Min Chi, Kuo Zhao, Hao
Wang, Becca Leising, Andrea Ambrosi

Strategic Disconnection Overview

Guiding Principles:
Focus upon a convergent fragment-based proposal
Minimization of protecting group manipulations
Prioritization of existing literature to maximize viability
Emphasis upon chemical minimalism: the simpler the better
Avoidance of wasteful technologies, e.g. kinetic resolutions

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Overall Retrosynthetic Strategy

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Fragment A Disconnections

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Fragment A Synthetic Proposal

Org. Prep. Proc. Int. 2004, 36, 87-91

Eur. J. Org. Chem. 2015, 2428-2449

J. Org. Chem. 1980, 45, 2006-2009

J. Org. Chem. 1987, 52, 34-44

Org. Lett. 2002, 4, 447-449

J. Org. Chem. 2007, 72, 8361-8370

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Fragment B Disconnections

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Fragment A and B Union Pt.1

Chem. Comm. 2006, 1757-1759
Chem. Eur. J. 2007, 13, 3026-3038

Chem. Ber. 1969, 102, 31-37

Synlett. 1996; 10, 1010-1012

J. Het. Chem. 1994, 31, 1465-1471

Russian J. Gen. Chem. 2015, 85, 14401446

JOC. 1992, 57, 4047-4049

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Fragment A and B Union Pt.2

J. Med. Chem. 2007, 50, 233-240
Bioorg. Med. Chem. Lett. 2008, 18, 1124-1130

Chem. Comm. 2006, 1757-1759

Chem. Eur. J. 2007, 13, 3026-3038

Angew. Chem. Int. Ed. 2005, 44, 1378 1382

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Fragment C Initial Strategies

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Fragment C Retrosynthetic Strategy

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10

Fragment C Synthesis Pt.1

J. Chem. Soc., Perkin Trans. 1, 1986, 889-900
(direct precedent)

JACS. 1995, 117, 9608-9609

Angew. Chem. Int. Ed. 2008, 47, 3755 3758

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11

Fragment C Synthesis Pt.2

Synthesis. 1997, 61-67
JACS. 2009, 131, 8378-8379

JOC. 2011, 76, 1390-1397

JOC. 1999, 64, 9178-9188

JACS. 2004, 126, 15038 -15039

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Tetrahedtron Lett. 1986, 27, 1069-1072

Org. Biomol. Chem. 2003, 1, 30943101

12

Fragment Unification Pt.1

ACIE. 2013, 52, 1939 1943

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13

Fragment Unification Pt.2

Org. Lett. 2003, 5, 4219-4222

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14

Summary

Longest Linear Sequence: 22 Steps (dimethylcyclohexanone Forazoline A)

Total Number of Steps: 33

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15

Backup Slides and References

Backup Slides and References

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16

Preparation of heptanoic acid

Org. Prep. Proc. Int. 2004, 36, 87-91

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17

Sharpless Dihydroxylation
Eur. J. Org. Chem. 2015, 2428-2449

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18

Sharpless Dihydroxylation
Eur. J. Org. Chem. 2015, 2428-2449

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19

Lombardo Olefination

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20

Lombardo Olefination

Can. J. Chem. 1988, 66, 1359-1365.

Aust. J. Chem. 1989, 42, 497-510.

J. Org. Chem. 1980, 45, 2006-2009.

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J. Org. Chem. 1987, 52, 34-44.

21

Enolate Addition to An Alkyl Ester

Org. Lett. 2002, 4, 447-449.

J. Org. Chem. 2007, 72, 8361-8370.

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22

Fukuyamas Thiazoline Synthesis

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23

Fukuyamas Methyl (S)-Cysteine Synthesis

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24

S-Oxidation of Sulfides to Sulfoxides

J. Org. Chem. 1992, 57, 4047-4049.

J. Heterocyclic Chem. 1994, 31, 1465-1471.

Russian Journal of General Chemistry, 2015, 85, 14401446.

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25

Pummerer Rearrangement with Alkoxide Nucleophiles

Synlett. 1996; 10, 1010-1012

DOI: 10.1055/s-1996-5648

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26

Saponification

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27

Asymmetric -Pentadienylation

Also J. Chem. Res, Synop. 1983, 31

And J. Chem. Res. Miniprint. 1983, 342-351

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28

Asymmetric Vinylation

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29

Desymmetrization Pt.1

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30

Desymmetrization Pt.2

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31

Desymmetrization Pt.3, Hoveydas Computational Evidence

J. Am. Chem. Soc. 2009, 131, 8378-8379

H-bonding between the hydroxyl and a Cl elevates electrophilicity at the carbene carbon
(+0.41 in I vs +0.35 in III),6a while the electron density at the coordinating olefin is enhanced
(+0.14 and +0.12 in I vs +0.24 and +0.13 in III). Such an increase in electron density
differences
between
the
carbene
and
alkene
carbons
facilitates
metallacyclobutane formation
32
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Desymmetrization Pt.4, Schrock Catalysts

JACS. 2009, 131, 943

Chiral Mo-based metathesis catalyst is involved and is able

to yield excellent e.r. and good yield on the substrate that is
very similar to ours.
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33

Mild Allylic Alcohol Oxidation

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34

Asymmetric Conjugate Addition

JOC. 1999, 64, 9178-9188

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35

Yamamoto Chlorination

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36

Selective L-Selectride Reduction

Equatorial attack (axial alcohol)

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Chem 535 Lecture Notes

37

Selective L-Selectride Reduction

Tetrahedtron Lett.
1986, 27, 1069-1072.

Org. Biomol. Chem.

2003, 1, 30943101.

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38

Z-Selective Ring-Closing Metathesis

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39

Synthesis of L-F0rosamine

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40

Synthesis of L-F0rosamine

Org. Lett. 2010, 12, 684-687.

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41

Synthesis of L-F0rosamine
Org. Lett. 2009, 11, 5270-5273
(direct precedent)

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42

Iodination and -Selectivity

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43

Protecting Group Compatibility, Pt.1

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44

Protecting Group Compatibility, Pt.2

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45

Hydrolysis of methyl ester by

Trimethyltin hydroxide

Angew. Chem. Int. Ed. 2005, 44, 1378 1382

Hydrolysis of methyl ester by Trimethyltin hydroxide

Angew. Chem. Int. Ed. 2005, 44, 1378 1382