Analysis of a Synthesis of Sphingofungin F

1. Found at: http://pubs.acs.org/isubscribe/journals/joceah/65/i26/pdf/jo005612g.pdf

2. http://www.umich.edu/~chemh215/W00HTML/SSG1/ssg5/question/question.htm

Reviewed by:� Amy Liesmaki, Kristin Wilde, Nick Wold

Medicinal Interest:

Sphingofungin F was derived from the sphinofugin family and isolated from the fermentation broth of poecilomyces variotii, which is a thermotolerant fungus and an infectious agent that affects both man and animals.��²� Sphingofungin F are such novel compounds that they attract the attention of many synthetic chemists since so little is known about their physiological properties.� The enzyme, Serinepalmitolyl transferase, plays a key role in the biosynethesis of sphingolipids because Sphingofungin F exhibits inhibitory effects toward the enzyme in the sphingolipid pathway.� Myrocin and fumifungin remain the only compounds thus far that chemists have found to structurally resemble Sphinofungin F.� There may be an ecological or environmental correlation between the thermotolerance of poecilomyces variotti and use of these compounds.�

Retrosynthetic Scheme:

(1) Sphingofungin F

�

(2)

�

(3)

�

(4)

�

(5)

�

(6)

�

(7) Phosphonium salt

(8) an Aldehyde

�

(9)

�

(10)

�

(11)

�

(12)

�

(13)

�

(14) L-(+)-tartaric acid

Discussion:

There is a very specific stereoconformation observed in naturally occuring

Sphinogofungins (variety F in this case) which, if altered at all during

synthesis, are not functionally the same compounds.� Thus, in the laboratory

synthesis, special care must be taken in each step to preserve this stereo

structure.� At the forefront of the retrosynthesis we see compound (1), the final

product with the necessary stereoconformation, which would need to be produced

from three consecutive steps with the same confirmed conformation (compounds (2), (3), and (4)).

�Product (3) is merely a confirmation that the stereochemistry of product (4)� is

consistent with sphingofungin F.� Compound (4), which is an ester, was produced

through a series of oxidation, methylation and E2 elimination/S_N2 substitution (to

produce alcohol) reactions where two ester functional groups replaced the

trichloroacetonitrile ring of compound (5).� Given the OH group on (5), we see

evidence that it� was a direct result of an addition reaction of an N-nucleophile

to an epoxide from compound (6).� As we will see further down the retrosynthetic

chain, the stereochemistry of this reaction is imperative; the epoxide must be in

the correct stereoconformation for the N-nucleophile to be able to react.�

Compound (6), which is an alcohol, came from an E2 elimination of water (hence the

double bond) between the reagents in (7) and (8).� Both reagents were synthesized, but we will focus only on the aldehyde.� Compound (9) is the product of the Sharpless

epoxidation reaction and S_N2 substitution (at the BnO and OH functional groups).� It is here that we find the pivotal point of the reaction.�

We must make sure that we synthesize the epoxide into this specific

stereoconformation or the subsequent reactions (specifically the epoxide reaction converting (6) into (5), mentioned previously) will not yield the correct product.� The Sharpless asymmetric epoxidation was chosen in this case as a second choice.� The original reaction produced an asymmetric product, but surprisingly, in favor of the

unexpected product (which was speculated to be because of the lack of steric

hindrance in this particular reaction).� Therefore, the researchers focused on the

Sharpless reaction, which produced a 3:1 ratio of the desired compound (10) to the undesired compound (not shown).� (This reaction is surprisingly inefficient for a Sharpless, especially in comparison to others in this synthesis.)� The epoxide came from an alcohol (11), which was derived from the reduction of an ester.� This ester with the double bond came from an S_N2 substitution reaction where an alcohol was converted into the ester.� This alcohol was synthesized from a literature procedure from L-(+)-tartaric acid (14).�

Assessment of participants� contributions:�

�� Amy:� Found the article that we are using.� Researched and wrote about the medical interest of our compound.� Researched for extra information within the medical paragraph about the fermentation broth used.

�� Kristin: Wrote up the descriptions for the synthesis of our compound and helped to find an article.� Did extra research for information on asymmetric epoxidations.

�� Nick:� Developed retrosynthetic scheme.� Analyzed retrosynthesis and assisted in writing up the description of the synthesis of our compound.