Tetrahedron Letters
Total synthesis of the novel benzophenone NP-011694
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Alain Noncovich , Jane Ung, Andrew Patron
Senomyx Inc., 4767 Nexus Centre Dr, San Diego, CA 92121, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the total synthesis of NP-011694, a previously unreported fungal fermentation product from
Analyticon Gmbh. The convergent synthesis employs Turbo Grignard and lithiation strategies, along with
novel conditions for the simultaneous removal of multiple phenolic MOM groups.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 28 May 2015
Revised 23 June 2015
Accepted 24 June 2015
Available online 29 June 2015
Keywords:
Sweet receptor
Turbo Grignard
Lithium-halogen exchange
Ortho lithiation
Microwave-assisted synthesis
Total synthesis
The discovery of non-nutritive sweeteners as an alternative to
sucrose (common table sugar) has been an active area of research
for many years. More recently, there has been growing interest in
the discovery of natural high potency sweeteners as alternatives to
artificial sweeteners such as aspartame and sucralose. Examples of
this industry trend toward plant derived, high-intensity sweeten-
ers include the recent regulatory approval of purified extracts of
Stevia rebaudiana (containing ent-kaurane diterpene glycosides
stevioside and rebaudioside A) (Fig. 1) and Siraitia grosvenorii (also
known as Luo Han Guo, containing cucurbitane-type tripene glyco-
sides such as mogroside V),1a as well as the discovery of new sweet
tasting flavonoids such as of rhoifolin1b (Fig. 1).
saccharide (hernandulcin,1a and the synthetic high potency
sweeteners like aspartame,5a advantame,5b sucralose1a and
saccharin1a
activating
)
a
(Fig. 2). All these sweeteners are capable of
GPCR-mediated signal transduction cascade in
mammalian cells stably transfected with the hT1R2/hT1R3
heterodimer and their rank order of potency in this assay fits
well with the reported sensory data for these compounds.
This hT1R2/hT1R3 cell based assay6 was used to screen a com-
mercial collection of natural products purchased from Analyticon
Gmbh7 as well as other sources. During this screening campaign,
a
potent agonist of the human sweet receptor, NP-011694
(Compound 1) was discovered (Fig. 3). The compound was a previ-
ously unreported fungal fermentation product containing a rather
unique chemical structure.7 Intrigued by the preliminary biological
profile and novel chemical class, we decided to explore the synthe-
sis of compound 1 to afford a larger quantity of material for further
evaluation. This poly-functionalized benzophenone is reminiscent
of the benzophenolic acid portion of balanol (2) (Fig. 3),8 but bears
a different substitution pattern. The bisphenolic ring contains a
geranyl chain ortho to one of the two hydroxyls in place of the car-
boxyester of the hydroxyazepane fragment. The remaining pheno-
lic ring bears an additional carboxylic acid group meta to the
phenolic group. We also found two closely related structures
reported in the literature, pestalone (3)9 and arugosin H (4)
(Fig. 3).10 Both of these structures contain the poly-functionalized
benzophenone core and similar prenyl side chains.
All of these diverse sweet agonists function by activating the
sweet receptor, a heterodimeric GPCR composed of the two pro-
teins, hT1R2 and hT1R3. The variety in structures found to impart
a sweet taste is quite large, suggesting the possibility that these
agonists may bind in different modes and at different sites.2
A
review of the literature clearly shows that a diverse set of chemo-
types are capable of activating the sweet receptor, ranging from
high molecular weight proteins (monellin,3 brazzein,4 etc.) to low
molecular weight molecules such as aspartame and saccharin
(Fig. 2). For the low molecular weight molecules, one can group
these agonists into three main subsets: saccharides (such as fruc-
tose, sucrose, etc.) (Fig. 2), glycosides of secondary metabolites
(such as rebaudosides, glycyrrizin glycosides, mogrosides, etc.)
(Fig. 1)1a and sweet tasting molecules not linked to any
The initial approach to the synthesis of compound 1 was to
utilize a coupling between 5 and the acid chloride 17, employing
the chemistry developed by Knochel.11 Unfortunately, attempts
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Corresponding author. Tel.: +1 858 646 8415; fax: +1 858 4040752.
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.