ChemComm
Communication
16
group, except for thioglucopyranose. For this reason, HS–Si(i-Pr)
3
was considered, though it did not appear to have been applied to
the sulfenylation of hydroximoyl chlorides. In a first attempt,
addition of HS–Si(i-Pr) to a solution of hydroximoyl chloride 17
3
in DCM/Et N and reaction monitoring by TLC indicated complete
3
consumption of the starting material in 30 min. HRMS and
1
H NMR data of the reaction mixture indicated a product
18 2 6
Fig. 1 Possible chemical structures of compound X (14) (C16H N O S)
and selected HMBC correlations.
containing two 1-t-Boc-4-methoxyindolyl moieties and one Si(i-Pr)
3
group. Further modifications of the reaction conditions and
isolation of the intermediate product suggested that it contained
bis-indolyl moieties connected by an O-silylated thiohydroximoyl
methanesulfonyl and sulfate groups (CH
3 2 4
SO + SO K) from
anhydride (–(HONQ)C–S–C (Q NO–Si(i-Pr) )–). Much to our delight,
3
1
-MeSO -glucorapassicin A (9) (C H N O S ), and t-Boc and
2
17 21 2 12 3
treatment of this product with a solution of TFA (20–30% in DCM)
sulfate groups (Me CCO + SO K) from 1-t-Boc-glucorapassicin
3
2
4
1
13
yielded a mixture that, upon standing in DCM/Et
yielded rapalexin A (4) and 4-methoxyindole-3-carboxylic acid (21)
ca. 1 : 1). Varying the reaction temperature or the concentration
of HS–Si(i-Pr) (1–5 eq.) did not affect product yields. Eventually,
3
N for 60 min,
27 2 12 2
A (10) (C21H N O S ). The H and C NMR spectroscopic
data of compound X (14) indicated that the spin systems of
(
the b-D-glucopyranosyl and the indolyl moieties were intact
1
3
(
3
H NMR obtained in CD OD). Methylation of product X (MeI/
a one-pot synthesis of rapalexin A from oxime 16 was carried out
in ca. 30% yield (Scheme 7).
NaH) was carried out to establish the number of free hydroxyl
substituents present in X (14).
The formation of product 19 is likely due to an intramolecular
MS and NMR spectroscopic data of the methylated derivative
[1,4]-S- to O-silyl migration in the first formed reaction intermediate
15 were consistent with the presence of three methoxy and one
17a, followed by nucleophilic attack of the resulting sulfide 18 on
N-methyl groups, in addition to the expected methoxy group at
C-4 of indole. These results indicated that one of the hydroxyl
groups of glucose was not methylated and thus it was likely
attached to another atom. Based on the molecular formula of X
the hydroximoyl carbon of 17. This silyl migration activates
thiohydroximate, a prerequisite for the Lossen type rearrangement
to occur, which is further encouraged by the N-deprotection of the
indolyl moiety (Scheme 7). Previously, [1,4]-S- to O-silyl migrations
were reported to proceed intramolecularly and transformed esters
(
C
16
H
18
N
2
O
6
S, nine degrees of unsaturation) and comparison of
its NMR, HMBC and HMQC spectroscopic data with those of
-MeSO -glucorapassicin A (9), either chemical structure A or B
17
into ketones using organolithium reagents.
1
2
As summarized in Scheme 8, hydrolysis of 1-t-Boc-glucorapassicin
A (10) under acidic conditions is likely to yield the unstable
intermediate thiohydroximic acid 22, which undergoes a spon-
taneous Lossen type rearrangement to yield rapalexin A (4).
These chemical transformations, similar to the formation of
isothiocyanates in plants, lend further support to the proposed
appeared likely (Fig. 1). The final proof was obtained by X-ray
crystallographic analysis of a single crystal of tetramethyl-X (15),
establishing the chemical structure of X as A (Fig. 2).
Further examination of the biomimetic synthesis of rapalexin A
(Scheme 6) suggested that an efficient route might be achieved if
thioglucopyranose tetraacetate were to be substituted for a more
economical sulfur donor containing a leaving group. Although
sulfenylation of hydroximoyl chlorides has been reported using
diverse sulfides, these sulfides do not possess a reasonable leaving
8
rapalexin A biosynthetic pathway. Likewise, transformation
of 1-MeSO -glucorapassicin A (9) under acidic conditions yields
2
1
-MeSO -rapalexin A (11). By contrast, in basic media (K CO /
2
2
3
MeOH), a skeletal rearrangement of 1-t-Boc-glucorapassicin A
10) and 1-MeSO -glucorapassicin A (9) yields the unique product X
14), likely via the azirine intermediate 23 that undergoes a
Neber type rearrangement upon nucleophilic attack by the HO–
C-2) of glucose. This transformation appears to generate the
first preparation of a 1-deoxy-1-thioimidocarbonyl-b-D-glucopyranose
(
2
(
(
1
8
heterocyclic ring system. Recently, reactions of silyl-protected
enol diazoacetates with nitrile oxides were reported to yield
rearrangement products via dipolar cycloadditions followed by
1
9
either Neber or Lossen rearrangements.
In summary, the first biomimetic synthesis of rapalexin A (4)
instigated a novel one-pot preparation that revealed a novel
application of the Lossen rearrangement. Furthermore, the first
bicyclic glucose-fused product (14) formed via Neber rearrangement
was discovered. The scope of these transformations and other
approaches to synthesize glucorapassicin A (2) are currently
under investigation.
Fig. 2 Single crystal X-ray structure of compound tetramethyl-X (15) with
thermal ellipsoids at 30% of the probability level and the corresponding
chemical drawing.
We thank the Natural Sciences and Engineering Research
Council of Canada (Discovery Research Grant to MSCP),
This journal is ©The Royal Society of Chemistry 2016
Chem. Commun.
Pedras
