C O M M U N I C A T I O N S
conditions afforded compound 20. Oxidation of the hydroxyl group
using Dess-Martin reagent17 followed by zinc chloride-catalyzed
Strecker reaction provided amino nitrile 21 as one single stereo-
isomer, thus accomplishing the construction of the bicyclo[3.3.1]
system with high efficacy.
The synthesis is straightforward without using sophisticated reaction
conditions and should potentially be amenable to large-scale
production.
Acknowledgment. Financial support from CNRS and this
institute is gratefully acknowledged.
The configuration of 21 was determined as follows. Treatment
of an acetonitrile solution of 21 with HF‚H2O effected a sequential
O-desilylation and in situ lactonization leading to, after removal
of N-Alloc and O-allyl protective groups, the rigid tetracyclic
compound 19 (Scheme 5). The characteristic NOEs observed
between H1/H21 and H21/H14 (Et 743 numbering) indicated that
the configuration of 19, hence that of 21, is (1R,3R,11R,13S,21R).
With the absolute configuration of 21 being assigned, the
synthesis was pursued by installation of ring B with a correct
oxidation state at C4 (Scheme 4). Reduction of the ester function
and subsequent acetylation of the resulting primary alcohol afforded
compound 22. O-Desilylation followed by Dess-Martin oxidation
of the C4 hydroxyl group afforded aldehyde 23. The Pomerantz-
Fritsch-type cyclization7d,e,18 of 23 took place smoothly under acidic
conditions (TFA in dichloromethane) to afford the A-B-C-D-E
polyheterocycle 24 with concomitant removal of the phenolic
MOM-protecting group. Although of no consequence, the cycliza-
tion is highly stereoselective (dr > 20/1) and the configuration at
C4 of the major isomer was tentatively assigned as S based on the
coupling constant (compound 25: JH3-H4 ) 10.1 Hz) and in analogy
to the work done by Fukuyama and co-workers.5b Saponification
of 24 followed by coupling of the resulting alcohol 25 with (R)-
N-Troc-(S-4,4′,4′′-trimethoxyltrityl) Cys (6) under standard condi-
tions afforded compound 26 in 94% yield. With the hexacyclic
compound 26 in hand, a one-pot S-deprotection/cyclization to the
1,4-bridged 10-membered ring via formation of C-S bond was
sought next.5b,7f,8 Gratifyingly, by simply dissolving 26 in TFE
containing 1% of TFA, the bridged macrocycle 27 was produced
in 77% isolated yield after masking the phenol as the corresponding
acetate. In this operationally simple experiment, a complex reaction
sequence involving S-trityl deprotection, 1,4-â elimination leading
to ortho-quinone methide and macrocyclization via an intramo-
lecular Michael addition occurred in a highly ordered manner, to
accomplish the key C-S bond-forming process. Simultaneous
removal of N-Alloc and O-allyl functions under Guibe´’s condi-
tions,19 followed by reductive N-methylation, provided the key
intermediate 28 in excellent overall yield.
Supporting Information Available: Experimental procedures and
product characterization for all compounds synthesized. This material
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Following Corey’s protocol, compound 28 was converted to Et
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