Enantioselective total synthesis of salicylihalamides A and B

Article abstract of DOI:10.1016/S0040-4039(01)00278-7

We have devised a total synthesis of (12R,13S,15R) salicylihalamides A and B, which allowed revision of the absolute stereochemistry of the natural compounds. The same strategy was then applied to the preparation of naturally occurring salicylihalamides.

Full text of DOI:10.1016/S0040-4039(01)00278-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2645–2648
Enantioselective total synthesis of salicylihalamides A and B
Denis Labrecque,* Sylvie Charron, Rabindra Rej, Charles Blais and Serge Lamothe
Department of Medicinal Chemistry, Biochem Pharma Inc., 275 Armand-Frappier Blvd, Laval, Que´bec, Canada H7V 4A7
Received 18 January 2001; revised 16 February 2001; accepted 19 February 2001
Abstract—We have devised a total synthesis of (12R,13S,15R) salicylihalamides A and B, which allowed revision of the absolute
stereochemistry of the natural compounds. The same strategy was then applied to the preparation of naturally occurring
salicylihalamides. © 2001 Elsevier Science Ltd. All rights reserved.
Salicylihalamides A (1) and B (2) were recently reported
by Boyd and co-workers as novel cytotoxic macrolides
possessing an unusual conjugated enamide side-chain.1
The lack of correlation of cytotoxicity profile of these
compounds in the NCI 60-cell line human tumor assay
with known antitumor agents suggested a potential
novel mechanism of action. The emergence of several
novel biologically active macrolides bearing similar
structural features2 prompted us and others3 to devise
synthetic routes to these compounds. The absolute
configuration of salicylihalamide A (1) was recently
revised through total synthesis by De Brabander and
co-workers.3a,b We have independently reached the
same conclusion and we present herein our total syn-
thesis of both enantiomers of salicylihalamides A (1)
and B (2).
The two main synthetic challenges associated with these
target molecules are the efficient preparation of the
macrocyclic core structure in an enantioselective fash-
ion and the stereoselective construction of the enamide
Scheme 1. (a) NaAl(OMe)3H, THF, 0°C, then warm to rt and add methanol, TMSCl and p-anisaldehyde, 16 h (80%); (b)
DIBAL-H, CH2Cl2, 0°C, 1 h; (c) Dess–Martin reagent, CH2Cl2, rt, 1 h; (d) (S,S)-diisopropyl tartrate-(E)-crotylboronate, toluene,
−78°C, 8 h (75% from 4); (e) TBDPSCl, imidazole, DMF, 100°C, 16 h; (f) 9-BBN, THF, rt, 30 min, then NaBO3, 16 h (67% from
5); (g) Dess–Martin reagent, CH2Cl2, rt, 30 min; (h) Ph3PꢀCH2, THF, −78°C to rt, 1 h; (i) DDQ, CH2Cl2, rt, then H2O, 30 min
(24% from 6).
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00278-7

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D. Labrecque et al. / Tetrahedron Letters 42 (2001) 2645–2648
side-chain. Recent work by Fu¨rstner and co-workers
describing the use of olefin metathesis strategy for the
preparation of macrocyclic lactones provided an attrac-
tive solution to the formation of the core structure of
the salicylihalamides.4
Diene 9 was cyclized via a metathesis reaction using
Grubb’s catalyst giving the macrocycle 10 in high yield
with a 9:1 selectivity favoring the E-olefin. The minor Z
isomer was separated by flash chromatography on silica
gel. Concomitant cleavage of the benzyl and the methyl
ethers with BBr3 provided phenol 117 in high yield.
9
The known epoxide 35 served as the chiral template for
our synthesis (Scheme 1). This epoxide was transformed
using a one-pot procedure to the protected 1,3-diol 4 in
80% yield via sequential reduction and in situ protec-
tion. Cleavage using DIBAL-H followed by Dess–Mar-
tin oxidation and reaction with (S,S)-diisopropyl
tartrate-(E)-crotylboronate following the procedure
developed by Roush6 afforded 5 (contaminated with
25% of a diastereomer) in 75% yield. Since separation
of the minor isomer was not possible at this stage, the
one carbon homologation sequence was accomplished
on the mixture. Silylation of the secondary alcohol and
hydroboration of the terminal olefin afforded 6 in 67%
yield. Dess–Martin oxidation and coupling of the
resulting aldehyde with methylene triphenylphospho-
rane gave the homologated product. Subsequent release
of the PMB protected alcohol with DDQ in wet
dichloromethane afforded compound 7,7 which was
separated from its diastereomeric contaminant via flash
chromatography in 24% overall yield from 6.
In our efforts to devise a synthetic route to the enamide
side-chain, we reasoned that elimination of an amide
group from a symmetrical N,N%-bis-acylated aminal
under the conditions reported by Katritzky and co-
workers10 could provide the desired product. The
appropriate precursor amide with correct stereochem-
istry was prepared in four steps from alcohol 12 as
described in Scheme 3. TPAP oxidation11 followed by
Horner–Emmons coupling12 in a one-pot operation
afforded Z,Z-diene ester 13 in good yield. Subsequent
hydrolysis13 using barium hydroxide and amidation via
mixed anhydride afforded amide 14.7
Oxidation11 of alcohol 11 (Scheme 4) followed by pro-
tection of the phenolic hydroxyl with a triisopropylsilyl
group gave aldehyde 15 as the template for introduc-
tion of the enamide moiety. Condensation of amide 14
with this aldehyde provided the key N,N%-bis-acylated
aminal 16 in 38% overall yield from 11. This compound
underwent elimination when treated with sodium
hydride in trifluorotoluene at 60°C for 4.5 hours to
yield a mixture of enamides 17a and 17b which were
separated by column chromatography. The TBDPS
group on the secondary alcohol was found to be partic-
ularly resistant to standard deprotection conditions.
Compound 7 was coupled to the allyl-anisic acid 88
(Scheme 2) via the Mitsunobu esterification procedure
with inversion at C-15 providing the cyclization precur-
sor 9 having all the required stereogenic centers in
place.
Scheme 2. (a) 1. s-BuLi, TMEDA, THF, −95°C; 2. MgBr2, allyl bromide, −78°C to rt, 16 h (18%); (b) 7, DEAD, PPh3, Et2O,
0°C to rt, 1 h (73%); (c) bis(tricyclohexylphosphine)benzylidine ruthenium(VI) dichloride, CH2Cl2, reflux, 3 h (75%); (d) BBr3,
CH2Cl2, −78°C, 30 min (80%).
,
Scheme 3. (a) TPAP, NMO, CH2Cl2, 4 A mol. sieves, 0°C, 1 h, then (CF3CH2O)2POCH2COOCH3, KH 60%, 18-crown-6, THF,
−78°C, 15 min (73%); (b) Ba(OH)2·H2O, MeOH, 16 h (93%); (c) ClCOOEt, Et3N, THF, 0°C, 20 min, then NH3(g), 15 min, rt
(63%).

D. Labrecque et al. / Tetrahedron Letters 42 (2001) 2645–2648
2647
,
Scheme 4. (a) 1. TPAP, NMO, CH2Cl2, 4 A mol. sieves, rt, 30 min; 2. TIPSCl, DIPEA, DMAP, DMF, 70°C, 1 h; (b) 14,
TMSOTf (0.5 equiv.), ClCH2CH2Cl, rt, 2 h then NaHCO3 work-up (38% from 11); (c) NaH 60%, PhCF3, 60°C, 4.5 h (48%); (d)
TBAF, THF, rt, 1 h (70% for 17a“18a and 76% for 17b“18b); (e) TBAF, HMPA, THF, 40°C, 48 h (52% of a 1:1 mixture of
1 and 2 for 18a and 35% of a 1:2 mixture of 1 and 2 for 18b).
Treatment of 17a or 17b under such conditions (TBAF
in THF) afforded 18a or 18b, respectively. Removal of
the remaining silyl group required more drastic condi-
tions (TBAF in THF–HMPA at 40°C for 48 hours)
which caused isomerization of the enamide double
bond. Therefore, reaction of pure isomers 18a or 18b
both provided mixtures of 1 and 2. Direct formation of
the mixture of 1 and 2 from unseparated 17a and 17b
using these conditions gave lower yields. The two iso-
mers were separated by HPLC and their spectroscopic
characteristics were in agreement with those reported
for the natural products1 except for optical rotation
which was of the same magnitude but of opposite
sign.14 These results suggested that the absolute
configuration of the products as described previously
was incorrect and that the structures of natural (−)-sal-
icylihalamides A and B should be represented by 19
and 201,3 respectively. Therefore, using the same syn-
thetic sequence and starting from the enantiomer of 3,
we have prepared the natural compounds 19 and 20.14
Biological profiles of the presented compounds as well
as closely related analogues will be reported in due
course.
References
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Acknowledgements
We would like to thank Mrs. Nola Lee and the analyt-
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D. Labrecque et al. / Tetrahedron Letters 42 (2001) 2645–2648
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9H), 1.22–1.80 (m, 10H), 3.37 (t, J=6.3 Hz, 2H), 3.66
(app. sept., J=3.8 Hz, 1H), 3.84 (dt, J=3.5, 9.0 Hz, 1H),
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compound 2, [h]D +86° (c 0.18, MeOH); lit. (Ref. 1) for
salicylihalamide B: [h]D −73° (c 0.3, MeOH); for com-
pound 19, [h]D −27° (c 0.2, MeOH); for compound 20,
[h]D −85° (c 0.32, MeOH).
1
9.39 (s, 1H). For 14: H NMR (400 MHz, CDCl3) l 1.01
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.
.