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Table 1: Optimization of diastereoselective aldol reaction.
(Bn), carboxybenzyl (Cbz), and benzyloxymethyl (BOM)
protecting groups were selected and are readily removed by
palladium-catalyzed hydrogenation. The protected 6 was
prepared using a) the Mitsunobu reaction to construct the
seven-membered diazepanone, and b) a diastereoselective
aldol reaction of the isocyanate 8 and aldehyde 9 with the
thiourea catalyst 10 to obtain the syn-b-hydroxy amino acid
derivative 7.[10]
The fatty-acid side chains 4 and 5 were first prepared. The
b-siloxy carboxylic acid 4 was synthesized from the acid
chloride 11 by a modified Noyori asymmetric reduction[11] of
the b-ketoester 12[12] (Scheme 2). Enantioselective desym-
Entry
Catalyst
Yield [%][a]
Yield [%]
(19)
1
2
3
4
5
Et3N (10 mol%)
50 (d.r.=1:1.8)
64 (d.r.=3.1:1)
77 (d.r.=6.5:1)
80 (d.r.=5.0:1)
80 (d.r.>1:20)
10
7
9
0
10
(S,S)-10a (10 mol%)
(S,S)-10b (10 mol%)
(S,S)-10b (7 mol%)
(R,R)-10b (10 mol%)
[a] Diastereomeric ratio (d.r.) was determined by 1H NMR spectroscopy.
selectivity was improved to 6.5:1 by changing to the thiourea
catalyst (S,S)-10b (10 mol%; entry 3). Formation of byprod-
uct 19 was suppressed by reducing the amount of catalyst
(7 mol%; entry 4). Use of the thiourea catalyst (R,R)-10b
(10 mol%) gave the undesired diastereomer 18b in 80%
yield with high selectivity (> 20:1; entry 5). This protocol was
also applied to the large-scale synthesis of 18a.
Scheme 2. Synthesis of the fatty-acid side chains 5 and 6. Reagents
and conditions: a) BnOAc, LDA, THF, À788C; b) H2, (S)-BINAP-RuBr2
(4.0 mol%), MeOH, 508C, 48%, 94% ee for two steps; c) TESOTf, 2,6-
lutidine, CH2Cl2, 08C, 94%; d) H2, 10% Pd/C, EtOAc, 258C, 92%;
e) BnOH, catalyst 14 (10 mol%), CPME, 86%, 92% ee; f) Ghosez
reagent, CH2Cl2, 08C; then nBuLi, THF, 48%; g) H2, 10% Pd/C,
EtOAc, 258C, 92%. BINAP=2,2’-bis(diphenylphosphanyl)-1,1’-
binaphthyl, CPME=cyclopentyl methyl ether, Ghosez reagent=1-
chloro-N,N,2-trimethylpropenylamine, LDA=lithium diisopropylamide,
Tf =trifluoromethanesulfonyl, THF=tetrahydrofuran.
The aldol adduct 18a was converted into syn-b-hydroxy
amino acid derivative 7 in good yield by regioselective
decarboxylation and transesterification of the resultant ther-
modynamically stable trans-oxazolidinone in the presence of
the zinc cluster Zn4(OCOCF3)6O (Scheme 3).[16] The minor
isomer was removed during these transformations. Following
the procedure of Matsuda, Ichikawa, and co-workers,[7] the
fluoride 21 underwent b-selective glycosylation, reduction of
the azido group, Cbz protection, and hydrolysis under basic
conditions to give 22. The carboxylic acid 22 was treated with
the Ghosez reagent[17] and coupled with the anti-b-hydroxy
amino acid derivative 23.[18] The TBS group was selectively
removed and construction of the diazepanone core was
extensively investigated. The Mitsunobu reaction of 25 using
PPh3 and di-tert-butyl azodicarboxylate (DBAD) proceeded
to give the seven-membered ring without epimerization or
other side reactions. Finally, protecting group manipulation of
26 gave the protected caprazol 6 and the structure was
confirmed through conversion into caprazol (2).[1,7a,8a]
With the side-chain fragments 4 and 5 and protected
caprazol 6 in hand, we focused on the introduction of the
fatty-acid side chain. This side chain readily decomposes
through b-elimination of the b-acyloxy carbonyl under basic
conditions and cleavage of the O-acylglycoside under acidic
conditions. In fact, attempts to introduce the fatty-acid side
chain 27[19] to model diazepanone 28 using EDCI caused b-
elimination to give unsaturated carboxylic acid 30 instead of
the desired 29 (Scheme 4). DCC and PyBOP were also
metrization of 3-methyl glutaric anhydride (13) using the
cinchona alkaloid catalyst 14 and the procedure reported by
Song and co-workers[13] gave the carboxylic acid 15 with high
enantioselectivity (92% ee). Condensation of 15 with the l-
rhamnose derivative 16,[14] followed by removal of the benzyl
group from ester 17 by hydrogenolysis, gave 5.
Construction of the syn-b-hydroxy amino acid moiety with
an S configuration at C5’ was then investigated. Several
strategies have been employed for this in the past,[5d,e,6g,i–k,7a,8a]
two of which were used for the total synthesis of caprazol.
One is a Sharpless asymmetric aminohydroxylation of the
a,b-unsaturated ester[7a] and the other is the diastereoselec-
tive isocyanoacetate aldol reaction.[8a] We anticipated that the
stereochemistry at C5’ could be controlled with a novel
diastereoselective aldol reaction using the isocyanate 8 in the
presence of an organocatalyst.[10]
Initially, 9[15] was treated with 8 and Et3N (10 mol%) in
toluene to give a mixture of the aldol adducts 18a and 18b in
50% yield with poor diastereoselectivity (1:1.8; Table 1,
entry 1). In contrast, treatment with the (S,S)-thiourea
catalyst 10a (10 mol%) in toluene gave the desired aldol
adduct 18a as the major product in 64% yield (3.1:1), along
with a small amount of byproduct (19; entry 2). The
2
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Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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