1942
N. Murakami et al. / Tetrahedron Letters 42 (2001) 1941–1943
Scheme 1. Reagents and conditions: (a) m-CPBA, CH2Cl2, rt; (b) MeONHMe·HCl, Me2AlCl, CH2Cl2, rt, 66% two steps; (c)
n
LiCꢀCTMS, THF, −78 to 10°C; (d) TMSCl, BuLi, THF, 83% two steps; (e) TsCl, pyridine, CH2Cl2, 4°C to rt; (f) NaI, acetone,
55°C, 91% two steps; (g) B-3-pinanyl-9-borabicyclo[3.3.1]nonane, THF, rt, 82% (94% ee).
Our retrosynthetic analysis is illustrated in Fig. 1. Dis-
connection between C-10 and C-11 gives an optically
active alkyl halide (segment A) with an (R)-3-hydroxy-
1-yne moiety and a long-chain 1-alkyne (segment B)
with a Z,Z-1,5-diene moiety. The 3R-hydroxyl function
of the former segment was provided by asymmetric
reduction using Alpine-borane to a propargyl ketone,
which was prepared from the corresponding Weinreb
amide i. The latter segment was facilely prepared from
a diene alcohol ii by a one-carbon elongation using
dimethyl-1-diazo-2-oxopropylphosphonate6 via an alde-
hyde. The diene alcohol ii was formed by a coupling of
a terminal alkyne iv and an alkyl iodide iii. The diyne iv
was prepared from 4-pentyn-1-ol and 1-iodohexadecane
by the same method from ii into segment B. This
strategy was carried out as follows.
Condensation of 4-pentyn-1-ol and 1-iodohexadecane
(7) mediated with n-BuLi in THF–HMPA gave a
hydroxyalkyne, which was further submitted to Dess–
Martin oxidation to afford an aldehyde. Construction
of the terminal alkyne was carried out by a one-carbon
elongation from the aldehyde using dimethyl-1-diazo-2-
oxopropylphosphonate6 to afford a diyne 8 in 57%
yield for three steps. Elongation of the three-carbon
unit by coupling of
8
and 3-iodopropoxy-t-
butyldimethylsilane using n-BuLi, followed by hydro-
genation in the presence of the Rosenmund catalyst,
provided a Z,Z-diene, which was further transformed
into a primary alcohol 9 by removal of the TBS group
with tetrabutylammonium fluoride (TBAF). The pri-
mary alcohol 9 was converted to the desired segment B
(10) by the same procedure for the preparation of 8 in
40% yield from 8 for five steps (Scheme 2).
Baeyer–Villiger oxidation of cyclooctanone (2) using
m-CPBA and subsequent treatment with N,O-
dimethylhydroxylamine hydrochloride in the presence
of Me2AlCl afforded a Weinreb amide 3 in 66% yield
for two steps.7 Nucleophilic substitution for 3 with
lithium (trimethylsilyl)acetylide followed by TMSCl
treatment to supplement the partially deprotected
trimethylsilyl group provided a hydroxyalkyne 4 in 83%
yield for two steps. Then, the hydroxyalkyne 4 was
treated with tosyl chloride in pyridine to give the corre-
sponding tosylate, which was subjected to nucleophilic
substitution with sodium iodide to afford a keto-iodide
5 in 91% yield for two steps. Asymmetric reduction
of 5 using B - 3 - pinanyl - 9 - borabicyclo[3,3,1]nonane
(Alpine-borane),8 which was prepared from (+)-a-
pinene (97% ee) and 9-BBN, proceeded in 82% yield
with high enantiomeric selectivity (94% ee) to furnish
segment A (6) (Scheme 1).
Segments A (6) and B (10, 1.9 equiv. for 6) were
connected by n-BuLi (2.2 equiv. for 6) treatment, and
subsequent deprotection of the TBS group furnished
lembehyne A (1) in 51% yield for two steps. The
synthesized lembehyne A (1) was shown to be superim-
posable with the natural product isolated from the
1
marine sponge by comparison of the H–13C NMR, IR,
MS, and optical rotation data. Thus, the absolute
stereostructure of lembehyne A (1) previously presented
by us was confirmed. Investigation on the structure–
activity relationship by use of synthetic analogs involv-
ing a search for the pharmacophore is currently in
progress.
The absolute configuration of 6 was confirmed by the
modified Mosher method.9 Namely, the distribution of
Dl values [l(S)-MTPA ester−l(R)-MTPA ester] shown
in Fig. 2 supported the intended 3R configuration in 6.
The enantiomeric excess was assessed by integration of
the respective signals due to the 3-proton in the 1H
NMR spectrum of the (S)-MTPA ester of 6.
Figure 2. Confirmation of the absolute configuration at C-3
in 6.