Synthetic Studies toward Galbulimima Alkaloids
Upon studying the literature, we were surprised to find
that no one has reported a strategy to synthesize GB 13 by
introducing its C-ring at a late stage, as this would probably
provide a more-convergent approach to GB 13 because we
could disconnect it into two equally complex fragments. On
the basis of this analysis, we started our retrosynthetic analy-
sis for (À)-GB 13 (3). As depicted in Scheme 2, we envi-
sioned that the C-ring of (À)-GB 13 could be constructed by
Scheme 3. Reagents and conditions: a) 1,3-cyclohexanedione, 4 ꢁ MS,
THF, reflux; b) CBr4, Ph3P, CH3CN, RT; then DIPEA, reflux; c) Pt/C, H2
(80 atm.), AcOH, 458C, cis/trans 4:1; d) (Boc)2O, NaOH, benzene/THF/
H2O, reflux; e) IBX, DMSO, 658C.
the a face of the enamine 32, thus directing the hydrogena-
tion to the desired b face to form the reduction product
(34a). Accordingly, Pt/C-catalyzed hydrogenation of 32 was
carried out in acetic acid at 608C and 80 atm. After the re-
action, the desired 34a was isolated together with trans-
isomer 34b in a ratio of 1.8:1. We reasoned that the forma-
tion of 34b might result from partial epimerization of the
hydrogenation intermediate 33a, and therefore decided to
inhibit this side-reaction by reducing the reaction tempera-
ture. To our delight, a better ratio (4:1) was observed, when
the hydrogenation was conducted at 408C. Further reducing
of the reaction temperatures inhibited the hydrogenation.
The separated 34a was protected with (Boc)2O (Boc=tert-
butoxycarbonyl) and oxidized with 2-iodoxybenzoic acid
(IBX)[13] to deliver enone 35.
The preparation of O-silylated ketene acetal 38 is depict-
ed in Scheme 4. Intramolecular Michael addition of 36
under the action of (S)-1-phenylethylamine proceeded
smoothly to deliver g-keto ester 37, after KOH-mediated
isomerization and subsequent esterification.[14] Diastereose-
lective reduction of the keto moiety in 37 with NaBH4 at
À788C followed by cyclization under acidic conditions pro-
vided a lactone. Following deprotonation of this lactone
with lithium diisopropylamide (LDA), the resultant anion
was trapped with trimethylsilyl chloride to deliver an 89%
yield over four steps.
Scheme 2. Retrosynthetic analysis of (À)-GB 13 and (+)-GB 16.
a SmI2-mediated carbonyl–alkene reductive coupling reac-
tion[7,8] of enone 25. The enone 25 could be assembled from
lactone 26 by ring-opening and a subsequent intramolecular
aldol reaction. The bond disconnection of 26 would give two
less-complicated bicyclic intermediates 27 and 28, which
could be connected to each other by a Mukaiyama–Michael
addition.[9] Apparently, by starting from the lactone 26, 1,3-
diketone 29 could be assembled by ordinary transforma-
tions. This intermediate would in turn provide (+)-GB 16
through the intramolecular condensation between its secon-
dary amine moiety and its 1,3-diketone. Herein, we detail
our results.[10]
Results and Discussion
Our synthesis started from the preparation of the two re-
quired partners for the Mukaiyama–Michael addition. As
shown in Scheme 3, condensation of commercially available
(S)-3-aminobutan-1-ol (30) with 1,3-cyclohexanedione in re-
fluxing tetrahydrofuran gave enamine 31 in 87% yield.[11]
Treatment of 31 with CBr4/Ph3P followed by Et3N-mediated
substitutive cyclization afforded bicyclic enamine 32.[12a] The
next step was a stereoselective hydrogenation of the C=C
double bond of 32. On the basis of our previous observa-
tions,[12] we anticipated that the methyl group would shield
Scheme 4. Reagents and conditions: a) (S)-1-phenylethylamine, 4 ꢁ MS,
MgSO4, THF, RT; b) KOH, MeOH, reflux, acid workup then CH2N2,
Et2O; 75% yield for 2 steps; c) NaBH4, MeOH, À788C; d) PTSA·H2O,
CH2Cl2, reflux; e) LDA, then TMSCl, THF, À788C.
Chem. Asian J. 2011, 6, 573 – 579
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