Total Synthesis of Marinomycins A
−
C
A R T I C L E S
Scheme 4. Preparation of Suzuki Coupling Precursor 39a
to give TMS diene 28 in 89% yield. ipso-Bromo desilylation
of TMS diene 28 with NBS in MeCN afforded the all-trans
bromo-diene 29 (88% yield), a compound that was stable to
moderate light, unlike its iodide variant, in which the trans ∆10,11
double bond would rapidly isomerize to cis, even under low-
light conditions. Saponification of 29 (KOH, 87% yield)
provided the corresponding salicylic acid, which was protected
as the acetate with acetic anhydride (1.1 equiv) in the presence
of catalytic amounts of Mg(ClO4)2 (96% yield),16 to yield the
desired acetoxy carboxylic acid 7, setting the stage for the
upcoming Mitsunobu esterification.
Preparation of Dimerization Precursor 39. With all the
key building blocks in hand, the assembly of desired dimer-
ization precursor 39 could commence (Scheme 4). Thus, a
Horner-Wadsworth-Emmons olefination reaction between
ketophosphonate 5 and aldehyde 6 under the influence of Ba-
(OH)2 proceeded smoothly to provide enone 31 in 95% yield.
Before the HWE coupling was found to be the highest yielding
method to prepare intermediate 31, a study was undertaken to
establish whether an olefin cross metathesis reaction could be
employed to generate this enone as summarized in Table 1.
Despite the initial success of this reaction between enone 40a
and the simple olefin 41 to furnish enone 42 (entry 1, Table 1),
the adoption of the real, and more complex, olefin 23 or 24 led
to unsatisfactory results (entries 2-5, Table 1). It is interesting
to note that in this instance the Hoveyda-Grubbs catalyst 4417
proved slightly more efficient than the Grubbs second generation
catalyst 4318 in generating the desired product, enone 31a (entry
5, Table 1).
With enone 31 in hand (Scheme 4), a 1,3-syn reduction of
the carbonyl group (Et2BOMe, NaBH4, -78 °C)19 set the final
stereocenter within the growing substrate, furnishing diol 32 as
a single stereoisomer and in high yield (89%), which was
silylated (TBSCl, imid.) to generate the fully protected hexaol
33 in 89% yield. Cleavage of the benzyl group (Ca, liq NH3)20
from the latter compound provided primary allylic alcohol 34
in 75% yield, which was subsequently oxidized to enal 35 with
Dess-Martin periodinane (87% yield). Reaction of this aldehyde
with the lithiated species from TMS-diazomethane and LDA21
resulted in acetylene formation, providing enyne 36 in high yield
(85% yield). The TES-ether of the latter compound was then
selectively cleaved by the action of catalytic amounts of PPTS
in EtOH at ambient temperature to provide the alcohol coupling
partner for the Mitsunobu reaction (37, 77% yield).
Despite literature precedent22 for the participation of salicylic
acid derivatives in Mitsunobu-type reactions, the Mitsunobu
reaction of alcohol 37 and carboxylic acid 45 under standard
conditions (i.e., DEAD, PPh3) failed to produce the expected
product, even after 20 h at ambient temperature (Scheme 5).
To develop suitable conditions to accomplish the coupling of
a Reagents and conditions: (a) 5 (1.0 equiv), 6 (1.1 equiv), Ba(OH)2‚H2O
(0.75 equiv), THF/H2O (20:1), 25 °C, 1 h, 95%; (b) Et2BOMe (1.0 M in
THF, 1.1 equiv), THF/MeOH (4:1), -78 °C, 15 min; then NaBH4 (1.1
equiv), 3 h, 89%; (c) TBSCl (4.0 equiv), imid. (8.0 equiv), DMF, 25 °C,
8 h, 89%; (d) 33 in THF/ i-PrOH (3:1); then liq NH3; then Ca (30 equiv),
-78 °C, 1 h, 75%; (e) DMP (1.6 equiv), NaHCO3 (10 equiv), CH2Cl2,
25 °C, 30 min, 87%; (f) i-Pr2NH (1.8 equiv), n-BuLi (2.5 M in hexanes,
1.5 equiv), THF, -78 f 0 °C, 30 min; then TMSCHN2 (1.5 equiv), THF,
-78 °C, 30 min; then 35, -78 °C, 1 h, -78 f 25 °C, 2 h, 85%; (g) PPTS
(0.1 equiv), EtOH, 25 °C, 3 h, 77%; (h) DEAD (6.0 equiv), PPh3 (6.0 equiv),
7 (6.0 equiv), THF, 25 °C, 1 h, 93%; (i) K2CO3 (0.05 equiv), MeOH, 25 °C,
15 min; (j) TIPSOTf (30 equiv), 2,6-lut. (60 equiv), CH2Cl2, 25 °C, 18 h,
92% over two steps. Abbreviations: DMP, Dess-Martin periodinane; PPTS,
pyridinium p-toluenesulfonate; DEAD, diethyl azodicarboxylate; TIPS,
triisopropylsilyl; Tf, trifluoromethanesulfonyl; lut., lutidine.
these two compounds, a model study was undertaken in which
readily available alcohol 47 was employed in coupling reactions
with the simple salicylic acids 48a and its derivatives 48b and
48c as shown in Scheme 5. Interestingly, a notable rate
enhancement was observed when the phenolic group of the
salicylic acid component was protected (e.g., 48b and 48c), as
opposed to salicylic acid itself (i.e., 48a), in which the phenolic
group was free. Furthermore, it was found that the acetoxy
derivative (i.e., 48c) reacted significantly faster (complete
conversion in 1 vs 3 h) than its methoxy counterpart (i.e., 48b).
Proceeding in 81% yield, the Mitsunobu reaction of the acetoxy
salicylic acid derivative 50 provided further encouragement, and
when we finally attempted the coupling of our two real partners
(16) Chakraborti, A. K.; Sharma, L.; Gulhane, R.; Shivani, Tetrahedron 2003,
59, 7661.
(17) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168. (b) Gessler, S.; Randl, S.; Blechert, S.
Tetrahedron Lett. 2000, 41, 9973.
(18) For a recent review of metathesis reactions in organic synthesis, see:
Nicolaou, K.C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4490.
(19) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repicˇ, O.; Shapiro, M. J.
Tetrahedron Lett. 1987, 28, 155.
(20) Hwu, J. R.; Chua, V.; Schroeder, J. E.; Barrans, R. E., Jr.; Khoudary, K.
P.; Wang, N.; Wetzel, J. M. J. Org. Chem. 1986, 51, 4731.
(21) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun. 1992,
721.
(22) Fu¨rstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2, 3731.
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