occurred smoothly on the matched allylic alcohol to afford
SnH, this in situ method afforded 25 in superior yield and
geometric purity. Furthermore, as all spent reagents were
salts, 2 could be purified by passage through a plug of silica
gel, thereby minimizing any chance of destannylation.
Fragment 3 now needed to be prepared. Despite the
presence of the possibly reactive epoxide, Mitsunobu ester-
ifcation of 6 and 7 provided fragment 35 in good yield. We
were now ready to investigate the final intermolecular union.
Though conventional Stille coupling13 of 2 and 3 worked
fine (60% yield), substitution of stoichiometric Cu(I) thiophene
carboxylate (Liebeskind’s conditions) for catalytic Pd(0)
afforded diene 23 in significantly less reaction time (30 min
vs 18 h).14
75 as a single observable isomer.
With 4 and 7 prepared and fragments 52c and 64 known,
final assembly of 1 could begin. Dess-Martin oxidation of
fragment 4 gave a pseudosymmetric aldehyde. This afforded
us the option of introducing either alkene 5 or the northern
vinyl group first. In theory, we preferred to add the
commercially available vinyl-MgBr early and our synthetic
material late. However, in practice, chelation-controlled
addition of the Grignard reagent derived from 5 proved best,
affording 19 as a single diastereomer (Scheme 4). In contrast,
The stage was now set to study the key RCM step. We
initially hypothesized that by using the less reactive first-
generation Grubbs’ catalyst, the greater reactivity of mono-
substituted alkenes could be exploited and a selective C13-
C14 metathesis achieved.15 Unfortunately this catalyst only
truncated the allylic alcohol to give the methyl ketone.16 That
problem was virtually eliminated by using the imidazolium-
based catalyst,3b and more importantly, we achieved the
desired RCM. Though metathesis occurred in only moderate
yield and required high catalyst loading (50 mol %), no other
RCM products were detected and to our delight only the
C13-C14 E-isomer of 24 was observed.5
Scheme 4a
Attempts at removing the PMB groups on 24 were
complicated by formation of PMB-derived acetals with the
C12 hydroxyl. Thus the free OH of 24 was protected as a
TBS ether (Scheme 5), before removal of the PMB groups
by buffered DDQ oxidation. The two TBS groups were then
removed using TBAF buffered with HOAc to afford
presumed amphidinolide A (1). However, NMR data from
our synthetic material did not match those of the natural
product, primarily in the chemical shifts of protons at C4,
C8, C9, C11, C13, C17, and C19.5 Optical rotation of our
material (-56) also differed from the natural product (+46)
in magnitude and sign.
(a) DMP, pyridine, CH2Cl2, 98%. (b) 5, t-BuLi, Et2O, -78 °C,
then added MgBr2‚Et2O in Et2O/PhH (3:1), -78 °C f rt, 25 min,
then aldehyde + MgBr2‚Et2O in CH2Cl2/Et2O/PhH, 0 °C, 45 min,
70%. (c) TBSOTf, 2,6-lutidene, CH2Cl2, 0 °C, 30 min, 81%. (d)
Super-Hydride, THF, 0 °C, 35 min, glycerol workup, 88%. (e)
DMP, pyridine, 1.5 h, rt, 98%. (f) 21 + MgBr2‚Et2O in CH2Cl2/
Et2O/PhH, vinyl-MgBr in THF, 1 h, 0 °C, 60% (7:1). (g) NBS,
AgNO3, acetone, rt, 92%. (h) Bu3SnF, Red-Sil, (Ph3P)2PdCl2, cat.
TBAF, Et2O, rt, 2.5 h, 73%.
Assigning the structure of 1 on spectral data alone is
difficult. The diffierence between the synthetic and natural
products could be the result of a misassignment made during
our synthesis or during isolation of the natural product.17
Therefore, we set out to (a) secure the structure of our
synthetic material by single crystal analysis and (b) syntheti-
cally explore the possibility that Kobayashi misinterpreted
his spectral data.
Because the two stereochemical containing regions of 1
(C8-C12 and C18-C22) are separated, we hypothesized
that the original correlation of these two halves may have
been wrong. Starting with L-arabitol we constructed mac-
adding vinyl-MgBr to the same aldehyde gave a mixture of
products. Protective group manipulation and oxidation of 19
afforded 21. Fortunately, chelation-controlled addition of
vinylmagnesium bromide to this aldehyde proved reasonably
efficient, affording a 7:1 mixture of epimers at what would
become C12 in the final target. Because placement of a
bromide at the terminal position of an alkyne provides a good
regiocontrol handle10 for Pd(0)-mediated hydrostannations,
the acetylenic TMS group was reacted with NBS to afford
22. Bu3SnH for the hydrostannation was generated in situ11
with Bu3SnF, catalytic TBAF, and Red-Sil (silane capped
silica gel).12 Compared to the direct employment of Bu3-
(13) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1-652.
(9) Ranu, B. C.; Majee, A. J. Chem. Soc., Chem. Commun. 1997, 1225-
1226.
(14) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-
2749.
(10) (a) Zhang, H. X.; Guibe´, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857-1867. (b) Boden, C. D. J.; Pattenden, G.; Ye, T. J. Chem. Soc., Perkin
Trans. 1 1996, 2417-2419.
(11) Maleczka, R. E., Jr.; Terrell, L. R.; Clark, D. H.; Whitehead, S. L.;
Gallagher, W. P.; Terstiege, I. J. Org. Chem. 1999, 64, 5958-5965.
(12) Reed-Mundell, J. J.; Nadkarni, D. V.; Kunz, J. M., Jr.; Fry, C. W.;
Fry, J. L. Chem. Mater. 1995, 7, 1655-1660.
(15) (a) Ulman, M.; Grubbs, R. H. Organometallics 1998, 17, 2484-
2489. (b) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310-
7318.
(16) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123-1125.
(17) Comparisons to the natural product are complicated by the existence
of only a TLC sample of natural amphidinolide A. Kobayashi, J., Hokkaido
University, personal communication, 2000.
Org. Lett., Vol. 4, No. 17, 2002
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