Table 1. Cu(I)-Catalyzed Addition of Organometallics Derived
from Bromide 8 to Epoxide 12
Scheme 3. Preparation of Key Aldehyde 6 from 2-Methallyl
Alcohol
entry
conditions
yield of
13 (%)a
b
1
2
3
8, Mg (1.5 equiv), THF, Δ, 30 min then 12,
CuI, ꢀ40 to 0 °C, 2 h
ꢀ
8, Mg (1.5 equiv), THF, Δ, 3 h then 12,
CuI, ꢀ30 to 0 °C, 18 h
52
c
8, t-BuLi (2.1 equiv), Et2O, ꢀ78 °C,
ꢀ
CuCN (0.5 equiv) then 12, BF3 Et2O,
3
ꢀ78° to 0 °C, 1 h
4
8, t-BuLi (2.1 equiv), Et2O, ꢀ78 °C,
CuCN (0.5 equiv) then 12, ꢀ25 to 0 °C,
1 h
70
a Isolated yield. b No metalꢀbromine exchange was observed.
c Decomposition.
Regioselective hydroperoxysilylation of the disubsti-
tuted olefin within 17 accomplished by using Co(thd)2,16
in the presence of oxygen and triethylsilane, afforded the
protected hydroperoxide in almost quantitative yield. Fi-
nally treatment of 4 at low temperature with DBU gave,
via a three-step sequence, compounds 1 and 20 (58%)
along with the intermediate 19 and the epoxyalcohol 18.
The formation of epoxide byproduct in the intramolecular
Michael addition of the hydroperoxide groups is well-
precedented.17
derived from 8 to 12 afforded the tertiary alcohol 13 in
good yield (entry 4).
Prior to the Mukaiyama aldol reaction, we had to trans-
form the monoprotected diol 13 to the desired R- triethyl-
silyloxyaldehyde 6. After protection of the tertiary alcohol
within 13 as a TES ether, the resulting bis-TES ether was
subjected to a selective oxidative deprotection under stan-
dard Swern conditions. Conversely to literature prece-
dents, no reaction occurred.12 Consequently, we adopted
a stepwise method which consisted of selective deprotec-
tion of the primary TES ether with silica gel13 followed by
Swern oxidation to provide aldehyde 6 in 60% over three
steps from 13. With 6 in hand, the stage was set up for the
Mukaiyama aldol addition. After some experimentation,
we found that treatment of aldehyde 6 at ꢀ78 °C with
[(1-ethoxyethenyl)oxy]trimethylsilane 15, in the presence
of TiCl2(OiPr)2,14 led to the exclusive formation of the
syn-adduct 1615 (Scheme 4).
Exposure of 4 to DBU at 0 °C which effected β-elimina-
tion followed by successive addition of trifluoroethanol
and TBAF minimized the epoxide formation providing 1
and 20 in 72% yield, separated by preparative TLC. Struc-
tures of 1 and 20 and their relative configurations were
confirmed by 2D NMR experiments (HSQC, NOESY).
The synthetic sample of 1 was found to be identical in all
respects to the natural product except for the sign of the
20
optical rotation (Lit. values: [R]D þ8 (c 0.017, CHCl3);2g
Exposure of 16 to an excess of TBAF effected TMS and
TES ether deprotection and subsequent lactonization.
Acetylation of the resulting β-hydroxylactone furnished
the acetate 17 in 59% yield over three steps to form 6.
for the enantiomer: [R]D ꢀ8 (c 0.05, CHCl3);2d observed:
20
20
[R]D ꢀ9 (c 0.7, CHCl3). Since our synthetic route from
(S)-2-methylglycidol was unambiguous, Kashman and co-
workers misassigned the absolute configuration of pla-
kortolide I. Thus, the revised absolute configuration of
plakortolide I is 3S, 4S, 6R.
(12) (a) Tolstikov, G. A.;Miftakhov, M. S.;Adler, M. E.;Komissarova,
N. G.; Kuznetsov, O. M.; Vostrikov, N. S. Synthesis 1989, 940–942. (b)
Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron 1999,
40, 5161–5164. (c) Hanson, G. H.; Benavoud, F.; Burke, S. D.
J. Org. Chem. 2005, 70, 9390–9398.
In order to confirm Garson’s assumption that the struc-
ture of “plakortolide E” was in fact that of its corresponding
(13) For an example of TES ether deprotection with SiO2, see:
Nemoto, H.; Shiraki, M.; Fukumoto, K. Tetrahedron Lett. 1995, 36,
8799–8802.
(14) For an example of TiCl2(OiPr)2-catalyzed Mukaiyama Aldol reac-
tion with trimethysilyl ketene acetal, see: Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.;
Zhang, J.-W.; Yang, L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q.
Chem.;Eur. J. 2006, 12, 1185–1204.
(16) O’Neill, P. M.; Hindley, S.; Pugh, M. D.; Davies, J.; Bray, P. G.;
Park, B. K.; Kapu, D. S.; Ward, S. A.; Stocks, P. A. Tetrahedron Lett.
2003, 44, 8135–8138.
(17) (a) Murakami, N.; Kawanishi, M.; Itagaki, S.; Horii, T.; Ko-
bayashi, M. Tetrahedron Lett. 2001, 42, 7281–7285. (b) Murakami, N.;
Kawanishi, M.; Itagaki, S.; Horii, T.; Kobayashi, M. Biorg. Med. Chem.
2002, 12, 69–72. (c) Jin, H.-X.; Zhang, Q.; Kim, H.-S.; Wataya, Y.; Liu,
H.-H.; Wu, Y. Tetrahedron 2006, 62, 7699–7711.
(15) The relative stereochemistry of 16 was determined by 2D NMR
techniques after its transformation to the lactone 17.
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Org. Lett., Vol. 14, No. 2, 2012