Scheme 3
Scheme 4 a
a Conditions: (a) TBDMSOTf, Et3N, CH2Cl2, rt, 12 h. (b)
Mo(CO)6, MeCN, 90 °C, 1.5 h. (c) (1) DIBALH, toluene, -78 °C,
30 min, (2) TBAF, THF, rt, 4 h. (d) Trimethyl orthoformate, Ac2O,
140 °C, 4 d. (e) K2CO3, MeOH, rt, 1 h. (f) m-CPBA. (g) H2, Pd-
C. (h) Dimethoxypropane, TsOH, THF, rt, 30 min. (i) MsCl, Et3N,
DMAP, THF, rt, 2 h. (j) TsOH, MeOH, rt, 30 min. (k) NaOMe,
CH2Cl2, rt, 1 h.
Conversion of the cycloadduct 9 to 1 is outlined in Scheme
4. The hydroxy group of 9 was protected as a TBDMS ether
(10). Mo(CO)6-mediated reductive N-O bond cleavege14 of
10 followed with DIBALH reduction of the resulting keto
alcohol 11 in toluene at -78 °C and desilylation afforded a
separable mixture of triols (12a and 12b) in a 3:1 ratio.15
Hence we turned our attention to converting both triols
12a and 12b to the target molecule. Conversion of 12a to
the desired olefin 13 was successful by means of the thermal
cleavage of a cyclic ortho ester16 introduced into the cis-
diol part of 12a on treatment with trimethyl orthoformate
(140 °C, 4 d). The formate 13 led to the known intermediate
14 by basic hydrolysis. Epoxidation of 14 to 15 followed
by debenzylation provided 1 in good yield, following Trost’s
procedure.4j
TS3 (Z-nitronate) and TS4 (E-nitronate) for 6b (Scheme 3):
TS3 should suffer from severe A1(3)-like steric constraint
between the N-OTMS and C-OTMS groups, whereas TS2
and TS4 should suffer from not only such a constraint for
the nitronate group but also 1,3-diaxial-like destabilization
for the terminal olefin as indicated in Scheme 3. Hence
reaction pathways through these three transition states could
not lead to cycloadducts at all. It should be pointed out that
the geometry of nitronate must be Z on the basis of a model
as shown in 7 for the cycloaddition reaction to take place.
In general, however, the (E)-isomer should be more stable
thermodynamically than the (Z)-isomer for steric reasons.
Hence, the (E)-isomer must be isomerized to the (Z)-nitronate
such as 7 under the given reaction conditions.13
(8) Bernet, von B.; Vasella, A. HelV. Chim. Acta 1979, 62, 1990-2015.
A modified procedure for the synthesis of 2 is described in Supporting
Information.
(9) Saito, S.; Kuroda, A.; Tanaka, K.; Kimura, R. Synlett 1996, 231-
233.
(10) Simoni, D.; Invidiata, F. P.; Manfredini, S.; Ferroni, R.; Lampronti,
I.; Roberti, M.; Pollini, G. P. Tetrahedron Lett. 1997, 38, 2749-2752.
(11) For related diastereoselective Henry reaction, see: Hanessian, S.;
Kloss, J. Tetrahedron Lett. 1985, 26, 1261-1264. Other bases such as DBU
or KF resulted in lower yield with diastereoselectivity lower than that of
the TMG-catalyzed case.
(12) No cycloaddition reaction proceeded at all when recovered 6b was
subjected to the same reaction conditions as those for cycloaddition (footnote
e in Scheme 2): 6b was recovered unchanged again in 66%, and the rest
of 6b (34%) seemed to decompose or lead to a mixture of unidentifiable
products.
(13) Two possible mechanisms deserve consideration for such a geo-
metrical isomerization of nitronates: one might involve a protonation-
deprotonation process and the other might involve the 1,3-migration of a
trimethylsilyl group from oxygen to oxygen. For discussion with respect
to the 1,3-migration, see: Colvin, E. W.; Beck, A. K.; Bastani, B.; Seebach,
D.; Dunitz, J. D. HelV. Chim. Acta 1980, 63, 697-710.
(14) Nitta, M.; Yi, A.; Kobayashi, T. Bull. Chem. Soc. Jpn. 1985, 58,
991-994.
(15) Some other reducing agents employed for this conversion did not
effect stereochemical outcomes more selective than that of DIBALH in
toluene. For instance, other reducing conditions such as DIBALH/THF,
DIBALH/LiCl/THF, NaBH4/THF, NaBH4/LiCl, or NaBH4/CeCl/THF gave
less selective results: yields of 12a and 12b were 16% and 13%, 22% and
11%, 49% and 20%, 44% and 15%, or 20% and 33%, respectively.
(16) For a review for cleavage of cyclic ortho esters, see: Org. React.
1984, 30, 457-566.
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