Cl10 gave the optically pure (S)-R-hydroxysilane 3 (87%,
>95% ee). The (S,Z)-olefin 5 was prepared by the Pd-
catalyzed hydrostanylation of (S)-3 followed by an acidic
treatment (66%, two steps).11,12 The esterification of 5 with
racemic Boc-homoallylglycine was effected by using EDCI
in the presence of the catalytic DMAP to give the (S,Z)-R-
acyloxysilane 6 in 90% yield.
Next, we examined the enolate Claisen rearrangement of
(S,Z)-6 for the construction of the C5 and C9 stereocenters.
The treatment of (S,Z)-6 with LDA (4 equiv) in the presence
of ZnCl2 smoothly proceeded to give the desired (2S,3R)-
isomer 7 as an inseparable mixture of its diastereomer13
(83%, dr 7:1 by 1H NMR) (Scheme 3).14 The stereochemistry
group with a trifluoroacetyl (TFA) group gave 10 (91%),
which, upon ozonolysis, afforded the aldehyde 11 (dr 7:1).
The minor diastereomer was removed at this stage by flash
chromatography to give diastereomerically pure (2S,3R)-11
(73%).
For completion of the total synthesis of 1, the unexploited
spirohemiaminal formation and dibromination of the aromatic
group remained to be solved. The initial attempt for
construction of the spirohemiaminal was the treatment of
11 with excess methylamine in MeOH. The reaction gave
the desired spirohemiaminal 12 as the exclusive diastereomer
in 32% yield but was not reproducible. Control experiments
using 5 equiv of methylamine revealed that the reaction gave
a mixture of products consisting of the desired 12 (24%),
spirolactone 1316 (18%), butenolide 14 (22%), and lactam
15 (12%) (Scheme 4).17 It was assumed that the attack of
Scheme 3
Scheme 4
a Conditions: (1) OsO4 (0.05 equiv), NMO (2 equiv), 1,4-dioxane-H2O,
(3:1), rt, 16 h; (2) NaIO4 (1.7 equiv), t-BuOH-pH 6.7 buffer (3:2), rt, 3 h;
(3) NaBH3CN (1.7 equiv), AcOH, 70 °C, 1 h.
the methylamine on the proton attached to the R-position of
the carbonyl group resulted in the formation of the retro-
Michael products 14 and 15, since further treatment of each
product under the same reaction conditions remained un-
changed. Based on these results, we postulated that the
sterically bulky heptamethyldisilazane instead of the methy-
lamine would prevent the undesired ꢀ-elimination reaction.
In fact, the treatment with excess heptamethyldisilazane gave
12 in 50% yield and was reproducible. Only 15 was the
byproduct (12%) isolated from the reaction mixture (Scheme
5). The relative stereochemistry of 12 including the hydroxy
group at C8 was assigned as shown in Scheme 5 by the NOE
experiments. Prior to examining the dibromination of 12,
we observed that the bromination of the phenol derivative
10 with NBS (DMF, 0 °C) gave the 2′,4′,6′-tribrominated
product as the exclusive product indicating that NBS or Br2
is not a suitable reagent for the 4′,6′-dibromination of 12.18
Thus, we chose tetrabutylammonium dichlorobromate (n-
of the products was determined by converting them into the
corresponding spirolactams 12 (vide infra). The fact that
(2S,3R)-7 was obtained as the major diastereomer suggested
that the chairlike transition state D (Scheme 1) is the
preferential pathway for this transformation. The mixture was
converted to the R-substituted proline 8 by the following
sequence of reactions: (1) chemoselective dihydroxylation
of the terminal olefin with OsO4, (2) oxidative cleavage of
the resulting diol with NaIO4, and (3) reductive amination
with NaBH3CN in AcOH (67%, three steps from 7). The
silyl group was removed under acidic conditions to avoid
the troublesome oxidative cleavage of the vinylsilane
group.15 This reaction gave the protection-free phenol
derivative 9 in 88% yield. Reprotection of the resulting amino
(10) (a) Sonderquist, E. J.; Anderson, C. L.; Miranda, E. I.; Rivera, I.
Tetrahedron Lett. 1990, 31, 4677–4680. (b) Dahr, R. K. Aldrichim. Acta
1994, 27, 43–51.
(11) Liron, F.; Garrev, P. L.; Alami, M. Synlett 1999, 246–234
.
(15) It is reported that the ozonolysis of the vinylsilane does not give
the corresponding aldehyde; see: (a) Bu¨chi, G.; Wu¨est, H. J. Am. Chem.
Soc. 1978, 100, 294–295. (b) Murakami, M.; Sakita, K.; Igawa, K.;
Tomooka, K. Org. Lett. 2006, 8, 4023–4046.
(12) Hydrogenation of 3 using the Lindlar catalyst did not give any olefin
product even at high pressure (5 atm). The use of Pd/C produced the
corresponding alkane.
(13) The absolute configuration of the minor isomer was not
determined.
(16) The spirolactone 13 was obtained as a single diastereomer. The
relative stereochemistry of 13 was not determined.
(14) The reaction without ZnCl2 resulted in the decreased yield of 7
(28%).
(17) Lower amounts of methylamine (2 equiv) resulted in the decreased
yield of 12 (<20%).
Org. Lett., Vol. 10, No. 23, 2008
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