A R T I C L E S
Ni et al.
a
14
Scheme 3. Preparation of Cyclization Precursors
of this type. While this sequence was chemically efficient, as
9a
we noted in our communication of isodomoic acid G, this route
led to variable levels of epimerization of the stereocenter
embedded within the oxazolidinone. Evaluating the enantiopurity
of each intermediate during the sequence illustrated that
oxazolidinone 14 was obtained in >99% enantiomeric excess
(
ee) and that a slight erosion of enantiopurity occurred during
N-alkylation to afford N-butynylated intermediate 15 in 91%
ee. The major source of epimerization, however, was NaBH
4
1
5
reduction of this species to alcohol 16. Depending on the rate
of addition of NaBH and internal temperature, this step
4
proceeded with variable extents of epimerization, with ee values
ranging from approximately 60% to 85%.
Given the sensitive nature of this early sequence, the route
was modified so that initial NaBH
4
reduction of oxazolidinone
1
4 at -5 °C was followed by THP protection to afford 18
followed by N-butynylation and PPTS deprotection of the THP
moiety to afford 16. While it added two steps to the overall
conversion of 13 to 17, this sequence proceeded in good overall
yield and reliably furnished unsaturated acyl oxazolidinone 17
in 90-95% ee. A similar sequence involving N-propargylation
of 18 instead of N-butynylation afforded cyclization substrate
2
0 via alcohol 19.
Total Synthesis of Isodomoic Acid G. As described in our
9a
preliminary report, the synthesis of isodomoic acid G requires
the coupling of butynylated oxazolidinone 17 with vinyl
zirconium species 23. Reagent 23 was therefore obtained by
an Evans alkylation of acyl oxazolidinone 21 with methyl
a
Conditions: (a) Triphosgene, THF, reflux, 98%. (b) KHMDS, 1-bromo-
, ethanol, 0 °C to rt, 90%. (d)
, -78 °C; and then 4,4-dimethyl-3-[2-
triphenylphosphinio)acetyl]oxazolidin-2-one bromide, DMAP, -15 °C,
0% (two steps). (e) NaBH , ethanol, -5 °C, 90%. (f) Dihydropyran, PPTS,
CH Cl , 40 °C, 88%. (g) Procedure b, 77%. (h) PPTS, ethanol, 55 °C, 87%.
i) KHMDS, propargyl bromide, THF, 0 °C to rt, 88%. (j) PPTS, ethanol,
5 °C, 90%. (k) Procedure d, 90%.
2
(
(
-butyne, THF, 0 °C to rt, 74%. (c) NaBH
4
COCl) , DMSO, Et N, CH Cl
2
3
2
2
1
6
9
4
iodide, followed by oxazolidinone reduction with LiBH
4
and
2
2
alcohol protection as the TIPS (triisopropylsilyl) ether 22
(
5
17
(
(
Scheme 4). Hydrozirconation of alkyne 22 in tetrahydrofuran
THF) was directly followed by treatment with substrate 17 in
the presence of 10 mol % Ni(COD)
2 2
and 20 mol % ZnCl to
afford pyrrolidine 24 in 74% isolated yield with complete control
compound 8, whereas zirconium species 7 should be easily
derived from hydrozirconation of terminal alkyne 9. The strategy
to prepare isodomoic acid H would then involve a similar
sequence, wherein the timing of methyl and alkenyl substituent
introduction would be reversed. Nickel-catalyzed cyclization of
substrate 10 with dimethylzinc would afford the Z stereochem-
istry of isodomoic acid H. The required enyne 10 could be
accessed by Sonogashira coupling of terminal alkyne 11 with
E-vinyl iodide 12. Compound 11 should be readily accessed
from compound 8 by N-propargylation, whereas vinyl iodide
1
8
of the C2-C3 relative stereochemistry. It should be stressed
that this single step addresses most of the challenges associated
with this total synthesis, including formation of the pyrrolidine
ring, control of the C2-C3 relative stereochemistry, formation
of the 1,3-diene, and control of stereochemistry of the C4-C1′
and C2′-C3′ alkenes.
Methanolysis of the acyl oxazolidinone linkage of 24 with
MeOMgBr then afforded ester 25. With compound 25 in hand,
methanolysis of the remaining internal oxazolidinone with
MeONa was accomplished (Scheme 4). This two-step procedure
proceeded in higher yield than a one-step procedure with either
reagent. Additionally, compound 25 was a useful structure for
NMR characterization before rotamer-derived spectral com-
plexities were introduced by installation of an acyclic carbamate.
1
2 should be available from zirconium species 7 utilized in the
isodomoic acid G synthesis.
Routes to Cyclization Precursors. The desired strategy for
synthesis of isodomoic acids G and H requires the synthesis of
N-propargylated oxazolidinone intermediates (Scheme 3). The
route originally employed in our prior syntheses of kainic acid,
allokainic acid, and isodomoic acid G involved the conversion
of D-serine methyl ester (13) to oxazolidinone 14, followed by
After n-Bu
oxidized to the corresponding diacid (Dess-Martin followed
by NaClO ). Exhaustive hydrolysis and sequential ion exchange
4
NF-mediated deprotection, the resulting diol 26 was
2
N-alkylation to 15, and then ester reduction with NaBH
4
to
(14) Seo, J.; Fain, H.; Blanc, J. B.; Montgomery, J. J. Org. Chem. 1999,
1
3
6
4, 6060.
afford alcohol 16. Swern oxidation followed by Wittig
olefination afforded unsaturated acyl oxazolidinone 17 for
exploring nickel-catalyzed cyclizations. Our prior studies had
demonstrated that unsaturated acyl oxazolidinones were far
superior substrates than enoates in nickel-catalyzed reactions
(
15) For discussion of epimerization pathways in related transformations,
see (a) reference 2d. (b) Wee, A. G. H.; McLeod, D. D. J. Org. Chem.
2003, 68, 6268.
(
16) Reagent 21 was prepared in a fashion analogous to the reported
procedure for a phenylalanine-derived reagent: Evans, D. A.; Black,
W. C. J. Am. Chem. Soc. 1993, 115, 4497.
(
(
17) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853.
18) (a) Ni, Y.; Amarasinghe, K. K. D.; Montgomery, J. Org. Lett. 2002,
(
13) (a) Doyle, M. P.; Dyatkin, A. B.; Protopopova, M. N.; Yang, C. I.;
Miertschin, C. S.; Winchester, W. R.; Simonsen, S. H.; Lynch, V.;
Ghosh, R. Recl. TraV. Chim. Pays-Bas 1995, 114, 163. (b) Sibi, M. P.;
Rutherford, D.; Sharma, R. J. Chem. Soc., Perkin Trans. 1 1994, 1675.
2
4, 1743. (b) For the use of ZnCl in promoting additions of alkenyl
zirconium reagents: Negishi, E; Okukado, N.; King, A. O; Van Horn,
D. E; Spiegel, B. I J. Am. Chem. Soc. 1978, 100, 2254. (c) See also
Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912.
1
7716 J. AM. CHEM. SOC. 9 VOL. 131, NO. 48, 2009