two steps. This stereodiverse set of N-Fmoc-amino acids 12
represents a defined version of scaffold 5, which can be
further diversified at either end.
The synthesis of scaffold 6 relied on enantiomerically
enriched butadiene monoxide13 to define the absolute stereo-
chemistry of the C-terminal intermediates 14 and 15 (Scheme
3). Nucleophilic epoxide opening of butadiene monoxide can
analogy to the synthesis of the N-terminal intermediate 9,
the efficiency of this nonselective route and ease of separation
and identification of the cis and trans lactones 14 made this
an attractive alternative to a stereoselective synthesis.18
Lactone 14 was converted to thioester 15 by treatment with
t-BuSH-AlMe3.19 It was immediately evident that the
γ-hydroxy thioester was not stable in its unprotected form,
as evidenced by the partial reversion of 15 to 14 upon
exposure to silica gel chromatography,20 although this could
be minimized by addition of Et3N to the solvent. Thioester
anti-15 was successfully tethered to syn-1621 according to
the procedure described above and subjected to RCM to
provide a Z-olefin product 17 analogous to 11 in modest
(37%) yield (Figure 2). Removal of the silyl tether proceeded
Scheme 3a
a Key: (a) LDA, LiCl, THF, 0 °C; (b) H2SO4, dioxane, 95 °C,
60%, two steps, 1:1 syn/anti; (c) t-BuSH-AlMe3, CH2Cl2, 4 °C,
78% anti, 70% syn.
Figure 2. Initial coupling of 15 with N-terminal partner 16 to
produce tethered, metathesized 17.
produce three regioisomeric products, resulting from SN2
attack (primary or secondary carbon) or SN2′ attack. Initially,
it was thought that the relative preference for these three
products might be modulated by the choice of enolate.
However, ester and thioester enolates gave low yields of the
epoxide-opened products due to competing Claisen conden-
sation.14 In contrast, the enolate derived from N,N-dimethyl-
propionamide exclusively gave products resulting from
epoxide opening.15 Further screening of reaction conditions
found that lower temperatures (0 °C) favored SN2 attack at
the primary carbon over the secondary carbon and addition
of excess LiCl disfavored competing SN2′ attack. Thus,
treatment of (R)-butadiene monoxide with the enolate derived
from N,N-dimethylpropionamide and an excess of LiCl at 0
°C produced a separable 2:1 mixture of regioisomers
resulting from SN2 attack where the major product 13 was
generated as a 1:1 mixture of diastereomers at the R-carbon.
Diastereomers 13 were treated with H2SO4 in dioxane at 95
°C to form lactones syn-14 and anti-14.16 The diastereomers
were separated by silica gel chromatography and their relative
configurations established by comparison of the magnitude
of their vicinal coupling constants to known disubstituted
lactones.17 The remaining two isomers of 14 were produced
in an identical manner from (S)-butadiene monoxide. In
without difficulty, although attempts to hydrolyze the
thioester to an acid did lead to relactonization. It became
apparent that the γ-hydroxy group would need to be protected
in order for the carbonyl group to be useful as a point of
diversification and that the Me2Si tether was not robust
enough for this purpose.
In light of these results, a modified route was developed
based on a cross-metathesis strategy, which would allow for
protection of the problematic γ-hydroxy group (Scheme 4).
Lactone 14 was employed as a metathesis partner for the
N-terminal partner 16, in a cross-metathesis reaction to
provide 18 (Scheme 4). Ratios of 14/16 from 3:1 f 1:2 were
screened in the metathesis reaction to determine what
conditions would maximize the yield of the desired hetero-
coupled product. These investigations revealed that the ratio
of homocoupled and heterocoupled products was statistically
determined, as would be expected from two similar olefin
partners. While it was possible to get higher yields of the
desired product (based on the limiting partner) by using an
(17) Hussain, S. A. M. T.; Ollis, W. D.; Smith, C.; Stoddart, J. F. J.
Chem. Soc., Perkin Trans. 1 1975, 1480-1492. Myers, A. G.; McKinstry,
L. J. Org. Chem. 1996, 61, 2428-2440.
(13) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307-1315.
(14) Taylor, S. K. Tetrahedron 2000, 56, 1149-1163.
(15) Sauriol-Lord, F.; Grindley, T. B. J. Org. Chem. 1981, 46, 2831-
2833.
(18) A stereoselective route was explored based on Myers’ pseudoephe-
drine methodology (ref 18); however, the reaction of (S)-butadiene monoxide
with the enolate derived from (+)-pseudoephedrine (a stereochemically
“matched” case) provided a modest 4: 1 ratio of trans/cis lactones.
(19) Hatch, R. P.; Weinreb, S. M. J. Org. Chem. 1977, 42, 3960-3961.
(20) Evans, B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J. P.;
Hirshfield, J.; Veber, D. F. J. Org. Chem. 1985, 50, 4615-4625.
(21) Available as detailed in ref 4.
(16) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem.
Soc. 1994, 116, 9361-9362.
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