Communication
ly to give the corresponding ketones 6g-l in excellent yields
with good diastereoselectivities (Table 2, entries 7–12).[10]
The synthetic utility of the present reaction was successfully
demonstrated in the short formal synthesis of (À)-methyleneo-
lactocin (Scheme 5),[11–13] which has potent antibacterial and
antitumor activities. First, treatment of ketone 6j with LiBH4 re-
sulted in the formation of g-butyrolactone 7. Then, hydrolysis
of 7 and subsequent decarboxylation afforded g-butyrolactone
8 in 36% overall yield, which can be converted to (À)-methyle-
neolactocin.[13a] Although the stereoselectivity of the product
was slightly decreased, g-butyrolactone 8 was obtained in only
three steps from ketone 6j. It is also worth noting that during
this transformation, (À)-8-phenylmenthol was successfully re-
covered in 83% yield.
iodine(III) reagent, particularly for the development of new
carbon–carbon bond formation reactions, is under investiga-
tion.
Experimental Section
In
a
reaction tube containing benzylidenemalonate 5b
(0.15 mmol), hypervalent iodine(III) reagent 1 (0.03 mmol) and cy-
clohexanecarboxaldehyde 2a (0.225 mmol) were mixed in a 1:1
CH3CN/CH2Cl2 solvent mixture (2.4m with regard to 5b) under
argon atmosphere. The mixture was irradiated with UV light (l=
365 nm) with stirring for 12 h. After completion of the reaction, the
solvent was removed under reduced pressure. The diastereoselec-
tivity of ketone 6b was determined by 1H NMR analysis of the
crude mixture. The residue was purified by flash column chroma-
tography on silica gel (hexane/ethyl acetate=20:1 to 4:1 as
eluent) to afford ketone 6b (91.1 mg, 0.124 mmol, 83% yield, d.r.=
92:08); [a]2D3 =137.97 (c=1.3 in CHCl3); 1H NMR (500 MHz, CDCl3):
d=7.32–7.07 (15H, m), 4.80 (1H, dt, J=11.0, 4.5 Hz), 4.72 (0.08H,
m), 4.55 (1H, dt, J=11.0, 4.5 Hz), 4.47 (0.92H, d, J=11.5 Hz), 3.95
(1H, m), 2.43 (1H, m), 2.12 (1H, m), 1.94 (1H, m), 1.78 (2H, m),
1.64–1.45 (6H, m), 1.42–1.05 (24H, m), 0.97–0.86 (2H, m), 0.82 (3H,
d, J=6.5 Hz), 0.67 (1H, m), 0.60 (3H, d, J=6.5 Hz), 0.52–0.43 ppm
(1H, m); 13C NMR (125 MHz, CDCl3; data given for major isomer):
d=210.4, 168.4, 167.6, 150.6, 150.4, 134.1, 129.8, 128.9, 128.1,
126.1, 126.0, 125.5, 125.3, 76.6, 76.2, 56.3, 55.4, 50.8, 50.3, 49.9,
41.1, 40.6, 40.3, 34.6, 34.2, 31.5, 31.3, 31.0, 29.5, 28.8, 28.6, 27.2,
27.1, 26.0, 25.8, 25.4, 25.1, 23.1, 21.8, 21.5 ppm; IR (neat): n˜ =2929,
1739, 1707, 1594, 1264 cmÀ1; HRMS (ESI-TOF): m/z calcd for
C49H64NaO5: 755.4646 [M+Na+]; found: 755.4653.
Scheme 5. Formal total synthesis of (À)-methyleneolactocin.
Acknowledgements
Based on the observed stereochemistry of the product,
a proposed explanation for this diastereoselectivity is depicted
in Figure 1. At the addition step of the acyl radical to the
olefin, effective shielding of one diastereotopic face of alkylide-
nemalonates might be realized by the phenyl group of one
chiral auxiliary, which would explain the low diastereoselectiv-
ity achieved when using 5a’.
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the MEXT (Japan).
Keywords: hydroacylation
reactions · diastereoselectivity · photolysis
· hypervalent iodine · radical
[3] a) Y. Taura, M. Tanaka, X. M. Wu, K. Funakoshi, K. Sakai, Tetrahedron
Int. Ed. 2015, 54, 12492;or recent review, see m) S. K. Murphy, V. M.
Figure 1. Proposed transition state model for explanation of diastereoselec-
tivity.
In summary, we developed a diastereoselective radical hy-
droacylation of chiral alkylidenemalonates with aldehydes in
combination with a hypervalent iodine(III) reagent and UV-
light irradiation. This process represents the first example of di-
astereospecific addition of acyl radicals to olefins for the syn-
thesis of chiral ketones in a highly stereoselective fashion. Fur-
ther application of the present photoreaction of hypervalent
2009, 131, 10872; d) Z.-Q. Rong, Y. Li, G.-Q. Yang, S. L. You, Synlett 2011,
Chem. Eur. J. 2016, 22, 6552 – 6555
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