Scheme 1. Ti-Mediated Aldol Reaction of Lactyl-Bearing Chiral Oxazolidin-2-one
molecule. Generally, Sharpless asymmetric dihydroxylation
from five component parts: phosphonate 3,6 lactyl derivative
4, aldehyde 5, iodide 6, and boronate 7. We planned that
each of these five fragments would be assembled as follows:
of (Z)-trisubstituted alkenes gives anti-1,2-diols in low
j
enantioselectivity. In fact, Kuwajima and Omura adopted a
stepwise approach to construct the anti relationship of the
C4-C5 asymmetric centers of 2 instead of asymmetric
dihydroxylation.
C2-C3 by Horner-Wadsworth-Emmons (HWE) reaction
2a,c
j
(as reported by Kuwajima and Omura),
C4-C5 by Ti-
mediated aldol reaction, and C7-C8 and C13-C14 by Pd-
catalyzed coupling reactions. In this modular approach, the
order of fragment assembly is crucial, especially for the
C4-C5 bond formation. The reactivity and stereoselectivity
of the aldol reaction forming the C4-C5 bond is likely to
be highly dependent on the substituent X of 5 at C7. We
initially investigated the Ti-mediated aldol reaction of lactyl
derivative 4 with various unsaturated aldehydes.
The results of the Ti-mediated aldol reaction are sum-
marized in Table 1. We planned the aldol reaction to be
conducted at a late stage after Pd-catalyzed C-C bond
formation at C7-C8. Thus, we first attempted the aldol
reaction with (2E,4E)-hexa-2,4-dienal7 as a model compound
(entry 1). Unfortunately, the reaction with dienal gave aldol
product in only moderate yield with unsatisfactory selectivity.
Next, we surveyed aldehydes that gave aldol products
suitable for Pd-catalyzed coupling reactions. Although 3-(tri-
methylsilyl)-propynal8 (entry 2) and (E)-3-iodopropenal9
(entry 3) were not good substrates, aldol reaction of (E)-3-
(tributylstannyl)propenal10 (entry 4) predominantly gave the
desired anti-aldol product (>20:1)11 in high yield. We
postulated that the electronic and steric effect of the
We previously reported a novel methodology for the
stereoselective construction of 1,2-diols,3,4 including second-
ary and tertiary alcohols, by a Ti-mediated aldol reaction of
lactyl-bearing chiral oxazolidin-2-one5 (Scheme 1). Thus, the
protecting group of the alcohol in the lactyl moiety (Bn or
TBS) controls the stereochemistry of lithium enolate, result-
ing in the stereoselective formation of an anti- or syn-diol
derivative through chelation-controlled Zimmerman-Traxler-
type transition states. We reasoned that the anti-1,2-diol unit
of 2 could be effectively constructed by using our methodol-
ogy. Herein, we describe a highly convergent and efficient
total synthesis of (+)-2 which illustrates the capability of
our novel synthetic approach.
Our synthetic strategy is depicted in Figure 2. Inspection
of the nafuredin-γ molecule suggests it can be synthesized
(3) (a) Kamino, K.; Murata, Y.; Kawai, N.; Hosokawa, S.; Kobayashi,
S. Tetrahedron Lett. 2001, 42, 5249–5252. (b) Murata, Y.; Kamino, K.;
Hosokawa, S.; Kobayashi, S. Tetrahedron Lett. 2002, 43, 8121–8123.
(4) For recent examples, see: (a) Crimmins, M. T.; Shamszad, M.;
Mattson, A. E. Org. Lett. 2010, 12, 2614–2617. (b) Ohtani, T.; Tsukamoto,
S.; Kanda, H.; Misawa, K.; Urakawa, Y.; Fujimaki, T.; Imoto, M.;
Takahashi, Y.; Takahashi, D.; Toshima, K. Org. Lett. 2010, 12, 5068–5071.
(5) Davies, S. G.; Sanganee, H. J.; Szolcsanyi, P. Tetrahedron 1999,
55, 3337–3354.
(6) Nakamura, E. Tetrahedron Lett. 1981, 22, 663–666.
(7) (2E,4E)-Hexa-2,4-dienal was prepared from ethyl sorbate through
DIBAL reduction followed by MnO2 oxidation.
(8) Velcicky, J.; Lanver, A.; Lex, J.; Prokop, A.; Wieder, T.; Schmalz,
H. G. Chem.sEur. J. 2004, 10, 5087–5110.
(9) (a) Marek, I.; Meyer, C.; Normant, J. F. Org. Synth., Coll. 1998, 9,
510–515. (b) Trost, B. M.; Frederiksen, M. U.; Papillon, J. P. N.; Harrington,
P. E.; Shin, S.; Shireman, B. T. J. Am. Chem. Soc. 2005, 127, 3666–3667.
Figure 2. Synthetic strategy toward (+)-nafuredin-γ.
Org. Lett., Vol. 13, No. 1, 2011
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