New method for the synthesis of α-substituted tetrahydrofuran -2-methanols through diastereoselective addition of THF to aldehydes mediated by Et3B in the presence of air

Article abstract of DOI:10.1039/a904745j

The tetrahydrofuranyl radical, generated from THF with Et₃B in the presence of air, was found to react with aldehydes threo-selectively to afford α-substituted tetrahydrofuran-2-methanols, the common structural motifs of biologically active ace

Full text of DOI:10.1039/a904745j

New method for the synthesis of a-substituted tetrahydrofuran-2-methanols
through diastereoselective addition of THF to aldehydes mediated by Et3B in
the presence of air
Takehiko Yoshimitsu,* Maki Tsunoda and Hiroto Nagaoka*
Meiji Pharmaceutical University, Noshio, Kiyose, Tokyo 204-8588, Japan. E-mail: takey@my-pharm.ac.jp
Received (in Cambridge, UK) 14th June 1999, Accepted 26th July 1999
The tetrahydrofuranyl radical, generated from THF with
Et3B in the presence of air, was found to react with
aldehydes threo-selectively to afford a-substituted tetra-
hydrofuran-2-methanols, the common structural motifs of
biologically active acetogenin polyketides, in moderate
yields.
radical addition of THF to aldehydes to give threo-a-substituted
tetrahydrofuran-2-methanols 1 stereoselectively is presented in
this paper for the first time.8
The results of the addition of THF to 4-methoxybenzalde-
hyde 4a, mediated by Et3B either in the presence or absence of
air at room temperature, are listed in Table 1.†‡
The radical reaction in the presence of air, which is necessary
for radical initiation,7,9 proceeded threo-selectively (ca. 90+10)
to afford alcohols (1a and 2a) along with unchanged aldehyde
4a. It should be emphasized that the continuous admission of air
greatly enhanced the efficiency of the reaction. The chemical
yield was also increased by additional amounts of reagents, but
it was not significantly improved by prolonged reaction time. Its
a-Substituted tetrahydrofuran-2-methanols 1 and 2 are common
structural units present in acetogenins that possess important
biological properties, such as antineoplastic and immunosup-
pressive activity.1 Numerous attempts have thus been made to
Table 1 Radical reaction of THF with 4-methoxybenzaldehyde 4aa
Reagents/equiv.
elaborate these structural units,2–4 but the direct addition of
tetrahydrofuranyl synthons to aldehydes is a rare case of a
carbon–carbon bond-forming reaction in the convergent synthe-
sis of acetogenins.5,6 The authors have accordingly established
a new method for the stereoselective synthesis of 1 through the
addition of tetrahydrofuranyl radical 3 generated from THF
with Et3B in the presence of air7 to aldehydes 4, thereby
facilitating the construction of core structural motifs of
acetogenins (Scheme 1). To the best of our knowledge, the
Entry
Et3B
THF
t/h
Yield (%)f
1a+2ag
1b
3
3
3
1
3
31
31
31
10
31
12
36
12
12
12
42 (37)
44 (38)
4 (81)
11 (70)
1 (99)
91+9
2b
90+10
88+12
90+10
93+7
3c
4bd
5be
a
Unless otherwise stated, aldehyde (1.0 mmol) and 1.0 M THF solution
of Et3B (3.0 ml) were used. b Air was introduced through a syringe needle
with a balloon (ca. 10–20 ml h21). The reaction was carried out under
c
d
argon. Aldehyde (1.0 mmol) and 1.0 M THF solution of Et3B (1.0 ml)
e
f
were used Galvinoxyl (0.3 equiv.) added. Isolated yields: yields of
recovered aldehyde 4a are given in parentheses. g Ratio determined from the
1H NMR spectrum of the diastereomeric mixture.
Scheme 1
Table 2 Radical reaction of THF with aldehydes 4a
Reagents/equiv.
Entry
Et3B
THF
t/h
4
R
Yield (%)b
1+2c
1
2
3
4
5
6
3
3
3
3
3
3
31
31
31
31
31
31
12
17
12
12
12
12
4a
4b
4c
4d
4e
4f
4-MeOC6H4
1,3-benzodioxol-5-yl
Ph
2-BrC6H4
C12H25
42 (37)
47 (38)
44 (21)
45 (20)
37 (—)d
32 (—)d
91+9
89+11
85+15
71+29
62+38
54+46e
c-C6H11
a
Aldehydes (1.0 mmol) and 1.0 M THF solution of Et3B (3.0 ml) were used. Air was introduced through a syringe needle with a balloon (ca. 10–20 ml
h21). b Isolated yields: yields of recovered aldehydes 4 are given in parentheses.c Ratio determined from the 1H NMR spectrum of the diastereomeric mixture
or based on isolated yields of the corresponding acetates derived from the crude products. d Unreacted aldehyde 4 was not recovered. e Stereochemistry of
the major isomer yet to be determined.
Chem. Commun., 1999, 1745–1746
1745

‡ The relative configuration of the major adducts 1 was unambiguously
determined by comparison of 1H NMR spectral data with those of authentic
threo-alcohols prepared by dihydroxylation of (E)-allyl tosylate 5.
§ Satisfactory analytical (high-resolution mass) and spectral (IR, 1H NMR,
and MS) data were obtained for new compounds.
1 F. Q. Alali, X.-X. Liu and J. T. McLaughlin, J. Nat. Prod., 1999, 62,
504; A. Cave, B. Figadere, A. Laureno and D. Cortes, in Progress in the
Chemistry of Natural Products, ed. W. Hery, G. W. Kirby, R. E. Moore,
W. Steglich and C. Tamm, Springer, New York, 1997, vol. 70, p. 81; L.
Zeng, Q. Ye, N. H. Oberlies, G. Shi, Z.-M. Gu, K.He and J. L.
McLaughlin, Nat. Prod. Rep., 1996, 275.
Scheme 2
2 B. Figadere and A. Cave, in Studies in Natural Products Chemistry, ed.
Atta-ur-Rahman, Elsevier, Amsterdam, 1996, vol. 18, p. 193; B.
Figadere, Acc. Chem. Res., 1995, 28, 359; U. Koert, Synthesis, 1995,
115; R. Hoppe and H.-D. Scharf, Synthesis, 1995, 1447.
inhibition by radical inhibitors such as galvinoxyl10 clearly
indicated that the reaction proceeds via a radical mechanism
(entry 5 in Table 1). The radical reaction was also applied to
representative aldehydes 4b–f.
Table 2 demonstrates the general applicability of the present
method to various aldehydes, though in only moderate yields.11
The threo-selectivity of the addition was generally high for
aromatic aldehydes, and low to moderate in the cases of
aliphatic and ortho-substituted aromatic aldehydes (entries 4, 5
and 6 in Table 2).§ The reasons for the stereochemical outcome
remain unclear but a transition state (III) in which boron atoms
tether radical 3 to aldehydes 4 may be reasonably assumed
(Scheme 2).12
In summary, a new method has been established for the
stereoselective synthesis of threo-a-substituted tetrahydro-
furan-2-methanols 1 by addition of tetrahydrofuranyl radical 3,
generated from THF with Et3B in the presence of air, to
aldehydes 4. This method is quite easy to conduct and readily
provides access to common structural motifs of biologically
important acetogenins. It may thus be considered a superior
means for the synthesis of these natural products. The
mechanism of the reaction and potential applications to total
synthesis of acetogenins are presently under investigation.
3 Recent syntheses (after 1998); Z. Ruan and D. R. Mootoo, Tetrahedron
Lett., 1999, 40, 49; S.-T. Jan, K. Li, S. Vig, A. Rudolph and F. M.
Uckun, Tetrahedron Lett., 1999, 40, 193; S. Takahashi and T. Nakata,
Tetrahedron Lett., 1999, 40, 723; Y. Mori, T. Sawada and H. Furukawa,
Tetrahedron Lett., 1999, 40, 731; L. Lemee, A. Jegou and A. Veyrieres,
Tetrahedron Lett., 1999, 40, 2761; P. Li, J. Yang and K. Zhao, J. Org.
Chem., 1999, 64, 2259; A. Sinha, S. C. Sinha, S. C. Sinha and E. Keinan,
J. Org. Chem., 1999, 64, 2381; Q. Yu, Z.-J. Yao, X.-G. Chen and Y.-L.
Wu, J. Org.Chem., 1999, 64, 2440; S. Hanessian and T. A. Grillo,
J. Org. Chem., 1998, 63, 1049; H. Zang, M. Seepersaud, S. Seepersaud
and D. R. Mootoo, J. Org. Chem., 1998, 63, 2049; S. E. Schaus, J.
Branat and E. N. Jacobsen, J. Org. Chem., 1998, 63, 4876; J. A.
Marshall and H. Jiang, J. Org. Chem., 1998, 63, 7066.
4 J. B. Gale, J.-G. Yu, X. E. Hu, A. Khare, D. K. Ho and J. M. Cassady,
Tetrahedron Lett., 1993, 34, 5847; Y. Morimoto and T. Iwai, J. Am.
Chem. Soc., 1998, 120, 1633; F. E. McDonald, T. B. Towne and C. C.
Schultz, Pure Appl. Chem., 1998, 70, 355; M. Champdore, M. Lasalvia
and V. Piccialli, Tetrahedron Lett., 1998, 39, 9781.
5 F. Zanardi, L. Battistini, G. Rassu, L. Pinna, M. Mor, N. Culeddn and G.
Casiraghi, J. Org. Chem., 1998, 63, 1368; B. Figadere, J.-F. Peyrat and
A. Care, J. Org. Chem., 1997, 62, 3428.
6 T. Cohen and M.-T. Lin, J. Am. Chem. Soc., 1984, 106, 1130.
7 Precedents of the reaction of tetrahydrofuranyl radical with olefins;
H. C. Brown and M. M. Midland, Angew. Chem., Int. Ed. Engl., 1972,
11, 692; A. J. Clark, S. Rooke, T. J. Sparey and P. C. Tayler,
Tetrahedron Lett., 1996, 37, 909.
8 A ketone–THF coupling reaction, mediated by SmI2 and iodobenzene,
has been reported; H. B. Kagan, J. L. Namy and P. Girard, Tetrahedron
Suppl. No. 1, 1981, 37, 175; J. Inanaga, M. Ishikawa and M. Yamaguchi,
Chem. Lett., 1987, 1485.
9 A. Suzuki, J. Synth. Org. Chem. Jpn., 1971, 29, 995.
10 G. W. Kabalka, H. C. Brown, A. Suzuki, S. Honma, A. Arase and M.
Itoh, J. Am. Chem. Soc., 1970, 92, 710.
Notes and references
† Representative procedure: To 4-methoxybenzaldehyde 4a (136 mg, 1.0
mmol) was added 1.0 M Et3B in THF (3.0 ml, 3.0 mmol) at room
temperature. The mixture was stirred at the same temperature with
continuous bubbling of air through a syringe needle with a balloon (flow
rate; 10–20 ml h21) for 12 h. The mixture was treated with AcOH and then
extracted with CH2Cl2, and washed with sat. NaHCO3. The organics were
dried over MgSO4. Following solvent evaporation, the residue was purified
by column chromatography on silica gel (EtOAc–hexane 1+2) to afford a
colorless solid consisting of a-(4-methoxyphenyl)tetrahydrofuran-2-metha-
nols (88 mg, 42%) as a diastereomixture (1a+2a = 91+9) and unreacted
aldehyde 4a (51 mg, 37%).
11 Yields not yet optimized.
12 A recent report on multiple roles of Et3B as radical initiator and Lewis
acid: H. Miyabe, M. Ueda, N. Yoshioka and T. Naito, Synlett, 1999,
465.
Communication 9/04745J
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Chem. Commun., 1999, 1745–1746