Generation of organotantalum reagents and conjugate addition to enones

Article abstract of DOI:10.1002/1521-3773(20020415)41:8<1389::AID-ANIE1389>3.0.CO;2-D

A superior method of conjugate allylation: The transmetalation of allyltin compounds with TaCl₅ yielded active tantalum reagents for conjugate addition to enones. Even bulky allyl moieties could be introduced to enones in this manner (see scheme). Both cyclic and acyclic enones reacted facilely under extremely mild conditions.

Full text of DOI:10.1002/1521-3773(20020415)41:8<1389::AID-ANIE1389>3.0.CO;2-D

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[3] K. C. Nicolaou, P. S. Baran, Angew. Chem. 2002, 114, in press; Angew.
Chem. Int. Ed. 2002, 41, in press.
[4] K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, K. Sugita, J. Am. Chem. Soc.,
in press.
[5] K. C. Nicolaou, Y.-L. Zhong, P. B. Baran, Angew. Chem. 2000, 112,
636; Angew. Chem. Int. Ed. 2000, 39, 622; Corrigendum: K. C.
Nicolaou, Y.-L. Zhong, P. B. Baran, Angew. Chem. 2000, 112, 1592;
Angew. Chem. Int. Ed. 2000, 39, 1532.
[6] K. C. Nicolaou, K. Sugita, P. S. Baran, Y.-L. Zhong, J. Am. Chem. Soc.,
in press.
[7] K. C. Nicolaou, P. S. Baran, R. Kranich,Y.-L. Zhong, K. Sugita, N.
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[8] K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, S. Barluenga, K. W. Hunt, R.
Kranich, J. A. Vega, J. Am. Chem. Soc., in press.
[9] a) K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, Angew. Chem. 2000, 112,
636; Angew. Chem. Int. Ed. 2000, 39, 625; b) K. C. Nicolaou, P. S.
Baran, Y.-L. Zhong, J. A. Vega, Angew. Chem. 2000, 112, 2625;
Angew. Chem. Int. Ed. 2000, 39, 2525.
[10] K. C. Nicolaou, T. Montagnon, Y.-L. Zhong, P. S. Baran, J. Am. Chem.
Soc., in press.
Generation of Organotantalum Reagents and
Conjugate Addition to Enones**
Ikuya Shibata,* Takeyoshi Kano, Nobuaki Kanazawa,
Shoji Fukuoka, and Akio Baba*
Organotin compounds are good precursors for generating
active organometallic agents through transmetalation.[1, 2] For
example, active allylic titanium complexes generated from
allylic tin complexes have performed effective allylation of
carbonyl compounds.[1] In contrast, generation and synthetic
use of similar earlytransition metal complexes such as
tantalum reagents[3] have not been reported so far, although
À
Ta C bonds are known to be moderatelyreactive to electro-
philes.[4, 5] We report here on the preparation of active
tantalum reagents bythe transmetalation of organotin com-
pounds with tantalum(v) chloride. Of particular interest is that
certain tantalum reagents promote the conjugate allylation of
enones (Scheme 1).
[11] K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, J. Am. Chem. Soc. 2000, 122,
7596.
[12] K. C. Nicolaou, T. Montagnon, P. S. Baran, Angew. Chem. 2002, 114,
1035; Angew. Chem. Int. Ed. 2002, 41, 993.
TaCl5
[13] K. C. Nicolaou, T. Montagnon, D. L. F. Gray, S. T. Harrison, Angew.
Chem. 2002, 114, 1038; Angew. Chem. Int. Ed. 2002, 41, 996.
[14] A search with SciFinder Scholar uncovered a plethora of current
industrial applications for these iodine oxides; for selected examples,
see: a) U. Hiroto, N. Keiji, O. Katsumi, Patent no. JP 06040710, 1994
[Chem. Abstr. 1994, 120, 326849]; b) T. Ueno, H. Shiraishi, T.
Iwayanagi, S. Nonogaki, J. Electrochem. Soc. 1985, 132, 1168.
[15] Iodic acid is available for about 25 cents per gram from ABCR GmbH
and Co. and iodine pentoxide is available for about 75 cents per gram
from Fluka. Both are also available from Aldrich.
"
"
Ta Nu
Bu3Sn Nu
R2
– Bu3SnCl
R2
R3
R1
"
"
R1
Ta Nu
Nu
O
R3
O
2
1
OMe
,
Ph,
R,
Nu:
R'
O
Scheme 1. Generation of an active tantalum nucleophile complex and
subsequent addition to an enone.
[16] IP is purified as white crystal by sublimation at 2508C: K. Selte, A.
Kjekshus, Acta Chem. Scand. 1968, 22, 3309. There are a number of
papers that deal with the thermal chemistryof these iodine oxides. The
most recent advocates the thermolysis reaction of IP as a ™first
chemistrylesson∫ for school children, which attests to the confidence
that chemists have in its predictable behavior at elevated temper-
atures: J. Kuhmstedt, Prax. Naturwiss. Chem. 1999, 48, 13.
[17] K. Selte, A. Kjekshus, Acta. Chem. Scand. 1970, 24, 1912.
[18] IBX was reported to be explosive under excessive heating and also
upon impact: J. B. Plumb, P. J. Harper, Chem. Eng. News 1990, 68(29),
3; these reports maybe related to the method used to synthesize the
IBX: D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277.
[19] Selected examples: halogenation/dehalogenation: D. L. Boger, Y.
Zhu, J. Org. Chem. 1994, 59, 12; R. J. Heffner, M. M. Joullie, Synth.
Commun. 1991, 21, 2231; DDQ oxidation: J. T. K. Angandi, K. G. S.
Rao, Indian J. Chem. Sect. B 1983, 22, 735; selenium-based reagents:
M. Fukuoka, Chem. Pharm. Bull. 1978, 26, 2365.
[20] The conversion of cyclopentanone into cyclopentenone is considered
to be challenging to industryand prompted www.innocentive.com, an
Eli Lillybusiness venture, to post a $25000 reward for cheap novel
methods for this reaction.
[21] CCDC-176208 (4) contains the supplementarycrystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ,
UK; fax: (‡44)1223-336-033; or deposit@ccdc.cam.ac.uk).
Compared with the direct allylation of carbonyl groups,
little has been reported on the selective conjugate allylation of
enones.[6] The onlychoice for this purpose has been the
Hosomi Sakurai reaction (allylsilane and TiCl4).[7a] Later,
modified reagents such as allylbarium[7b] and allylcopper[7c]
were developed to avoid strong acidic conditions. However,
with these modified reagents the allylation of acyclic enones is
far more difficult than that of cyclic ones. The present system
could be the method of choice for conjugate addition of allylic
[8]
nucleophiles including stericallyhindered ones to enones.
The results of the conjugate allylation of enones, both
acyclic and cyclic substrates, are given in Table 1. Under the
conditions described in the Experimental Section, benzal-
acetone (1a) was allylated to give the conjugate adduct 2a in
91% yield (entry 1, Table 1). The yield decreased to 50%
[*] Dr. I. Shibata, Prof. Dr. A. Baba, T. Kano, N. Kanazawa, S. Fukuoka
Department of Molecular Chemistry& Frontier Research Center
Graduate School of Engineering, Osaka University
2
1 Yamadaoka, Suita, Osaka, 565-0871 (Japan)
Fax : (‡81)6-6879-7387
E-mail: shibata@ap.chem.eng.osaka-u.ac.jp
[**] This work was supported bya Grant-in-Aid for Scientific Research
from the Ministryof Education, Science, Sports, and Culture of the
Japanese Government. We thank Mr. H. Moriguchi, Facultyof
Engineering, Osaka University, for assistance in obtaining mass
spectra.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 8
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Table 1. Conjugate allylation of enones 1 according to Scheme 1 (Nu ˆ
Table 2. Generation of active tantalum reagents ™Ta Nu∫ according to
Scheme 1.[a]
allyl, R3 ˆ E or Z H).[a]
EntryStarting
compound
R1
R2[b]
Solvent Product Yield [%]
EntryNu
Solvent
nBu3SnR
Yield of nBu3SnCl
[equiv]
[%]
1
2
3
4
5
6
7
8
9
1a
Me Ph
Me Ph
Me Ph
Me Ph
CH3CN 2a
91 (50[c]
trace
49
7
99
63
48
63[d]
83
)
1
2
3
4
5
6
allyl
allyl
allyl
allyl
THF
1
1
2
3
2
2
99 (16[b]
99 (99[b]
189
250
76
83
)
)
1a
1a
1a
1b
1c
1d
1e
1 f
1g
1h
CH2Cl2
THF
Et2O
2a
2a
2a
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Ph
Ph
Ph
Ph
Et
Ph
Me
H
CH3CN 2b
CH3CN 2c
CH3CN 2d
PhCH2
ꢀ
PhC C
[a] Yields are from GLC and based on TaCl5. The reactions were carried
out in 1 mL of solvent using TaCl5 (1 mmol) and allyltin at À408C for
30 min. [b] Reaction time of 5 min.
PhMeCH CH3CN 2e
Me
CH3CN 2 f
CH3CN 2g
CH3CN 2h
À
À
10
11
(CH2)2
56
81
À
(CH2)3
À
[a] Conditions: allyltributyltin (2 mmol), TaCl5 (1 mmol), enone
1
The synthetic advantage of this tin tantalum system is the
stabilityand easyavailabilityof various tin precursors.
(1 mmol), solvent (1 mL). [b] Entries 1 9: E isomers; entries 10 and 11:
Z isomers. [c] Allyltin (1 mmol). [d] d.r. ˆ 89:11.
[1, 2]
Thus various groups could be introduced to enones by
conjugate addition [Eq (1), Table 3]. Methallyltri-n-butyltin
gave the corresponding adduct 3a (entry1, Table 3). When g-
substituted allyltin derivatives were used, the addition occur-
red at the g-position selectivelyto give 3b 3 f (entries 2 6).
Besides allylic reagents, benzyltri-n-butyltin, alkynyltri-n-
butyltin derivatives, and a-stannyl esters could be used to
give the conjugate adducts 3g 3k, respectively(entries 7
11). In the case of allenyltri-n-butyltin, the b-propargylated
adduct 3l was obtained (entry12).
when one instead of two equivalents of the allyltin reagent was
used. Acetonitrile is the solvent of choice (see entries 2 4 for
the results with other solvents). Aromatic and aliphatic enones
are similarlyapplicable to this conjugate allylation to give 2b
2h (entries 5 11). In all cases, the 1,2-adduct was not obtained.
The use of allyltrimethylsilane in place of allyltri-n-butyltin
under the identical conditions resulted in lower yield of 2b
(27%), perhaps because TaCl5 does not interact with allylsi-
lane. The reaction of allylmagnesium bromide, TaCl5, and 1b
in THF at À408C afforded only1,2-adduct
(34%). Furthermore, attempted allylation with
Table 3. Conjugate addition of tantalum reagents to enone [Eq (1)].[a]
allyltitanium generated from allyltri-n-butyltin
and TiCl4 did not afford anyproducts. Thus, the
allyltin tantalum system seems to be the one
efficient combination for conjugate allylation.
That the transmetalation of the tin species
with TaCl5 is facile is evident in Table 2. When
equimolar amounts of TaCl5 and allyltri-n-
butyltin were stirred at À408C in THF or
CH3CN for 30 min, quantitative yields of
nBu3SnCl were obtained but the transmetala-
tion is faster in the latter solvent (entries 1 and
2, Table 2). When an excess of allyltin was
used, nBu3SnCl was formed in over 100%
yield based on TaCl5, which indicates that
R1
R2
Nu
R1
R2
"
"
Ta Nu
O
O
1
3
EntryTin precursor
Enone
Product
Yield [%]
54
1
1b
3a
2
3
1b
1 f
R1,R2 ˆ Ph,Ph
R1,R2 ˆ Et,Me
3b
3c
70[b]
79[c]
4
5
1b
1 f
R1,R2 ˆ Ph,Ph
3d
3e
89[d]
97[e]
R1,R2 ˆ Et,Me
À
several Ta Cl bonds are responsible for the
6
7
1b
1b
3 f
3g
83[f]
97
transmetalation (entries 3 and 4). The 119Sn
NMR spectrum confirmed the formation of
nBu3SnCl (d ˆ 123) and complete disappear-
ance of allyltri-n-butyltin (dˆ 20). Unfortunate-
ly, no actual reacting species has been identi-
8
9
1b
1 f
R1,R2 ˆ Ph,Ph
R1,R2 ˆ Et,Me
3h
3i
76
99
1
fied by H NMR spectroscopy, as in the case
for allylic titanium.[1] We observed onlythe com-
pletelydemetalated product, propene. Although
the actual structure of the tantalum species,
whether the allyl ligand is s- or p-bound, is not
10
11
12
1b
1b
1b
3j
3k
3l
57
50
60
clear as yet, the active tantalum species is
[9]
formed bytransmetalation.
In addition to
allyltin, benzyl- and alkynyltin compounds
also reacted to give benzyl- and alkynyltanta-
lum compounds, respectively(entries 5 and 6,
Table 2).
[a] All reactions were carried out in CH3CN (1 mL) using tin compound (2 mmol), TaCl5
(1 mmol), and enone 1 (1 mmol) at À408C for 2 h. [b] d.r. ˆ 56:44. [c] d.r. ˆ 77:23. [d] d.r. ˆ
82:18. [e] d.r. ˆ 69:31. [f] d.r. ˆ 77:23.
1390
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As shown in Scheme 2, even tri-n-butylprenyltin effectively
gave the corresponding products 3m 3p in high yields in
spite of the bulky gem-dimethyl substituents at the g-position.
trapped byMe 3SiCl to form silyl enolate along with the
regeneration of TaCl5.
In conclusion, various tantalum reagents could be gener-
ated from organotin compounds bytransmetalation. In
particular, the system described is more broadly applicable
on the conjugate allylation of enones than conventional
methods.
R1
R2
R2
R3
R1
R3
CH3CN, -40 °C, 2 h
O
SnBu3
TaCl5
+
O
Experimental Section
R1= Ph
R1= Ph
R1= Me
R1= Et
R2= Ph
R2= Me
R2= Ph
R2= Me
R3= H
R3= Me
R3= H
R3= H
92%
82%
56%
90%
3m
3n
3o
3p
Representative procedure of conjugate addition: To a drynitrogen-filled
10-mL round-bottomed flask containing TaCl5 (0.358g, 1 mmol) in MeCN
(1 mL) was added allyltri-n-butyltin (0.662 g, 2 mmol) at À408C. TaCl5 was
partlyinsoluble. The mixture was stirred at À408C for 30 min, before
benzalacetone (1a) (0.146 g, 1 mmol) was added. As the reaction pro-
ceeded, the mixture graduallyturned homogeneous and verypale yellow; a
drastic change in color was not observed. After the mixture had been
stirred at À408C for 2 h, MeOH (2 mL) was added and the volatiles were
removed under reduced pressure. The residue was chromatographed on a
silica-gel column (FL100-DX (Fuji silysia)); eluting with hexane/EtOAc
(3/1) gave conjugate adduct 2a (0.171 g, 91%).
Scheme 2. Conjugate prenylation of enones.
In particular, the product 3n bearing contiguous quaternary
carbon centers could be obtained in 82% yield.[10] We
confirmed that the Sakurai Hosomi reagent, trimethylpre-
nylsilane/TiCl4, under the standard conditions[7] resulted in
lower yields of 3n (11% at À788C. 17% at À408C).
Interestingly, in the competition experiment shown in
Scheme 3, more stericallydemanding prenyltin reacted pre-
dominantlyover allyltin to give 3m.[11]
Received: September 24, 2001
Revised: January21, 2002 [Z17955]
[1] a) G. E. Keck, D. E. Abbott, E. P. Borden, E. J. Enholm, Tetrahedron
Lett. 1984, 25, 3927 3930; b) J. A. Marshall, B. S. DeHoff, J. Org.
Chem. 1986, 51, 863 872; c) Y. Yamamoto, Y. Saito, K. Maruyama, J.
Organomet. Chem. 1985, 292, 311 318; d) Y. Yamamoto, S. Nishii, K.
Maruyama, T. Komatsu, W. Ito, J. Am. Chem. Soc. 1986, 108, 7778
7786; e) Y. Yamamoto, N. Maeda, K. Maruyama, J. Chem. Soc. Chem.
Commun. 1985, 1429 1431; f) D. Hoppe in Stereoselective Synthesis,
Vol. 3 (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schau-
mann), Georg Thieme, Stuttgart, 1996, chap. 1.3.3.8, pp. 1551 1583.
[2] Allyltri-n-butyltin is a good precursor of active allylic metal com-
plexes containing, for example, boron,[2a] tin,[2b] and indium.[2c] a) Y.
Tanigawa, I. Moritani, S. Nishida, J. Organomet. Chem. 1971, 28, 73
79; G. Hagen, H. Mayr, J. Am. Chem. Soc. 1991, 113, 4954 4961; D.
Marton, G. Tagliavini, M. Zordan, J. L. Wardell, J. Organomet. Chem.
1990, 390, 127 138; P. Harston, J. L. Wardell, D. Marton, G.
Tagliavini, P. J. Smith, Inorg. Chim. Acta 1989, 162, 245 250; E. J.
Corey, S. S. Kim, Tetrahedron Lett. 1990, 31, 3715 3718; b) G. E.
Keck, D. E. Abbott, Tetrahedron Lett. 1984, 25, 1883 1886; S. E.
Denmark, T. M. Wilson, T. M. Willson, J. Am. Chem. Soc. 1988, 110,
984 986; S. E. Denmark, E. J. Weber, T. M. Wilson, T. M. Willson,
Tetrahedron 1989, 45, 1053 1065; G. E. Keck, M. B. Andrus, S.
Castellino, J. Am. Chem. Soc. 1989, 111, 8136 8141; c) J. A. Marshall,
K. W. Hinkle, J. Org. Chem. 1995, 60, 1920 1921; T. Miyai, K. Inoue,
M. Yasuda, A. Baba, Synlett 1997, 699 700.
SnBu3
(1 mmol)
SnBu3
(1 mmol)
TaCl5
+
+
(2 mmol)
Ph
Ph
Ph
Ph
+
Ph
Ph
O
(1 mmol)
1b
O
O
CH3CN, –40 °C, 0.5 h
74%
26%
3m
2b
Scheme 3. Competition experiment between conjugate prenylation and
allylation.
In all cases discussed above, the required molar ratio of
TaCl5 to the allylic tin reagent was 1:2. However, we found
that addition of an equimolar amount of trimethylsilyl
chloride (Me3SiCl) enabled the catalytic use of TaCl5
(Scheme 4). Careful isolation afforded the conjugate adducts
as silyl enolates, which were converted to 2b, 3d, and 3m by
simple protonolysis. As a tentative catalytic cycle, it can be
assumed that the conjugate adduct, tantalum enolate, is
[3] For example, J. A. Labinger in Comprehensive Organometallic
Chemistry, Vol. 3 (Eds.: G. Wilkinson, F. G. A. Stone, E. W. Abel),
Pergamon, Oxford, 1982, pp. 705 782.
Ph
Ph
TaCl5 (20 mol%)
[4] Y. Kataoka, J. Miyai, K. Oshima, K. Takai, K. Utimoto, J. Org. Chem.
1992, 57, 1973 1981; Y. Kataoka, M. Tezuka, K. Takai, K. Utimoto,
Tetrahedron 1992, 48, 3495 3502; Y. Kataoka, Y. Oguchi, K.
Yoshizumi, S. Miwatashi, K. Takai, K. Utimoto, Bull. Chem. Soc.
Jpn. 1992, 65, 1543 1549.
+
+
Me3SiCl
(1 mmol)
Bu3Sn Nu
(1 mmol)
CH3CN, –40 °C, 2 h
O
1b (1 mmol)
Ph
Ph
Ph
Me3SiO Nu
Ph
[5] h3-Allylniobium and -tantalum are isolated as stable complexes, which
allylate aldehydes at elevated temperature. H. Yasuda, T. Arai, T.
Okamoto, A. Nakamura, J. Organomet. Chem. 1989, 361, 161 171.
[6] Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207 2293; W. R. Roush
in Comprehensive Organic Synthesis, Vol. 2 (Eds.: B. M. Trost, I.
Fleming, C. H. Heathcock), Pergamon, Oxford, 1991, chap. 1.1, pp. 1
53.
[7] a) A. Hosomi, H. Sakurai, J. Am. Chem. Soc. 1977, 99, 1673; I.
Fleming, J. Dunogues, R. Smithers, Org. React. 1989, 37, 57 575; H.
Sakurai, A. Hosomi, J. Hayashi, Org. Synth. Collect. Vol. 1990, 7, 443;
b) A. Yanagisawa, S. Habaue, K. Yasue, H. Yamamoto, J. Am. Chem.
Nu
O
Nu:
2b: 99%
Ph
3d: 82%
3m: 72%
Scheme 4. Catalytic version of the TaCl5-mediated conjugate addition.
Angew. Chem. Int. Ed. 2002, 41, No. 8
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1391

COMMUNICATIONS
Soc. 1994, 116, 6130 6141; c) B. H. Lipshutz, E. L. Ellsworth, S. H.
Dimock, R. A. J. Smith, J. Am. Chem. Soc. 1990, 112, 4404 4410;
B. H. Lipshutz, C. Hackmann, J. Org. Chem. 1994, 59, 7437 7444;
D. E. Stack, W. R. Klein, R. D. Rieke, Tetrahedron Lett. 1993, 34,
3063 3066.
3
6
1
O
O
O
10
O
11'
O
O
O
[8] TaCl5 has scarcelybeen used in organic synthesis. a) J. Howarth, K.
Gillespie, Tetrahedron Lett. 1996, 37, 6011 6012; b) H. Maeta, T.
Nagasawa, Y. Handa, T. Takei, Y. Osamura, K. Suzuki, Tetrahedron
Lett. 1995, 36, 899 902; c) K. Suzuki, T. Hashimoto, H. Maeta, T.
Matsumoto, Synlett 1992, 125 128; d) T. Hashimoto, H. Maeta, T.
Matsumoto, M. Morooka, S. Ohba, K. Suzuki, Synlett 1992, 340 342.
[9] There is a possibilitythat low-valent tantalum species are involved in
the reaction; however, the reaction mixture did not displaysignificant
color.
1'
6'
3'
Me2N
18
1 : pamamycin-607
OH
O
[10] There are few examples of the conjugate prenylsilylation of enones
with TiCl4: ref. [2a] and R. L. Danheiser, D. M. Fink, Tetrahedron Lett.
1985, 26, 2509 2512.
HO2C
OTBS
O
HO
+
O
[11] Although we have no further information as yet, this order of
reactivitystronglyindicates an electron transfer mechanism. J. Otera,
Y. Fujita, N. Sakuta, M. Fujita, S. Fukuzumi, J. Org. Chem. 1996, 61,
2951 2962.
3
2
N3
Scheme 1.
proposed as the intermediates. Construction of the double
bonds in 9 and 21 was planned bymeans of a sulfone
olefination[14] and the Horner Emmons reaction. The C2
methyl group could be installed by the cuprate epoxide
opening of 23 (see Scheme 4), in which the regioselectivity
was assumed to be dictated bythe bulkysubstituent. In
addition, while the adjacent hydroxyl and methyl functional
groups of 9 were expected to be delivered from the known
alcohol 4 (Scheme 2),[15] those of 21 would be transformed by
a Paterson[16] aldol reaction and Evans anti reduction.[17]
To prepare the bottom subunit 2, alcohol 4 (78% de) was
consecutively subjected to silylation, hydroboration, Mitsu-
nobu reaction, and mCPBA oxidation to afford sulfone 5
(Scheme 2). The requisite aldehyde 8 (the coupling partner of
5) was obtained from the known diol 6[18] bya sequence of
benzylidene formation, DIBAH reduction,[19] and Swern
Total Synthesis of (‡)-Pamamycin-607**
Sung Ho Kang,* Joon Won Jeong, Yu Sang Hwang, and
Sung Bae Lee
The pamamycins are a novel family of naturally occurring
homologous macrodiolides, which are found in Streptomy-
9]
ces sp.[1 Theyinduce the aerial mcyelium formation in
[1
S. alboniger to displayautoregulatoryactivity.
3]. Theyalso
exhibit antibiotic activityagainst Gram-positive bacteria and
pathogenic fungi,[1,2] inhibit myosin light chain kinase,[5] and
mediate hydrophilic ion transport through lipophilic phases.[6]
[7]
7]
In addition, theyshow vasodilating, anionophoric,[2 pro-
tonophoric,[8] and autolytic properties.[9] A major component
of the familyis pamamycin-607 ( 1), which has a molecular
weight of 607. While the structure and relative stereochem-
istryof pamamycin-607 were elucidated byNMR spectro-
scopy, its absolute stereochemistry was later determined by a
OH
TESO
N
S
OTBS
a-d
h
SO2
OTBS
5
4
[10]
correlation study. The remarkable biological activityof
OBn
OH
pamamycin-607 and its unique structural features led us to
choose 1 as a synthetic target.[11] Herein we report an
asymmetric total synthesis of 1.
TESO
OTBS
OTBS
O
i-k
H
The two ester linkages of 1 were disconnected byretro-
synthetic analysis to provide alcohol 2 and carboxylic acid 3 as
the precursors of the C1' C11' and C1 C18 subunits,
respectively(Scheme 1). As we envisaged that the three cis-
2,5-disubstituted tetrahydrofurans comprising 2 and 3 could
be formed[12] byiodoetherification of g-triethylsilyloxyal-
kenes,[13] 9 (see Scheme 2) and 21 (see Scheme 3) were
2
9
OR
OBn
g
O
OH
8
6 : R=H
7 : R=Bn
e,f
Scheme 2. a) TESCl, imidazole, DMF, RT, 83% of desired diastereomer;
b) H3B ¥ SMe2, THF, RT, then aqueous NaOH, H2O2, RT, 85% ; c) Ph3P,
2-mercaptobenzothiazole, DEAD, THF, 08C !RT, 87 %; d) mCPBA,
CH2Cl2, RT, 90%; e) TsOH, PhCHO, PhMe, reflux (ÀH2O), 94%;
f) DIBAH, PhMe, 08C, 88% for 7; g) Swern oxidation; h) LiHMDS,
THF, À788C, then 8, RT, 80%; i) I2, Ag2CO3, Et2O, RT, 92 %; j) Ph3SnH,
Et3B, THF, 08C, 90%; k) H2, 10% Pd/C, MeOH, RT, 99%. TES ˆ tri-
ethylsilyl, DMF ˆ N,N-dimethylformamide, DEAD ˆ diethyl azodicarbox-
ylate, mCPBA ˆ 3-chloroperoxybenzoic acid, Ts ˆ toluenesulfonyl,
DIBAH ˆ diisobutylaluminum hydride, LiHMDS ˆ lithium bis(trimethyl-
silyl)amide.
[*] Prof. Dr. S. H. Kang, J. W. Jeong, Yu. S. Hwang, S. B. Lee
Center for Molecular Design and Synthesis
Department of Chemistry, School of Molecular Science
Korea Advanced Institute of Science and Technology, Taejon 305-701
(Korea)
Fax : (‡82)42-869-2810
E-mail: shkang@kaist.ac.kr
[**] This work was supported byC.M.D.S. and the Brain Korea 21 Project.
1392
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4108-1392 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 8