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Desymmetrization of Metalated Cyclohexadienes and Application to the Synthesis of Nephrosteranic Acid.

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Angewandte
Chemie
Asymmetric Synthesis
Desymmetrization of Metalated Cyclohexadienes
and Application to the Synthesis of
Nephrosteranic Acid**
Florian Schleth and Armido Studer*
The stereoselective nucleophilic addition of allylmetal compounds to carbonyl compounds is a very important C C
bond-forming reaction in modern organic synthesis.[1] Si,[2]
Sn,[3] B,[4] Li,[5] and Ti allyl compounds[6] have been used
successfully in asymmetric allylations. To the best of our
knowledge, no reports on the stereoselective allylation of
[*] Dipl.-Chem. F. Schleth, Prof. Dr. A. Studer
Fachbereich Chemie der Universit t
Hans-Meerwein-Strasse
35032 Marburg (Germany)
Fax: (+ 49) 6421-2825629
E-mail: studer@mailer.uni-marburg.de
[**] We thank the Deutsche Forschungsgemeinschaft (DFG) for support
and Dr. Klaus Harms for the X-ray structure analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 313 –315
DOI: 10.1002/anie.200352254
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
313
Communications
carbonyl compounds using metalated cyclohexadienes
[Eq. (1)] have appeared to date. A big challenge is the
differentiation of the two enantiotopic double bonds (desymmetrization of the 1,4-cyclohexadiene).[7] The face selectivity
Encouraged by these first results, we examined the
differentiation of the enantiotopic double bonds in cyclohexadienyl Ti compounds. Duthaler et al. have successfully
used TADDOL-derived[11] allyltitanium complexes for highly
enantioselective allylations.[12] In analogy, we prepared the
chiral cyclohexadienyltitanium complex 7. The reaction of 7
with benzaldehyde (THF, 78 8C) occurred with excellent
diastereoselectivity (syn/anti > 99:1). Furthermore, promising enantioselectivity was measured (e.r. 91:9, chiral GC),
however, syn-4 a was formed in low yield (19 %). Most likely
some decomposition of 7 occurred at 78 8C. Indeed, the
same reaction at lower temperature ( 100 to 110 8C, THF/
Et2O) provided syn-4 a in 83 % yield (syn/anti > 99:1) with
high enantioselectivity (e.r. 98:2, Table 1, entry 1).
Table 1: Reaction of 7 with various aldehydes.
of the electrophilic attack can probably be controlled by the
metal (open versus cyclic transition state). Another problem
to be solved is the control of the diastereoselectivity.
Furthermore, metallotropic 1,3-shifts have to be considered.[1]
Herein we describe our first results on the use of metalated
cyclohexadienes in highly stereoselective allylation reactions.
In addition we present a first application in a highly efficient
synthesis of nephrosteranic acid.
The reaction of benzaldehyde with various metalated
cyclohexadienes was studied first (Scheme 1). With silylated
Entry
R
Product
Yield [%]
d.r.
(syn/anti)
e.r.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
4-Me-Ph
4-MeO-Ph
4-Br-Ph
3-MeO-Ph
2-MeO-Ph
2-Me-Ph
2-Br-Ph
a-naphthyl
b-naphthyl
furyl
PhCH=CH
PhCC
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
83
82
63
94
58
61
56
92
96
81
72
93
86
40[d]
> 99:1[a]
> 99:1[a]
> 99:1[b]
> 99:1[a]
> 99:1[a]
> 99:1[a]
> 99:1[a]
> 99:1[c]
> 99:1[b]
> 99:1[b]
98:2[a]
> 99:1[b]
> 99:1[b]
> 99:1[a]
98:2[a]
95:5[a]
> 99:1[b]
97:3[a]
97:3[b]
> 99:1[a]
96:4[a]
> 99:1[c]
> 99:1[b]
90:10[b]
93:7[b]
90:10[b]
99:1[b]
91:9[e]
[a] Ratio determined by GC analysis. [b] Ratio determined by HPLC
analysis. [c] Determined after transformation to 4 a (tBuLi, THF, 78 8C;
H2O) by GC analysis. [d] The 1,4-diene 5 n was formed as a side product
and could not be removed (4 n/5 n 88:12). [e] Determined after oxidation
to (1R)-1-phenylpropanol by GC analysis.
Scheme 1. The reaction of cyclohexadienylmetalates with aldehydes
(only one enantiomer is shown).
cyclohexadiene 1[8] and stannylated diene 2 only low diastereoselectivities (< 3:1) were obtained in the presence of
different Lewis acids. In contrast, the reaction of the Ti
compound 3 with benzaldehyde at 78 8C occurred in
excellent yield and with high selectivity (99 %, syn/anti
9:1).[9, 10] The syn selectivity can be rationalized by considering
a six-membered chair transition state 6, in which the R group
of the aldehyde assumes a pseudo equatorial position .[1]
314
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
The reactions with para-, meta-, and ortho-substituted
benzaldehyde derivatives occurred with excellent diastereoselectivity and high enantioselectivity (products 4 b–h,
entries 2–8). a-Naphthaldehyde and phenylpropargyl aldehyde reacted with complete stereoselectivity, whereas furfural, b-naphthaldehyde, and cinnamaldehyde provided lower
but still good enantioselectivity and excellent diastereoselectivity (products 4 i–m, entries 9–13). Addition to propanal
occurred with high diastereo- but lower enantioselectivity
(entry 14), and the 1,4-diene 5 n formed as a side product. The
absolute configuration of the major isomers of all the new
compounds was assigned based on the rearomatization of 4 n
(Pd(OAc)2/Cu(OAc)2, MeOH) to provide (R)-1-phenylpropanol (e.r. 91:9). In analogy to the results of Duthaler et al.
addition of 7 occurs onto the Si face of the aldehyde.
Finally, our new method was applied to the synthesis of
nephrosteranic acid.[13] Reaction of 7 with dodecanal afforded
4 o (Scheme 1, R = C11H23, 79 %, syn/anti > 99:1).[14] Double
dihydroxylation under Upjohn conditions[15] provided the
corresponding pentol, which was directly subjected to diol
cleavage (NaIO4, THF/H2O) to give lactol 8 (Scheme 2).
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 313 –315
Angewandte
Chemie
Scheme 2. Synthesis of nephrosteranic acid: a) OsO4 (2 %), NMO
(3.5 equiv), acetone/H2O (4:1); b) NaIO4 (3 equiv), THF/H2O (1:1);
c) CrO3/H2SO4, acetone; d) NaHMDS, MeI, THF. HMDS = hexamethyldisilazane, NMO = N-methylmorpholine N-oxide.
Crude 8 was oxidized under Jones conditions to g-butyrolactone 9 (19 % yield over three steps). Methylation according to
a literature procedure[13d] afforded scalemic nephrosteranic
[13a]
acid (60 %, [a]25
[a]25
D = + 22.7 (c = 0.78 in CHCl3); lit.
D =
+ 27.2 (c = 1.45 in CHCl3)).
In conclusion, the easily prepared chiral cyclohexadienyltitanate 7 reacts with aldehydes in highly diastereo- and
enantioselective allylations. The resulting functionalized 1,3cyclohexadienes are highly useful building blocks for the
preparation of biologically important g-butyrolactones, as
documented by a short efficient synthesis of nephrosteranic
acid.
Received: June 30, 2003
Revised: September 22, 2003 [Z52254]
.
Keywords: asymmetric synthesis · natural products · synthetic
methods · TADDOLs · titanium · total synthesis
[1] Houben-Weyl, Vol. E21b (Eds.: G. Helmchen, R. W. Hoffmann,
J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1995, pp. 1357 –
1602; Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207.
[2] I. Fleming, A. Barbero, D. Walter, Chem. Rev. 1997, 97, 2063;
“Allylsilanes”: E. J. Thomas in Houben-Weyl, Vol. E21b (Eds.:
G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann),
Thieme, Stuttgart, 1995, p. 1491.
[3] “Allylstannanes”: E. J. Thomas in Houben-Weyl, Vol. E21bG
(Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1995, p. 1508; selected examples: M.
Kurosu, M. Lorca, Tetrahedron Lett. 2002, 43, 1765, and
references therein; C.-M. Yu, J.-Y. Lee, B. So, J. Hong, Angew.
Chem. 2002, 114, 169; Angew. Chem. Int. Ed. 2002, 41, 161, and
references therein.
Angew. Chem. Int. Ed. 2004, 43, 313 –315
[4] “Allylboron Reagents”: W. R. Roush in Houben-Weyl,
Vol. E21b (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E.
Schaumann), Thieme, Stuttgart, 1995, p. 1410; W. R. Roush, S.
Chemler in Modern Carbonyl Chemistry (Ed.: J. Otera), WileyVCH, Weinheim, 2000, p. 403.
[5] D. Hoppe, T. Hense, Angew. Chem. 1997, 109, 2376; Angew.
Chem. Int. Ed. Engl. 1997, 36, 2282.
[6] a) D. Seebach, B. Weidmann, L. Widler, Mod. Synth. Methods
1983, 3, 217; b) M. T. Reetz, Organotitanium Reagents in
Organic Synthesis, Springer, Berlin, 1986; c) “Allyltitanium and
Allylzirconium Reagents”: D. Hoppe in Houben-Weyl,
Vol. E21b (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E.
Schaumann), Thieme, Stuttgart, 1995, p. 1551.
[7] For stereoselective dihydroxylations of silylated 1,4-cyclohexadienes see: R. Angelaud, O. Babot, T. Charvat, Y. Landais, J.
Org. Chem. 1999, 64, 9613.
[8] Silylated cyclohexadienes have been used successfully as tin
hydride substituents in radical chemistry: A. Studer, S. Amrein,
Angew. Chem. 2000, 112, 3196; Angew. Chem. Int. Ed. 2000, 39,
3080; A. Studer, S. Amrein, F. Schleth, T. Schulte, J. C. Walton, J.
Am. Chem. Soc. 2003, 125, 5726.
[9] Ti compound 3 was readily prepared from 1,4-cyclohexadiene by
lithiation (sBuLi, TMEDA, THF, 788) followed by transmetalation with Ti(OiPr)4.
[10] The major isomer of 4 a was unambiguously assigned as the syn
isomer based on X-ray structure analysis. All the other
compounds were assigned in analogy. CCDC-213624 contains
the supplementary crystallographic 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 CB2 1EZ, UK;
fax: (+ 44) 1223-336-033; or deposit@ccdc.cam.ac.uk).
[11] For an excellent review on the use of TADDOLs in asymmetric
synthesis see: D. Seebach, A. K. Beck, A. Heckel, Angew. Chem.
Int. Ed. 2001, 113, 96; Angew. Chem. Int. Ed. 2001, 40, 92.
[12] A. Hafner, R. O. Duthaler, R. Marti, G. Rihs, P. Rothe-Streit, F.
Schwarzenbach, J. Am. Chem. Soc. 1992, 114, 2321.
[13] For recent syntheses of nephrosteranic acid see: a) H. Takahata,
Y. Uchida, T. Momose, J. Org. Chem. 1995, 60, 5628; b) P. A.
Jacobi, P. Herradura, Can. J. Chem. 2001, 79, 1727; c) M. P. Sibi,
P. Liu, J. Ji, S. Hajra, J.-x. Chen, J. Org. Chem. 2002, 67, 1738;
d) R. B. Chhor, B. Nosse, S. SMrgel, C. BMhm, M. Seitz, O. Reiser,
Chem. Eur. J. 2003, 9, 260.
[14] The regioisomeric 1,4-diene was formed as a side product and
could not be separated (4 o/5 o 87:13). Unfortunately, we were
not able to determine the enantiomer ratio of the major product
4 o. However, the same reaction with hexanal afforded the major
isomer with an enantiomer ratio of 93:7, as determined by GC
analysis. We assume that the reaction with dodecanal proceeds
with similar selectivity.
[15] V. VanRheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett. 1976,
1973.
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
315
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