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

Article abstract of DOI:10.1002/anie.200352254

Chiral cyclohexadienyl Ti-TADDOLate reacts with aldehydes to provide the corresponding homoallyl alcohols in high yields with excellent diastereo- and high enantioselectivities (see scheme). The new method has been used as the key step in an efficient syn

Full text of DOI:10.1002/anie.200352254

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 com-
À
pounds 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 Universität
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
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313

Communications
carbonyl compounds using metalated cyclohexadienes
Encouraged by these first results, we examined the
differentiation of the enantiotopic double bonds in cyclo-
hexadienyl 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, À788C) occurred with excellent
diastereoselectivity (syn/anti > 99:1). Furthermore, promis-
ing enantioselectivity was measured (e.r. 91:9, chiral GC),
however, syn-4a was formed in low yield (19%). Most likely
some decomposition of 7 occurred at À788C. Indeed, the
same reaction at lower temperature (À100 to À1108C, THF/
Et2O) provided syn-4a in 83% yield (syn/anti > 99:1) with
high enantioselectivity (e.r. 98:2, Table 1, entry 1).
[Eq. (1)] have appeared to date. A big challenge is the
differentiation of the two enantiotopic double bonds (desym-
metrization of the 1,4-cyclohexadiene).[7] The face selectivity
Table 1: Reaction of 7 with various aldehydes.
Entry
R
Product
Yield [%]
d.r.
e.r.
(syn/anti)
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.
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4 f
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]
98:2[a]
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
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]
9
The reaction of benzaldehyde with various metalated
cyclohexadienes was studied first (Scheme 1). With silylated
10
11
12
13
14
>99:1[b]
>99:1[b]
>99:1[a]
90:10[b]
99:1[b]
=
ꢀ
PhCH CH
PhC C
Et
91:9[e]
[a] Ratio determined by GC analysis. [b] Ratio determined by HPLC
analysis. [c] Determined after transformation to 4a (tBuLi, THF, À788C;
H2O) by GC analysis. [d] The 1,4-diene 5n was formed as a side product
and could not be removed (4n/5n 88:12). [e] Determined after oxidation
to (1R)-1-phenylpropanol by GC analysis.
The reactions with para-, meta-, and ortho-substituted
benzaldehyde derivatives occurred with excellent diastereo-
selectivity and high enantioselectivity (products 4b–h,
entries 2–8). a-Naphthaldehyde and phenylpropargyl alde-
hyde reacted with complete stereoselectivity, whereas furfu-
ral, b-naphthaldehyde, and cinnamaldehyde provided lower
but still good enantioselectivity and excellent diastereoselec-
tivity (products 4i–m, entries 9–13). Addition to propanal
occurred with high diastereo- but lower enantioselectivity
(entry 14), and the 1,4-diene 5n formed as a side product. The
absolute configuration of the major isomers of all the new
compounds was assigned based on the rearomatization of 4n
(Pd(OAc)2/Cu(OAc)2, MeOH) to provide (R)-1-phenylpro-
panol (e.r. 91:9). In analogy to the results of Duthaler et al.
addition of 7 occurs onto the Si face of the aldehyde.
Scheme 1. The reaction of cyclohexadienylmetalates with aldehydes
(only one enantiomer is shown).
cyclohexadiene 1[8] and stannylated diene 2 only low diaster-
eoselectivities (< 3:1) were obtained in the presence of
different Lewis acids. In contrast, the reaction of the Ti
compound 3 with benzaldehyde at À788C 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]
Finally, our new method was applied to the synthesis of
nephrosteranic acid.[13] Reaction of 7 with dodecanal afforded
4o (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).
314
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[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), Wiley-
VCH, 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-cyclohexa-
dienes see: R. Angelaud, O. Babot, T. Charvat, Y. Landais, J.
Org. Chem. 1999, 64, 9613.
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=hexamethyl-
disilazane, NMO=N-methylmorpholine N-oxide.
[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, À788) followed by transmeta-
lation with Ti(OiPr)4.
Crude 8 was oxidized under Jones conditions to g-butyrolac-
tone 9 (19% yield over three steps). Methylation according to
a literature procedure[13d] afforded scalemic nephrosteranic
acid (60%, [a]2D5 = + 22.7 (c = 0.78 in CHCl3); lit.[13a] [a]2D5
+ 27.2 (c = 1.45 in CHCl3)).
=
[10] The major isomer of 4a 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 CB21EZ, 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. Sꢀrgel, C. Bꢀhm, M. Seitz, O. Reiser,
Chem. Eur. J. 2003, 9, 260.
In conclusion, the easily prepared chiral cyclohexadienyl-
titanate 7 reacts with aldehydes in highly diastereo- and
enantioselective allylations. The resulting functionalized 1,3-
cyclohexadienes 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.
[14] The regioisomeric 1,4-diene was formed as a side product and
could not be separated (4o/5o 87:13). Unfortunately, we were
not able to determine the enantiomer ratio of the major product
4o. 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.
[3] “Allylstannanes”: E. J. Thomas in Houben-Weyl, Vol. E21bG
(Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schau-
mann), 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.
[15] V. VanRheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett. 1976,
1973.
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