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Intramolecular DielsЦAlder Reactions Diastereofacial Selectivity and Coupling with an Aliphatic Claisen Rearrangement.

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angles according to the Karplus equation. The isolated compound 6a is, however, not able to be transformed into the
diol under the same reaction conditions. This may be explained by a transannular reduction of the C-2 ketone by a
C-10 alkoxy borohydride. The cis hydroxylation of 6a with
osmium tetroxide yields a 1:1 mixture of two easily separable
diastereomers (7).The relative orientation of the stereocenters between the ester side chain and the tricycle cannot be
determined; a crystal structure analysis has as yet not been
possible. Both diastereomers 7 were subjected to an in vitro
tubulin test."] The diastereomer which is less polar in an
eluant system of dichloromethane/methanol on silica gel inhibits the depolymerization of tubulin and is thus the first
synthesis product with a taxol-analogous action. This result
confirms that less functionalized taxol derivatives also can be
of interest. We are at present studying a further simplification of the structure and its influence on the activity.
tron processes (Cope['] or ene
allow coupling
with the aliphatic Claisen rearrangement in a tandem reaction?
Allylic hydroxyl functions can be used in different ways
for stereocontrolled C-C bond formation, as shown by the
examples in equation (a) (1,3 -chirality transfer14]) and (b)
9 4
Received: October 30, 1990 [Z 4260 IE]
German version: Angew. Chern. 103 (1991) 428
CAS Registry numbers:
1, 33069-62-4; 2, 132203-65-7; 2 (OH instead of 0-CO-O-CH,-CH=CH,),
92695-03-9; 4, 132157-41-6;4 (carbonyl instead of hydroxy), 132178-08-6;5,
132157-42-7;5 (OH instead of Ph-CH=CH-CO-0), 123483-62-5;6a, 13215743-8; 6b,132157-45-0;6c, 132157-46-1;l a , 132157-44-9;7b, 132203-66-8.
[l] a) B. Lythgoe, The Alkaloids (Academic Press) 12 (1968) 597; b) R. W.
Miller, J. Nat. Prod. 43 (1980) 425; c) S . Blechert, D. Gu6nard in A. Brossi
(Hrsg.): The Alkaloids, Vol. 39, Academic Press, New York 1990, in press.
[2] M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon, A. T. McPhail, J. Am.
Chem. Soc. 93 (1971) 2325.
[3] M. Suffness, G. A. Cordell in A. Brossi (Ed.): The Alkaloids, Chemistry and
Pharmacology. Vol. 25, Academic Press, Orlando 1985, p. 6.
[4] Syntheses of tricyclic taxane frameworks with oxygen at C-13: C.S.
Swindell, B. P. Patel, J. Org. Chem. 55 (1990) 3; R. A. Holton, R. R. Juo,
H. B. Kim, A. D. Williams, S . Harusawa, R. E. Lowenthal, S. Yogai, J. Am.
Chem. Soc. if0 (1988) 6558; A. S. Kende, S. Johnson, P. Sanfilippo. J. C.
Hodges, L. N. Jungheim, ibid. f08 (1986) 3513.
IS] a) V. Senilh, F. Gueritte, D. Guenard, M. Colin, P. Potier, C. R. Acad. Sci.
Ser. 2 299 (1984) 1039; b) D. G. I. Kingston, D. R. Hawkins, L. Ovington,
J. Nut. Prod. 45 (1982) 466.
[6] H. Neh, A. Kiihling, S. Blechert, Helv. Chim. Aera 72 (1989) 101.
(71 Test according to F. Gaskin, C. R. Cantor, M. J. Shelanski, J. Mol. Biol.89
(1974) 73; we thank Dr. D. Guinard, Institut de Chimie des Substances
Naturelles, Gif-Sur-Yvette, France, for its execution.
(1,2 induction through radical cy~lization[~]).
In this way a
maximum of two (a) and three (b) stereocenters can be created; with the Diels- Alder reaction, however, up to four
stereocenters per step are created. Thus we esterified the
hydroxyester 1, obtained in two steps from O-tetrahydropyranyl(THP)lactaldehyde, with sorbic acid to obtain triene
2, which yields on heating (xylene, 160 "C, 3 days) the bicycle
4 (81 YO)as well as two further diastereomers (5 and 9% by
HPLC analysis) (Scheme 1). According to an X-ray crystal
Intramolecular Diels- Alder Reactions:
Diastereofacial Selectivity and Coupling
with an Aliphatic Claisen Rearrangement**
1. LiAIH,
Intramolecular Diels -Alder reactions (IMDA reactions)
are often studied because of their high regio- and stereoselectivity."] We were interested in two aspects of these reactions:
1) How can they be used for the rapid construction of acyclic
chiral compounds? 2) Do they, like other pericyclic six-elec[*] Prof. Dr. J. Mulzer, Dipl.-Chem. H. Bock, DipLChem. W. Eck
Institut fur Organische Chemie der Freien Universitat
Takusstrasse 3, W-1000 Berlin 33 (FRG)
Dr. J Buschmann, Prof. Dr. P. Luger
Institut fur Kristallographie der Freien Universitat Berlin
[*'I This work was supported by the Graduiertenkolleg "Structure determination and synthesis of small molecular compounds", the Fonds der
Chemischen Industrie, and Schering AG, Berlin-Bergkamen.
kkrlagsgesel/schaft mbH. W-6940 Weinheim. 1991
3.0, I NaBH,
By Johann Mulzer*, Harald Bock, Wowgang Eck,
Jiirgen Buschmann, and Peter Luger
Scheme 1. DCC = Dicyclohexylcarbodiimide, TBDPS = tert-butyldiphenylsilyl.
structure analysis on 4,[61H-2 and H-7 are in cis orientation,
in contrast to the (E,E) configuration in diene system 2.
Probably the primary adduct 3 epimerizes in situ at the CHacidic 7-position.
The relative configuration at the four new chirality centers
of 3 indicates that 2 reacts via conformation 6, in which the
methyl group shields one diastereoface of the dienophile.
The Newman projection of 6 (7) shows that the attack on the
dienophile conforms to the Houk model.[''
S 3.50FOt .25/0
Angew. Chem. Int. Ed. Engl. 30 (1991) No. 4
following conclusions: a) The relative amounts of products
formed via route A or B is controlled by the degree of substitution of the internal double bond.["' If it is trisubstituted
@a), route A dominates and chiefly the cyclization product
Table 1. Analysis of the tandem reactions of 8; see also Scheme 2.
6 (E=CO,Et)
The opening of 4 to further acyclic products can occur in
several ways; for example, to 5, which has a total of five
distinguishable hydroxyl functions. The chiral information
of 1 is thus transferred with high selectivity to the centers
C-2, 3, 4, and 7 of the open chain compound 5 (numbering
The coupling of two reactions is often considered a
tandem reaction when they proceed one after the other without change in reaction conditions or buildup of intermediates.18] In Scheme 2 we describe the first example of the
coupling of an aliphatic Claisen rearrangement with an
IMDA reaction.[g1
Diels-Alder reaction to
10 (route A)
12 (route B)
favored :
8b (n = 1) [4.6]-bicycle
8a (n = 3)
expected found (yield [%I,
10, 11
lOa/lla (75, 1O:l)
9, 12
9b/l2b (72, 1.3:l)
10a forms via intermediate 9a. In the case of disubstitution
(8b) on the other hand, the routes A and B are equally
favored so that 9b and l l b form in approximately equal
amounts. b) Diels-Alder reactions leading to rings of unfavorable size are avoided (9a + 10 b and 11 a + 12 b). Thus
the reaction of 8b leads to the formation of 9b and 12b in
Scheme 2. 8a-12a: n
3, R' = M e , R2 = H; 8b-12b: n = 1, R' = H, R2 = Me.
almost equal proportions, whereas 8 a yields 10 a as dominant product.
Stereochemically cyclization 9a + 10a differs from 11 b --t
12b. Compound 12b is generated as a 43:35:14:4 mixture of
the four diastereomers, whereas 10a yields an isomer distribution of 91 :9 (HPLC analysis). The relative configuration
The trienols 8a and 8 b are prepared from the known precursors 13['OI and 14["' according to Scheme 3 and on heating with ethyl orthoacetate in diglyme (2 mol% propionic
acid, 160 "C, 48 h) undergo a Claisen rearrangement (route A
and B), followed by the spontaneous Diels-Alder reaction to
10 or 12. The analysis of the reaction (Table 1) leads to the
Angew. Chem Int. Ed. Engl. 30 (1991) No. 4
Scheme 3. a) Ph,PCHCO,Me, CHCI,, A (61 %, E / Z
= 1O:l); b) Dimethylsulphoxide, CH2CI,, (CO),Cl,,
-6O"C, (quant.); c) Ph,PC(CH,)CHO, CHCI,, A
(73%); d) (CH,=CH)MgCI, Et,O, - 15°C. (7080%); e) OsOJNaIO, (80%); pyridine, H,O;
Ph,PCHCO,Me, CHCI,, A (70%); 0 Si0,/CH2CI,/
p-TsOH (95%); g) Ph,PCHCHO, CHCI,, A (71 Y o ) .
Verlagsgesellschafl mbH, W-6940 Weinheim. 1991
OS70-0833~91/0404-041S$ 3 . 5 0 f ,2510
41 5
[l] Reviews: G. Brieger. J. N. Bennett, Chem. Rev. 80 (1980) 63; E. Ciganek,
Org. React. 32 (1984) 1; A. G. Fallis, Can. J. Chem. 62 (1984) 183; particularexamples: R. K. Boekman, Jr., D. M. Demko, J. Org. Chem. 47(1982)
1789; G. Stork, E. Nakamuru, .
Am. Chem. Soc. 105 (1983) 5510; H.
Dyke, P. G. Steel, E. J. Thomos, J. Chem. Soe. Perkin Trans. 1 1989.525;
J. W. Coe, W. R. Roush, J. Org. Chem. 54 (1989) 915; K. Takeda, Y. Igarishi, K. Okazai, E. Yoshii, K. Yamaguchi, ibid. 55 (1990) 3431, and referCO,Me
ences quoted therein.
[2] A. F. Thomas, J. Am. Chem. Soc. 91 (1969) 3281; F. E. Ziegler, J. J. Piwinski, ibid. 101 (1979) 1611.
131 T. Mandai, S . Matsumoto, M. Kohama, M. Kawada, J. Tsuji, S. Saito, T.
Moriwake, J. Org. Chem. 55 (1990) 5671, and references quoted therein.
(41 Review: R. K. Hill in J. D. Morrison (Eds.): Asymmetric Synlhesis, Vol. 3,
Academic Press, Orlando, FL, USA 1984, p. 503ff.
[5] S. Hanessian, R. DiFabio, J.-F. Marcoux, M. Prud'homme, J. Org. Chem.
55 (1990) 3436; G. Stork, M. Kahn, J. Am. Chem. Soc. 107 (1985) 500.
[6] The X-ray crystal structure analysis was undertaken on racemic 4 (m.p.
< 20°C). Details of the crystal structure investigation may be obtained
from the Fachinformationszentrum Karlsruhe, Gesellschaft fur wissen18
schaftlich-technische Information mbH, W-7514 Eggenstein-Leopoldshafen 2 (FRG) on quoting the depository number CSD-55094, the names
of the authors and the journal citation. The starting compound for the
of the main diastereomer (18) of 10a was determined by
synthesis of the enantiomerically pure 4 was (9-1. For physical and spectroscopic data of 4 data see Table 2.
nuclear Overhauser enhancement (NOE) difference spec[7] P. Caramella, N. G. Rondan, M. N. Paddon-Row, K. N. Houk, J. Am.
The cyclization 9a -+ 10 a may be explained by
Chem. Soc. 103 (1981) 2438; K. N. Houk, M. N. Paddon-Row, N. G.
considering the reactive intermediates 15 and 16: intermediRondan, Y. D. Wu, K. F. Brown, D. C. Spellmeyer, J. T. Metz, Y. Li, R. J.
ate 15 appears to be less favorable than 16 as a result of
Loncharich, Science 231 (1986) 1108.
[8] Therein lies the difference from sequential reactions, which can be carried
out separately. See also F. E. Ziegler, Chem. Rev. 88 (1988) 1423;T. Nakai,
K. Mikami, ibid. 86 (1986) 885.
Table 2. Analytical data for the compounds 4, 12b (major diastereomer) and
(91 Aromatic series: G. A. Kraus, B. S. Fulton, J. Org. Chem. 50(1985) 1782;
18. 'HNMR: 270MHz. CDCI,, TMS as internal standard; "CNMR:
G. A. Kraus, S . H. Woo, ibid. 52 (1987) 4841.
67.5 MHz, CDCI,, TMS.
[lo] J. F. Carvalho, G. D. Prestwich, J. Org. Chem. 49 (1984) 1251.
1111 R. K. Boekman, Jr., S. S. KO, 1 Am. Chem. SOC.104 (1982) 1033.
4: [a];' = 32.5 (C = 2, CHCI,); 'HNMR: 6 = 0.90 (d, J = 7 Hz, 3H; CH,),
[I21 K. A. Parker, J. G. Farmar, Tetrahedron Lett. 25 (1985) 3655; S. Bancel, P.
Cresson, C.R. Acad. Sci. Ser C 268 (1989) 1535, and references cited
(ddd,J=2.5,4.5,8Hz, IH),4.19(q,J=7Hz, 1H),4.21 (9, J = 7 H z , 1H).
4.34(dq,J= 1,7Hz,lH),5.84(dd,J=4.5,10Hz,lH),5.97(ddd,J=2.5,6,
[13] Strong interactions are observed between H-I and H-5 as well as between
IOHz, IH); 13CNMR: 6 = 14.03, 15.436, 20.38, 30.248, 36.797, 38.417,
H-4 and H-5, whereas H-I and H-6 do not influence each other.
44.860, 60.612, 79.917, 119.503, 133.691, 172.877, 175.630; IR (Film):
?=2980, 1800-1700, 1380, 1280, 1250, 1230, 1175, 1110, 1035, 1020,
970 cm-'; C,H elemental analyis.
12b: 'HNMR:6=0.86,1.01(2xs,eachCH,),1.19(t,J=6Hz,CH,),1.63-
1.77(m,2H),1.92-2.11 (m,2H),2.13-2.29(m,4H),2.31-2.42(m,lH),2.49
(dd, J = 5, 15 Hz, 1 H), 3.60 (s, OCH,), 4.07 ( q , J = 6 Hz, 2H), 5.58-5.75 (m.
2H); IR (Film): ? = 2950,1735,1160,1030 cm-'; MS (EI, 80 eV, 100°C): mjz
294 (M"), 279,262,249,234,219,206,191,147,131,119, 105,91,79; HRMS:
279.1594 (calcd. for M e - CH,: 279.1596)
18: 'HNMR: (assignment by 'H-'H COSY): b = 0.77-0.97 (m.1 H), 0.861.06(m, 1H),1.23(t,J=7Hz,CH,),1.22-1.38(m,lH),1.26-1.43(m,lH),
Enantioselective Protonation of a Simple Enol:
Aminoalcohol-CatalyzedKetonization of a
1.44-1.61(m,1H;6-H),1.50-1.79(m,2H),1.56-1.74(m,lH;I-H),1.62(s,Photochemically Produced 2-Methylinden-3-01**
3H; 2-CH3), 1.69-1.80 (m, IH), 1.76-1.88 (m, IH), 1.89-2.00 (br. d, lH),
1.99-2.11 (br.d, 1 H), 2.18-2.50 (m, 2H), 2.28-2.45 (m, 1 H ; 4-H), 2.54 (dd,
J = 5.5, 10.5 Hz, 1H; 5-H), 3.65 (s, OCH,), 5.10 (9, J = 7 Hz, 2H), 5.36 (dq,
J = 1.5, 3Hz, l H , 3-H); "CNMR: 6 = 14.08, 20.73, 26.24, 26.87, 27.80,
29.64, 30.49, 32.01, 35.78, 37.39, 45.45, 49.56, 50.86, 60.01, 123.05, 136.95,; MS (EI, 80 eV, 40°C): m/z = 308 (M"), 276,263,248,220,202,
IR (film): C = 2930,1735,1160cm~';HRMS:
308.1987 (calcd. for M" 308.1987), 276.1726 (calcd. for M e - CH,OH:
transannular H-methyl repulsion, and the cyclization product 17 is formed in only small amounts. Table 2 lists analytical data of the key compounds 4,12 b (major diastereomer)
and 18.
Received: November 22, 1990 [Z4289 IE]
German version: Angew. Chem. 103 (1991) 450
CAS Registry numbers:
1,132341-85-6; 2,132298-17-0; 3,132298-18-1 ;4,132298-19-2;5,132298-20-5;
8a, 132298-22-7; 8b, 132298-21-6; 9b, 132298-23-8; lOa, 132298-24-9; l l a ,
132298-25-0; 12b, 132298-26-1; 13, 93545-84-7; 14, 79898-62-7; 16,
132298-27-2; 18, 132298-29-4; (E)-HO(CH,),CH=CHCO,Me, 68750-31-2;
132298-28-3; OHCCH=CH(Me)(CH,),CH=CHCO,Me,
132298-30-7; (MeO),CHCH,C(Me),CH=CHCO,Me,
(E)-OHCCH,C(Me),CH=CHCO,Me, 132298-32-9;
OHCCH=CHCH,C(Me),CH=CHCO,Me, 132298-33-0.
41 6
0 VCH krlagsgesellschaff mbH,
W-6940 Weinheim. 1991
By Franpise Henin,* Jacques Muzart, * Jean-Pierre Pete,
Anastase M'boungou-M'passi, and Hermann Rau
During the past few years, we have been concerned with
asymmetric protonations of dienols produced by a Norrish
type I1 photorearrangement of a,fi-unsaturated carbonyl
compounds.['] The mechanistic model that we have proposed to rationalize the stereochemistry of the discrimination step involves principally the enol part of the dienolt2]
and should apply equally well to enantioselective protonation of simple enols. As simpler enols could be generated
from a Norrish type I1 phot~elimination,~~~
we examined the
behavior of such prochiral enols under analogous conditions. Intensive research work has been devoted to the syn[*] Dr. F. Henin, Dr. J. Muzart, Prof. Dr. J. P. Pete, A. M'boungou-M'passi
Unite des Rearrangements Thermiques et Photochimiques Associke au
Universite de Reims Champagne-Ardenne
F-51062 Reims (France)
Prof. Dr. H. Rau
Fachgebiet Physikalische Chemie
Institut fur Chemie der Universitat Hohenheim
W-7000 Stuttgart 70 (FRG)
This work was supported by the Direction des Relations et la Coop6ration
Internationales (D.R.C.I.) (travel grants to F. H. and J. M.); We gratefully
acknowledge A . WONand B. Vogler for their efficient assistance.
OS70-0833/91j0404-04163 3.50+ .25/0
Angew. Chem. Int. Ed. Engl. 30 (f991) No. 4
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dielsцalder, rearrangements, intramolecular, selectivity, reaction, couplings, aliphatic, claisen, diastereofacial
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