Enantioselective synthesis of functionalized 1,5-cyclononadienes by intramolecular cycloalkylation under a,a′-diallyl coupling

Full text of DOI:10.1002/1521-3773(20000616)39:12<2105::AID-ANIE2105>3.0.CO;2-X

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Enantioselective Synthesis of Functionalized
1,5-Cyclononadienes by Intramolecular
a
O
Li
H
Cl
2
1
Li
2
R2N
S
O
Cycloalkylation under a,a'-Diallyl Coupling**
O
O
Cl
Alexander Deiters, Roland Fröhlich, and
Dieter Hoppe*
NR2
3
A
b
c
In spite of the biological importance of medium-size
carbocycles, only a few ring-closing reactions are known for
the synthesis of nine-membered monocarbocyclic rings.[1]
Classic examples are the acyloin condensation of nonanedioic
acid dimethyl esters[2a] and the McMurry reaction[2b]; how-
ever, for reasonable yields, a high dilution of the substrate and
a long reaction time are always necessary.[2c]
When we applied our protocol for an intramolecular
lithium ± ene reaction[3] on the (2Z,7Z)-9-chloro-2,7-nona-
dienyl carbamate 1, we found a suprisingly efficient synthesis
of a nine-membered carbocycle. The reaction proceeds to
completion without any by-products within 2 h, even in 0.15m
solution. On the other hand, the (2E,7E)-isomer furnishes the
expected cis-1,2-dialkenylcyclopentane 14, as we recently re-
ported (see Scheme 5).[3] Compound 1 was synthesized from the
known compound cis,cis-nona-2,7-diene-1,9-diol (Scheme 1).[4]
O
–LiCl
R
OCby
OH
O
NH
R
4
6
7
Cl
(CH3)3Si
NR2
=
N
O
R
d
N
N
CbyO
3
Cby = CONR2
(–)-Sparteine 2
5
Scheme 2. Cycloalkylation of the dienyl carbamate 1 and synthesis of the
silane 5. a) 2.0 equiv nBuLi, 2.0 equiv 2, toluene, À888C, 73%, e.r. ˆ 94:6
(88% ee.); b) 1.) 2.0 equiv CH3SO3H, CH3OH, D; 2.) 4.0 equiv KOH,
CH3OH, D, 96%; c) 3.0 equiv (R)-(‡)-1-phenylethyl isocyanate, CH2Cl2, D,
63%; d) 1.5 equiv nBuLi, 1.5 equiv (À)-sparteine, 2.7 equiv (CH3)3SiCl,
toluene, À788C, 61%, 87% ee.[23]
isocyanate furnished the carbamate 7. The X-ray analysis[13] of
7 (Figure 1) clearly shows the relative configuration l and
hence the R configuration for (‡)-6 and (‡)-4.
a
HO
OH
CbyO
OH
b
CbyO
Cl
1
Scheme 1. Synthesis of the dienyl carbamate 1. a) 0.3 equiv NaH, 0.3 equiv
CbyCl, THF, D, 85%; b) 1.0 equiv nBuLi, 1.3 equiv MsCl, 1.0 equiv LiCl,
THF, À788C !RT, 73 %.[23] Cby ˆ 2,2,4,4-tetramethyl-1,3-oxazolidin-3-
ylcarbonyl, Ms ˆ methanesulfonyl.
Treatment of 1 with n-butyllithium/(À)-sparteine (2)[5] in
toluene at À888C provided the (1R,2Z,7Z)-2,7-cyclonona-
dienyl carbamate 4 in 73% yield and withan ee value of 88%
(e.r. ˆ 94:6; Scheme 2).[6, 7] The S configuration of the inter-
mediate lithium complex 3 was confirmed by conversion into
the silane (R)-5 (87% ee).[8, 9] Thus, the a,a'-coupling[10] of the
allyl moieties in 3 proceeds under inversion of configuration
at the metal-bearing carbon atom and, therefore, presumably
passes through the transition state A.[11]
Figure 1. X-ray crystal structure analysis of 7.[13]
The analogous TBDPS-oxydienyl carbamate (R)-8 has been
synthesized starting from (S)-epichlorohydrin (Scheme 3).
Cyclization of (R)-8 (100% ee) by means of nBuLi/2 furnished
the enantiomericaly pure cyclononadiendiol derivatives
(1R,5S)-9 and (1S,5S)-9, in a diastereomeric ratio of 94:6,
which are easily separated by chromatography.[15] The stereo-
genic center at C-5 affects neither the deprotonation nor the
cyclization step; by use of the achiral base nBuLi/TMEDA,
(1R,5S)-9 and (1S,5S)-9 were obtained in the ratio 53:47.
Corresponding to this, rac-8 furnished, after treatment with
nBuLi/2, the epimers (1R,5S)-9 and (1R,5R)-9 in 74% yield
witha diastereomeric ratio of 55:45 and eachwithan ee value
of 92% (Scheme 4). After deprotection to the alcohol
(1R,5R)-10 and X-ray analysis, the relative configuration l
was confirmed (Figure 2).[16]
The cleavage[12] of the carbamate group led to the (R)-
cyclononadienol 6 and addition of this to (R)-1-phenylethyl
[*] Prof. Dr. D. Hoppe, Dipl.-Chem. A. Deiters, Dr. R. Fröhlich[‡]
Organisch-Chemisches Institut der Universität
Corrensstrasse 40, 48149 Münster (Germany)
Fax : (‡49)251-8339772
‡
[ ] X-ray analysis
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(Sonderforschungsbereich 424) and the Fonds der Chemischen
Industrie. A.D. gratefully acknowledges a fellowship from the Fonds
der Chemischen Industrie. We thank Mrs. C. Weitkamp for her
outstanding experimental assistance and Mr. J. Müller for his skillful
work during a laboratory course.
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/angewandte/ or from the author.
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The (Z,Z)-cyclonona-1,5-diene structure is destined for
Cope rearrangements which pass through boatlike transition
states:[17] After conversion of 6 into the potassium alcoholate
11 an anionic oxy-Cope rearrangement[18a] takes place at room
temperature. The aldehyde (‡)-13, obtained after protona-
tion of the potassium enolate 12, shows 95% stereoselectivity
for the rearrangement.[18b] This seems to be the highest grade
of chiral transmission in anionic oxy-Cope rearrangements of
dienols which only contain a stereogenic center at the oxygen-
bearing carbon atom.[19] The absolute configuration of 13 was
determined by its synthesis from 14[3] through deprotection of
the enol.[20] Together with the R configuration of 6, a reaction
pathway via the transition state B withan equatorial oxido
group[19c] takes place (Scheme 5).
OR2
OCb
a
O
OEE
b
OEE
R1O
R
1 = H, R2 = EE
c
R1 = TBDPS, R2 = EE
R1 = TBDPS, R2 = H
d
OTBDPS
OTBDPS
R
e
f
CbO
Cl
CbO
OH
8
Scheme 3. Synthesis of the enantiomericaly pure dienyl carbamate 8.
a) 1.) 1.0 equiv nBuLi, 0.5 equiv (S)-(‡)-epichlorohydrin, 1.0 equiv BF3 ´
OEt2, THF, À788C !RT; 2.) 1.0 equiv NaH, THF, À108C, 89%;
b) 2.0 equiv HCCCH2OCb,[14a] 2.0 equiv nBuLi, 2.0 equiv BF3 ´ OEt2,
THF, À788C !RT, 98 %;[14b] c) 1.2 equiv TBDPSCl, 2.5 equiv imidazole,
DMF, 83%; d) 0.07 mass% amberlyst 15, MeOH, 408C, 95%; e) H2,
5.0 mass% Lindlar catalyst, 0.15 equiv quinoline, MeOH, 96%;
f) 1.0 equiv nBuLi, 1.2 equiv MsCl, 1.0 equiv LiCl, THF, À788C !RT,
76%.[23] Cb ˆ diisopropylaminocarbonyl, EE ˆ ethoxyethyl, TBDPS ˆ tert-
butyldiphenylsilyl.
O
a
K
OH
6 (78% ee)
OK
B
11
b
OCby
OK
O
12
13 (74% ee)
14
Scheme 5. Enantioselective anionic oxy-Cope rearrangement. a) 1.3 equiv
KN(Si(CH3)3)2, THF, RT, 75%; b) 15 equiv AliBu2H, toluene, RT, 65%.
The method reported herein provides simple, flexible, and
also enantioselective access to highly functionalized nine-
membered carbocycles. The application of the homoenolate
chemistry[5a, 21] on the configuratively stable secondary lithium
species generated by deprotonation of 4 bears additional
possibilities in the synthesis of nine-membered ring com-
pounds.[22]
Experimental Section
Under argon, compounds 1 (500 mg, 1.52 mmol) and 2 (713 mg, 3.04 mmol)
were dissolved in toluene (10 mL). After cooling to À888C, a 1.6 m solution
of n-butyllithium in hexane (1.90 mL, 3.04 mmol) was slowly injected and
the solution was stirred at this temperature for 2 h. Subsequently, CH3OH
(1 mL) and saturated aqueous NH4Cl (1 mL) were added and the reaction
mixture was allowed to warm to room temperature. Standard work up and
purification by flash column chromatography over silica gel
(Et2O:pentane ˆ 2:5) furnished 4 (324 mg, 73%, 88% ee) as a colorless
solid (m.p. 728C).
Scheme 4. Cycloalkylation of the dienyl carbamate 8 and deprotection of
the product 9. a) 2.0 equiv nBuLi, 2.0 equiv diamine, toluene, À888C, 2 h;
b) 3.0 equiv tetrabutylammonium fluoride, THF, 74%.[23] TMEDA ˆ
N,N,N',N'-tetramethylethylenediamine.
Received: January 21, 2000 [Z14575]
[1] The synthesis of nine-membered rings is particularly strongly disfa-
vored because of the adverse entropic term, the Baeyer strain, and the
Pitzer strain, as well as the transannular interactions: E. L. Eliel, S. H.
Wilen in Stereochemistry of Organic Compounds, Wiley, New York,
1994, pp. 675 ± 685.
[2] a) A. T. Bloomquist, Y. C. Meinwald, J. Am. Chem. Soc. 1958, 80,
630 ± 632; b) T. Lecta in Active Metals (Ed.: A. Fürstner), VCH,
Weinheim, 1995, pp. 85 ± 132; J. E. McMurry, K. L. Kees, J. Org.
Chem. 1977, 42, 2655 ± 2656; c) Other ring-closing reactions leading to
monocarbocyclic nine-membered rings; intramolecular 1,4-addition
(35% yield): P. Deslongchamps, B. L. Roy, Can. J. Chem. 1986, 64,
2068 ± 2075; Thorpe ± Ziegler condensation (3% yield): J. P. Schaefer,
J. J. Bloomfield, Org. React. 1967, 15, 3 ± 203.
Figure 2. X-ray crystal structure analysis of (1R,5R)-10.[16]
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[3] A. Deiters, D. Hoppe, Angew. Chem. 1999, 111, 529 ± 532; Angew.
Chem. Int. Ed. 1999, 38, 546 ± 548.
5.7 Hz), 5.67 ± 5.81 (m, 3H, CH, CH, CH), 7.32 ± 7.70 (m, 10H,
CH(phenyl)). After cleavage of the TBDPS group, the enantiomeric
ratio of (1R,5S)-10 was determined as described in reference [7].
[16] a) X-ray crystal structure analysis of (1R,5R)-10: C16H27NO3, Mr ˆ
281.39, colorless crystal, 0.40  0.25  0.15 mm, a ˆ 26.159(5), b ˆ
[4] P. Lennon, M. Rosenblum, J. Am. Chem. Soc. 1983, 105, 1233 ± 1241.
[5] Reviews: a) D. Hoppe, T. Hense, Angew. Chem. 1997, 109, 2376 ± 2410;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2282 ± 2316; b) P. Beak, A. Basu,
D. J. Gallagher, Y. S. Park, S. Thayumanavan, Acc. Chem. Res. 1996,
29, 552 ± 560.
[6] If the reaction is carried out at À788C, 4 is obtained in 66% yield and
86% ee. By using the achiral base nBuLi/TMEDA in Et2O at À788C,
rac-4 is yielded in 76%.
10.884(2), c ˆ 12.918(3) Š, b ˆ 113.71(2)8, Vˆ 3367.5(12) Š3, 1calcd
ˆ
1.110g cmÀ3, m ˆ 6.04 cmÀ1, absorption correction with y-scan data
(0.794 ꢀ Tꢀ 0.915), Z ˆ 8, monoclinic, space group C2 (No. 5), l ˆ
1.54178 Š, Tˆ 223 K, w/2q scans, 3697 reflections collected (Æh, ‡k,
Æl), [(sinq)/l] ˆ 0.62 ŠÀ1, 3611 independent (Rint ˆ 0.077) and 3159
[7] Compound 4: Mp 728C; [a]2D0 ˆ ‡14.8 (c ˆ 0.59, CHCl3; 88% ee);
1H NMR (400 MHz, CDCl3): d ˆ 1.34 ± 1.56 (m, 14H, CH2,
CH3(Cby)), 1.85 ± 2.03 (m, 4H, CH2), 2.22 and 2.43 (bothm, each
with1H, CH 2), 3.70 and 3.71 (s, 2H, CH2(Cby)), 5.10 (dd, 1H, CHO,
3J ˆ 7.8, 7.8 Hz), 5.38 (dt, 1H, CH, 3J ˆ 9.6, 9.6 Hz), 5.47 (dt, 1H, CH,
3J ˆ 5.8, 10.1 Hz), 5.62 (m, 1H, CH), 5.79 (dt, 1H, CH, 3J ˆ 10.1,
observed reflections [I ꢁ 2s(I)], 372 refined parameters, R ˆ 0.044,
À3
wR2 ˆ 0.119, max./min. residual electron density 0.24/ À 0.17 eŠ
,
Flack Parameter 0.3(2), the asymmetric unit contains two independ-
ent, nearly identical molecules, hydrogens were calculated and refined
as riding atoms; b) The data sets were collected with Nonius CAD4
and Nonius KappaCCD diffractometers equipped witha Nonius
FR590 sealed tube generator or a Nonius FR591 rotating anode
generator. The following programs were used: For data collection,
EXPRESS (Nonius B.V., 1994) and COLLECT (Nonius B.V., 1998);
for data reduction, MolEN (K. Fair, Enraf ± Nonius B.V., 1990) and
Denzo-SMN (Z. Otwinowski, W. Minor, Methods Enzymol. 1997, 276,
307 ± 326); for absorption corrections for CCD data, SORTAV (R. H.
Blessing, Acta Crystallogr. Sect. A 1995, 51, 33 ± 37; R. H. Blessing, J.
Appl. Crystallogr. 1997, 30, 421 ± 426); for structure solution,
SHELXS-97 (G. M. Sheldrick, Acta Crystallogr. Sect. A 1990, 46,
467 ± 473); for structure refinement, SHELXL-97 (G. M. Sheldrick,
University of Göttingen, 1997); for graphics, SCHAKAL (E. Keller,
University of Freiburg, 1997). Crystallographic data (excluding
structure factors) for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-139019 and -139020. Copies
of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB21EZ, UK (fax: (‡44)1223-336-033;
e-mail: deposit@ccdc.cam.ac.uk).
8.5 Hz). The enantiomeric ratio of
4 was determined by gas
chromatography on a chiral stationary phase (Beta-Dex 120, Supelco,
USA).
[8] Compound 5: [a]2D0 ˆ ‡10.3 (c ˆ 1.27, CHCl3; 87% ee); 1H NMR
(300 MHz, CDCl3): d ˆ 0.05 (s, 9H, Si(CH3)3), 1.30 ± 1.51 (m, 14H,
CH2, CH3(Cby)), 1.96 ± 2.30 (m, 4H, CH2), 3.69 (s, 2H, CH2(Cby)),
4.07 (dd, 2H, CH2Cl, 4J ˆ 1.8, 3J ˆ 5.1 Hz), 5.35 ± 5.42 (m, 3H, CH,
CHSi), 5.58 ± 5.62 (m, 2H, CH). The enantiomeric ratio of the silane 5
was determined by 1H NMR shift experiments in the presence of
[Eu(hfc)3] (hfc ˆ 3-(heptafluoropropylhydroxymethylene)-d-campho-
rate). After hydrogenation of the double bonds and hydrogenolytic
cleavage of the chlorine atom, the corresponding 1-trimethylsilylnonyl
carbamate was obtained.[3] Its enantiomer was synthesized by the
sBuLi/(À)-sparteine method.[5a] A correlation of the optical rotations
assigned the R configuration for (‡)-5.
[9] Stereoinversion in the silylation of allyllithium-(À)-sparteine com-
plexes: K. Behrens, R. Fröhlich, O. Meyer, D. Hoppe, Eur. J. Org.
Chem. 1998, 2397 ± 2403; H. Paulsen, C. Graeve, D. Hoppe, Synthesis
1996, 141 ± 144.
[10] a) H. Yamamoto et al. reported intermolecular a,a'-allyl couplings by
the use of allylbarium reagents.[10b] However, an intramolecular
coupling reaction was unknown: A. Yanagisawa, K. Yasue, H.
Yamamoto, Synlett 1996, 842 ± 844; A. Yanagisawa, H. Hibino, S.
Habaue, Y. Hisada, H. Yamamoto, J. Org. Chem. 1992, 57, 6386 ± 6387;
b) A. Yanagisawa, H. Yamamoto in Active Metals (Ed.: A. Fürstner),
VCH, Weinheim, 1995, pp. 61 ± 84.
[17] By heating 4 up to 2208C, a stereospecific Cope rearrangement takes
place;[22] Cope rearrangement of (Z,Z)-cyclonona-1,5-diene: E. Vogel,
Â
W. Grimme, E. Dinne, Angew. Chem. 1963, 75, 1103.
[18] a) Review of anionic oxy-Cope rearrangements: L. A. Paquette,
Tetrahedron 1997, 53, 13971 ± 14020; b) anionic oxy-Cope rearrange-
ment of rac-6: L. A. Paquette, G. D. Crouse, A. K. Sharma, J. Am.
Chem. Soc. 1982, 104, 4411 ± 4423. The enantiomeric ratio of 13 was
determined as described in reference [7].
[11] Presumably, the topology of the transition state A is influenced by
p ± p* interactions of the allylic moieties by precoordination and,
therefore, favor the entropic term of the cyclization. In principle a
g,g'-coupling between C-3 and C-7 is also possible and would lead to
the cis configured five-membered ring. However, this would cause an
increase of transannular and diaxial interactions of the side chains
with the ring system; for this reason, the formation of a nine-
membered ring takes place.
[19] a) S.-Y. Wei, K. Tomooka, T. Nakai, Tetrahedron 1993, 49, 1025 ± 1042;
b) L. A. Paquette, G. D. Maynard, Angew. Chem. 1991, 103, 1392 ±
1394; Angew. Chem. Int. Ed. Eng. 1991, 30, 1368 ± 1370; c) in anionic
oxy-Cope rearrangements the oxido group prefers an equatorial
position: L. A. Paquette, G. Maynard, J. Am. Chem. Soc. 1992, 114,
5018 ± 5027.
[20] K. Tomooka, N. Komine, T. Sasaki, H. Shimizu, T. Nakai, Tetrahedron
Lett. 1998, 39, 9715 ± 9718.
[12] F. Hintze, D. Hoppe, Synthesis 1992, 1216 ± 1218.
[21] Review of homoenolate chemistry: D. Hoppe, Angew. Chem. 1984, 96,
930 ± 946; Angew. Chem. Int. Ed. Engl. 1984, 23, 932 ± 948.
[22] A. Deiters, D. Hoppe, unpublished results.
[23] All new compounds were analytically pure (error in C,H,N elemental
analyses Æ0.4).
[13] X-ray crystal structure analysis of 7: C18H23NO2, Mr ˆ 285.37, light
yellow crystal, 0.20  0.10  0.05 mm, a ˆ 23.258(1), c ˆ 5.106(1) Š,
g ˆ 1208, Vˆ 2392.0(5) Š3, 1calcd ˆ 1.189 gcmÀ3, m ˆ 0.77 cmÀ1, absorp-
tion correction withSORTAV (0.985 ꢀ Tꢀ 0.996), Z ˆ 6, trigonal,
space group P31 (No. 144), l ˆ 0.71073 Š, Tˆ 198 K, w and f scans,
20958 reflections collected (Æh, Æk, Æl), [(sinq)/l] ˆ 0.65 ŠÀ1, 7097
independent (Rint ˆ 0.056) and 4457 observed reflections [I ꢁ 2s(I)],
387 refined parameters, R ˆ 0.066, wR2 ˆ 0.131, max./min. residual
electron density 0.42/ À 0.25 eŠÀ3, Flack parameter À0.1(14), the
asymmetric unit contains two independent, nearly identical molecules,
hydrogens were calculated and refined as riding atoms.[16b]
[14] a) For 2-alkynyl carbamates, see: S. Dreller, M. Dyrbusch, D. Hoppe,
Synlett 1991, 397 ± 400; b) For a similar reaction sequence, see: S.
Hatakeyama, H. Irie, T. Shintani, Y. Noguchi, H. Yamada, M.
Nishizawa, Tetrahedron 1994, 50, 13369 ± 13376.
[15] Compound (1R,5S)-9: [a]2D0 ˆ À37.7 (c ˆ 0.43, CHCl3, 100% ee);
1H NMR (300 MHz, CDCl3): d ˆ 1.07 (s, 9H, tBu), 1.22 (d, 12H,
CH3(Cb), 3J ˆ 6.9 Hz), 1.93 ± 2.00 (m, 1H, CH2), 2.11 (dd, 2H, CH2,
3J ˆ 6.9, 3.6 Hz), 2.19 ± 2.38 (m, 2H, CH2, CH2), 2.53 (ddd, 1H, CH2,
2
3J ˆ 8.7, 9.0, J ˆ 12.9 Hz), 3.80 ± 4.03 (m, 3H, CH(Cb), CHOSi), 5.03
(dd, 1H, CHOCb, 3J ˆ 6.0, 6.9 Hz), 5.35 (dt, 1H, CH, 3J ˆ 10.6,
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