T H E JOURNAL OF VOLUME53, NUMBER22
Organic Chemistry 0 Copyright 1988 by the American Chemical Society
OCTOBER 28, 1988
An Approach to Pseudoguaianolides via Cobalt-Mediated Cyclopentannelation. A Stereochemical Aside Angel M. Montaiia, Kenneth M. Nicholas,* and Masood A. Khan+ Department of Chemistry, University of Oklahoma, Norman, Oklahoma 73019 Received April 19, 1988
As part of an approach to the total synthesis of pseudoguaiane sesquiterpenes a double stereoselectivity was observed in the reaction of the epimeric silyl enol ethers 4a,b with (l-ethoxypropargyliu)Co2(CO),BF, (6). Four (of eight possible) diastereomeric adducts 8a-d are produced in a 9:36:47:8 ratio and 75% yield. The structure of each isomer has been established by 'H and 13CNMR analyses and, in the case of 8c and Sd, confirmed by X-ray diffraction. All four isomers are found to possess the same relative configuration at C2 (adjacent to the carbonyl group), demonstrating a complete facial specificity in the attack of the cobalt complex on the exo face of 4a,b. Additionally, good selectivity in the formation of the C1' stereocenter (adjacent to the complexed triple bond) is observed as well, 3.81 (8b/8a)and 6:l (&/Sa). Product isomerization studies under the reaction conditions suggest that 8b and 8c are kinetically favored whereas 8a and 8c are thermodynamically favored. Various transition-state models are proposed to account for the observed stereoselection.
Introduction Scheme I (Propargylium)Co2(CO)6+BF4complexes have been pTMS shown to be versatile agents for carbon-carbon bond formation through their reactions with various carbon nucleophiles.' Key features of these reactions include: (a) regiospecific coupling to give propargylic derivatives exclusively and (b) utility with a wide variety of nucleophiles including aromatics, /3-dicarbonyl compounds, enol derivatives, allyl silanes, and alkyl and alkynyl aluminums. \ OR Subsequent elaboration of the demetalated acetylenic unit opens up new synthetic possibilities. For example, we have developed a cyclopentannelation methodology combining stereocenters. As these results may have important imthe cobalt complexes with silyl enol ethers followed by plications not only for the control of stereochemistry in demetalation, triple-bond hydration, and aldol condensaour pseudoguaiane approach but also to the general issue tion2 that has been utilized in the synthesis of dihydroof stereocontrol in alkylations by the cobalt-complexed jasmone3and the guaiane sesquiterpene cycloc~lorenone.~~~propargyl cations,8 we have sought to rigorously establish Recently we initiated studies directed toward the synthe stereochemical outcome of this reaction and probe the thesis of pseudoguaianolides using a variant of the above cobalt-based annelation (Scheme I). This class of sesquiterpenes has attracted several synthetic ventures6 be(1) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207. cause of the challenging stereochemical features and sig(2) Saha, M.; Nicholas, K. M. Isr. J. Chem. 1984, 24(2), 105. (3) Padmanabhan, S.; Nicholas, K. M. Synth. Commun. 1980, 10(7), nificant cytotoxic and antitumoral properties of several of 503. ~ . . its members.' In the alkylation step, which initiates the ( 4 ) Saha,M.; Muchmore, S.; van der Helm, D.; Nicholas, K. M. J. Org. annelation sequence, our plan called for reaction of a (1Chem. 1986,51(11), 1960. ( 5 ) Saha, M.; Bagby, B.; Nicholas, K. M. Tetrahedron Lett. 1986,27, alkoxypropargylium)Co2(C0)6+complex, i.e. 2, with a 915. suitably functionalized cycloheptanone derivative, e.g. 1. (6) Heathcock,C. H.; Graham, S. C.; Pirrung, M. C.; Plavac, F.; White, In carrying out this reaction we have uncovered a high C. T. In The Total Synthesis of Natural Products; ApSimon, J., Ed.; Wiley: New York, 1983; Vol. 5, pp 347-377. degree of stereoselectivity in the formation of the two new To whom direct inquiries regarding X-ray diffraction results should be addressed. f
0022-326318811953-5193$01.50/0
Lee, K. H.; Furukawa, H.; J u g , E. S. J. Med. Chem 1972,15, 609. (a) Seyferth, D. Adv. Organomet. Chem. 1976, 14, 97. (b) Schreiber, S. L.; Sammakia, T.; Crowe, W. E. J. Am. Chem. SOC.1986, (7) (8)
108,3128.
0 1988 American Chemical Society
5194
J. Org. Chem., Vol. 53,No. 22, 1988
H 1' H3' H6 H3 H1" H7 H4, H5 H9 H2" H8
MontaRa et al.
5.50 (s, 1 H) 5.39 (s, 1 H) 4.10 (br dd, J1 = 4.9, Jz = 6.2, 1 H) 4.44 (br d, J = 7.5, 1 H)
Table I. *HNMR Spectral 5.34 (s, 1 H) 5.34 (s, 1 H) 4.09 (br dd, J1= 2.6, Jz = 6.0, 1 H) 4.28 (br d, J = 7.3, 1 H)
3.97 (dq, 51 = 7.1, Jz = 8.8, 1 H), 3.84 (dq, 5 1 = 7.1, 52 = 8.8, 1 H) 2.66 (br dq, J1= 6.6, Jq = 6.2. 1 H) 1.5k1.25 (m, W1,2 = 85 Hz, 4 H) 0.81 (d, J = 6.6, 3 H) 1.19 (t, J = 7.1, 3 H) 1.06 (s, 3 H)
3.74 (dq, 51 = 6.9, Jz = 7.9, 1 H), 3.19 (dq, J1 = 6.9, J , = 7.9, 1 H) 2.86 (br dq, J l = 6.8, J g = 6.0. 1 HI 1.66-1.30 (m, Wllz = 70 Hz, 4 H) 0.79 (d, J = 6.8, 3 H) 1.02 (t, J = 6.9, 3 H) 1.05 (s, 3 H)
origins of its stereoselectivity. Herein we report our findings. Results The precursor ketone 3 to the requisite silyl enol ether 4 was prepared conveniently as a mixture of isomers (a, cis-endo; b, cis-exo; c, trans; 45:41:14 by GC, NMR) from 3-pentanone in 82% overall yield (three steps) following Noyori's procedureg (eq 1). Successive treatment of 3a-c
Data of 8a-d 5.49 ( 8 , 1 H) 5.28 (s, 1 H)
3.94 (dq, 5 1 = 7.0, Jz = 8.7, 1 H), 3.79 (dq 51 = 7.0, 52 = 8.7, 1 H) 1.92 (4, J = 7.8, 1 H)
5.39 (s, 1 H) 5.24 (s, 1 H) 3.86 (br dd, J1= 5.4, Jz = 1.9, 1 H) 4.38 (br dd, J1= 2.3, J = 7.2, 1 H) 3.78 (dq, 51 = 7.0, Jz = 8.2, 1 H), 3.33 (dq, J1 = 7.0, 52 = 8.2, 1 H) 2.00 (4, J = 7.8, 1 H)
1.60-1.35 (m, W1 = 75 Hz) 1.08 (d, = 7.8, 3 H) 1.17 (t, J = 7.0, 3 H) 1.05 ( 8 , 3 H)
1.60-1.35 (m, W,,, = 85 Hz, 4 H) 1.17 (d, J = 7.8, 3 H) 1.11 (t,J = 7.0, 3 H) 1.09 ( 8 , 3 H)
3.84 (br d, J = 6.2) 4.40 (br d, J = 5.8, 1 H)
Treatment of acetal complex 5 with HBF4.Et20 in propionic anhydride at -46 "C followed by ether flooding afforded 6 as a dark red moisture-sensitive solid in 85% yield (eq 2). The reaction of 6 with the epimeric mixture
HBF4.0Et2
'.
H P ', o E t cco)jco-co (W)3
,
&: 4,4
(CO\CO -co
5
a b C
3
4
R 1 R2 R3 R4 H MeH Me MeH M e H MeH H Me
R1 R2
a H M e b M e H
with LDA and MesSiCl afforded the corresponding silyl enol ehter as a mixture of C7 epimers, 4a (endo) and 4b (exo) (45/55). The epimers were separated by preparative GC for characterization, and their stereochemistry was established by 'H NMR correlation studies, homonuclear decoupling experiments, and examination of molecular models. The most diagnostic proton resonances were those at C8, C7, and C9. Thus in 4a (endo C9) the H7 signal appears as a broadened doubled quartet of quartets ( J = 7.3, 2.2, 4.0 Hz) due to coupling with the protons at C9, C8, and H8 and weak W coupling ( J < 0.9 Hz)with H5 (exo). In 4b (exo C9) the H7 resonance appears as a quartet of quartets ( J = 6.9, 1.4 Hz) due to coupling with the methyl protons at C9 and C8; no coupling is observed with H6 because the H6-H7 dihedral anglelo (from the Dreiding model) is approximately 85". Supporting this analysis is the higher field C7 methyl resonance in 4a (6 0.91) due to shielding interactions with H4 and H5 (versus a deshielding dipolar interaction of the C9 methyl with the bridging oxygen in 4b, 6 1.19) and the correspondingly lower field H7 resonance in 4a (6 2.82) compared to 4b (6
(2)
tcoI3
6
of silyl enol ethers 4a,b was carried out at -68 "C in CH2C12 over 3 h. Careful flash chromatography of the crude reaction mixture gave three very distinct dark red fractions. The least polar fraction provided a small quantity (6% of the product mixture) of [HC=CC(=O)H]Co,(CO), ( 5 ) , which results from hydrolysis of 6. The second (and major) fraction provided the alkylated ketones 8a-d in 75% yield (eq 3); no other isomeric products were detected in the OTMS
4a,b
6
8
8a
8b
1.72).
The alkoxy-substituted cation complex 6 was prepared by the general method that we have developed for the parent alkyl- and aryl-substituted complexes."J2 (9) (a) Noyori, R.; Hayakawa, Y.; Takaya, H.; Murai, S.; Kobayashi, R.; Sonoda, N. J. Am. Chem SOC.1978, 100(6),1759. (b) Takaya, H.; Makino, S.; Hayakawa, Y.; Noyori, R. J. Am. Chem. SOC.1978, 100(6), 1765. (c) Noyori, R.; Baba, Y.; Makino, S.; Takaya, H. Tetrahedron Lett. 1973, 1741. (d) Noyori, R.; Makino, S.; Takayo, H. Tetrahedron Lett. 1973, 1745. (10) (a) Jackman, L. M.; Sternhell, S. Applications ofNuclear Magnetic Resonance Spectroscopy in Organic Chemistry; Pergamon: New York, 1969; pp 281-292. (b) Haasnoot, C. A. G.; De Leeuw, F. A. A. M.; Altona, C. Tetrahedron 1980,36, 2738.
8C
8d
reaction mixture. The third and very polar fraction was composed of hydroxylated cobalt complexes derived from cleavage of the ether functions. From this last fraction a small quantity (1%) of hydroxy ketone complexes 9a,b was (11) Connor, R. E.; Nicholas, K. M. J. Organomet. Chem. 1977,125, c-45. (12) Saha, M.; Varghese, V.; Nicholas, K. M. Organic Syntheses, in press.
J . Org. Chem., Val. 53,No.22,1988 5195
Approach to Pseudoguaianolides
Figure 1. X-ray structures of Sc (stereoview). Thermal ellipsoids are shown at the 50% level.
Figure 2. X-ray structure of Sd (stereoview). Thermal ellipsoids are shown at the 50% level. isolated and characterized as the free alkynes 10a,b following demetalation. Compounds lOa,b were found to have the same stereochemistry (vide infra) aa 8a,b but with an OH group in place of OEt. The individual isomers Bad (in order of elution), which could be separated by careful rechromatography and crystallization, were obtained in a relative ratio of 9 3 6 4 7 8 (by 'H NMR). Their isomeric nature was apparent by comparison of their extremely similar IR and mass spectra (M+ - CO 493.98, see the Experimental Section) and 'H and NMR (Tables I and 11). In order to establish absolute reference points for spectroscopic correlations suitable crystals of isomers 8c and 8d were obtained for X-ray diffraction studies. Figures 1and 2 show the molecular structures of 8c and 8d determined by X-ray diffraction. Examination of these figures reveals that 8c and 8d differ fundamentally only in the relative configuration a t Cl', the carbon adjacent to the coordinated ethynyl group. In both compounds the C7 methyl group is exo while the one a t C2 is endo. Products 8c and 8d can thus be seen to derive from attack of complex 6 on the ex0 face of the silyl enol ether 4b. In the solid-state structures of 8c and 8d the oxan-6-one ring adopts a chair conformation with the C7 methyl and the bulky (ethoxypropynyl)Co,-
(CO),side chain a t C2 occupying pseudoaxial positions. The conformations of the C2 side chain is noticeably different in the two isomers but this could be due to crystal packing forces. All bond lengths and angles are unexceptional (Table IV, Experimental Section), hoth within the bicyclic system and within the cobalt cluster unit. With the solid-state structures of 8c and 8c in hand it is worthwhile to compare their 'H and lsC NMR spectra (Tables I and 11) in order to determine the spectroscopic parameters that are structurally diagnostic. The assignments shown in Table I were made by comparison of the spectra of products Sa-d with those of the starting ketone(s) 3 and the silyl enol ethers 4a,b, supported by homonuclear spin decoupling and phase-sensitive 2D-NOESYI3 experiments. The 13CNMR assignments (Table 11) were facilitated by 2D HETCOR," DEPT,'5 and off-res(13) (a) Bodenhausen, G.; Kogler, H.: Emst, R R. J. Mogn. Reson. 1984, 58 370. (b) Wider, G.: Macurs, S.; Kumar, A,; Emst, R. R.; Wuthrich, K. Biochem. Biophys. Res. Commun. 1980,95, 1. (14)(a) Blu, A,; Morris, G. A. J. Mag". Reson. 1981,42,501. (b) Bax, A. J . Mag". Reson. 1983, 53, 512. (c) Rutar, V. J. Mag". Reson. 1984,
2u(l)] 0.029
*
7.697 (2) 19.106 (6) 14.517 (6) 90 91.52 (3) 90 2134.3 4 1.625 3 < 28 < 560 5135 (&h,k,l) 4350 0.026 0.036
. -. . -
- -
in the final diff map ( A-3)
pmu
0.41
0.62
twice with NaHCO, (0.5 M) and brine. Finally the ethereal solution was dried over anhydrous MgS04, filtered through a short pad of neutral alumina, and concentrated, giving 9 g of a light yellow crystalline crude mixture. This product was submitted to a flash column chromatography over silica gel (20 g of SiOz/g of substrate), isolating by hexane-ether, 30/70,8.3 g (80% yield) of a white crystalline product containing a diasltereomeric mixture lla-d (9/36/47/8 by NMR). Working on a smaller scale it is possible to obtain a 95% yield IR (KBr) 3260,2980,2970,2870, 2110,1710,1450,1380,1340, 1250,1200,1140,1090,1030,1020, 950,930,900, and 840; mp 59-65 “C (hexane); HRMS (EI, 70 eV, DIP) calcd for C14H2003 236.1412, found 236.1416; MS (EI, 70 eV, GC/MS: tR(b) 10.6 min, tR(C) 10.9 min, tR(d) 10.3 min). l l a : ‘H NMR (CDCI,) 6 4.86 (d, J = 2.2, 1 H, Hl’), 4.47 (br dd, unresolved, 1H, H-C6), 4.54 (d, J = 6.8, 1H, H3), 3.84 (dq, J 1 = 2.2,JZ = 71, 1 H, Hl”), 3.50 (dq, J 1 = 2.2,JZ = 7.1, 1H, Hl”), 2.80 (br dq, J1= 4.9, J2= 6.7, 1 H, H7), 2.37 (d, J = 2.2, 1 H, H3’), 2.20-1.60 (m, W l l z= 100 Hz, 4 H, H4 and H5), 0.93 (d, J = 6.7, 3 H, H9), 1.24 (t, J = 7.1, 3 H, H2”), 1.05 (s, 3 H, H8); GC/MS 80 “C, 2 min, 10 “C/min, 270 “C; t~ 11.1min, m/e (%) 236 (M+, 0.3), 221 (M+ - C H , 3), 207 (M+ -Et, 4), 193 (M+ - CO - Me, 23), 191 (M’ - EtO, 2), 180 (12), 179 (24), 165 (12), 152 (ll), 93 (20), 91 (13), and 83 (100). l l b : lH NMR (CDCl,) 6 4.98 (d, j = 2.0, 1 H, Hl’), 4.46 (br dd, unresolved, 1 H, H6), 4.55 (d, J = 7.1, 1H, H3), 3.76 (dq, J1 = 2.5, J z = 7.1, 1 H, Hl”), 3.38 (dq, J1 = 2.5,JZ = 7.1,l H, Hl”), 2.92 (br dq, J1= 4.6, Jz= 6.7, 1 H, H7), 2.51 (d, J = 2.0, 1 H, H-C3’), 2.20-1.60 (m, W l j z= 100 Hz, 4 H, H4 and H5), 0.93 (d, J = 6.7, 3 H, H9), 1.11 (t, J = 7.1, 3 H, H2”), 1.07 (s, 3 H, H8); GC/MS [tR 10.6 min], m/e (%) 236 (M’, 0.2), 221 (M+ - CH3, 2), 207 (M+ - Et, 3), 193 (M+ - CO - Me, 15), 191 (M+ - EtO, 2), 180 (8), 179 (16), 107 (13), 93 (22), 91 (17), and 83 (EtOCHECH, 100). l l c : lH NMR (CDCl,) 6 4.82 (d, J = 2.1, 1 H, Hl’), 4.44 (br dd, unresolved, 1H, H6), 4.31 (d, J = 6.6, 1 H, H3), 3.84 (dq, J1 = 2.2, J z = 7.1, 1H, Hl”), 3.50 (dq, J1 = 2.2, J z = 7.1, 1H, Hl”), 2.28 (4, J = 7.6, 1 H, H7), 2.41 (d, J = 2.1, 1 H, H3’), 2.20-1.60 (m, Wllz= 100 Hz, 4 H, H4 and H5), 1.29 (d, J = 7.6, 3 H, H9), 1.23 (t, J = 7.1, 3 H, H2”), and 1.07 (5, 3 H, H8); GC/MS [ t R 10.6 min], m/e (%) 236 (M’, 0.2), 221 (M+- CH3, 3), 207 (M+ - Et, 4), 193 (M+ - CO - Me, 23), 191 (M+ -EtO, 2), 190 (M’ - EtOH, 2), 180 (14), 139 (25), 165 (13), 152 (14), 151 (lo), 109 (16), 107 (21), 93 (32), 91 (21), and 83 (EtOCHCECH, 100). l l d : ‘H NMR (CDC13) 6 4.94 (d, J = 2.1, 1 H, Hl’), 4.44 (br dd, unresolved, 1 H),4.33 (d, J = 6.3, 1 H, H3), 3.76 (eq, J1 =
Table IV. Selected Bond Lengths (A) and Bond Angles (deg) (std deviation, u for last digit) 8c 8d 1.324 (3) 1.336 (2) C(2‘)-C (3‘) 1.493 (3) 1.518 (2) C(1’)-c(29 1.555 (2) 1.570 (3) C(l,)-C(2) 1.423 (2) 1.419 (3) C(1’)-0(12) 1.546 (2) 1.535 (3) C(l)-C(2) 1.542 (2) 1.551 (4) C(2)-C(3) 1.524 (4) 1.530 (2) C(2)-C(8) 1.517 (4) 1.523 (2) C(1)-C(7) 1.536 (2) 1.525 (5) C(6)-C(7) 1.523 (5) 1.532 (2) C(7)-C(9) 1.443 (2) 1.437 (4) C(S)-O(lO) 1.526 (2) 1.522 ( 5 ) C(5)-C(6) 1.543 (2) 1.542 (4) C(3)-C(4) 1.436 (2) 1.428 (3) C(3)-0(10) 143.9 (1) 145.2 (2) C(l’)-C(2’)-C(31) 110.4 (1) 110.2 (2) C(20-C(1’)-0(12) 108.6 (1) c(2)-c(1~)-0(12) 107.0 (2) 112.6 (1) 115.6 (2) C(2)-C(l’)-C(2’) 107.9 (1) 110.8 (2) C(l)-C(2)-C(l’) 105.9 (2) 107.9 (1) C(l~)-C(2)-C(3) 110.4 (2) 110.7 (1) C(l’)-C( 2)-C(8) 108.0 (1) c (1)-c(2)-C(3) 107.5 (2) 109.1 (1) 111.1 (2) C(l)-C(2)-C(8) 111.0 (2) 113.0 (1) C(3)-C (2)-C (8) 111.1 (2) 110.0 (1) C(l)-C(7)-C(9) 111.4 (1) C(6)-C (7)-C (9) 111.8 (3) 2.5, J = 7.1, 1 H, Hl”), 3.38 (dq, J1 = 2.5, J z = 7.1, 1 H, Hl”), 2.30 (9, J = 7.6, 1 H, H7), 2.49 (d, J = 2.0, H39, 2.20-1.60 (m, WliZ= 100 Hz, 4 H, H4 and H5), 1.29 (d, J = 7.6, 3 H, H9), 1.13 (t, J = 7.1, 3 H, H29, and 1.10 (s, 3 H, H8);GC/MS [tR10.9 min], m/e (%) 236 (M+, 0.2), 221 (M+ - CH,, 2), 207 (M+ - Et, 3), 193 (M+- CO - Me, E ) , 191 (M+ - EtO, 2), 190 (M’ - EtOH, 2), 179 (20), 152 (lo), 121 (lo), 111 (lo), 110 (lo), 109 (E), 107 (20), 93 (20), 91 (20), and 83 (EtOCHCECH, 100). X-ray Analysis of 8c a n d 8d. Single crystals of 8c and 8d suitable for X-ray analysis were obtained in n-hexane at -20 “C under CO. The crystals selected were mounted on a glass fiber, and the data were collectd on an Enraf-Nonius CAD-4 automatic X-ray diffractometer fitted with a liquid Nz low temperature device, using Mo K a radiation (A 0.71069 A) by the methods standard in this laboratory.” Unit cell dimensions were refined by least-squares analysis of the diffractometer angular setting of 25 well-centered reflections (26’ range = 30-40’). The data were corrected for Lorentz and polarization effects; no absorption correction was applied since it was deemed to be negligible. The atomic scattering factors were obtained from ref 25. Both structures were solved by the heavy atom method and refined by least-squares analysis (SHELX-76),26miminizing Zw((F,J lFC1)’. All the non-hydrogen atoms were refined anisotropically, and all the hydrogen atoms were refined isotropically. Data regarding collection and refinement are summarized in Table 111. Selected bond angles and lengths are given in Table IV.
Acknowledgment. Financial support was provided by the National Institutes of Health (Grant GM 34799) and a Fulbright-MEC postoctoral fellowship ( t o A. M. M o n M a ) . W e also t h a n k Dr. Tom Karns and John Laing for obtaining mass spectra. Supplementary Material Available: Complete listings of bond lengths and angles, thermal parameters, and atomic coordinatesfor 8c and 8d (23 pages). Ordering information is given on any current masthead page. ~~~~~
(24) Hossain, M. B.; van der Helm, D.; Poling, M. Acta Crystallogr., Sect. B: Struct. Sci. 1983,B39, 258. (25) International Tables for X - R a y Crystallography; Kynoch Birmingham, 1974; Vol. IV. (26) Sheldrick, G. M. S H E L X 76. Program for Crystal Structure Determination; Cambridge University: England.
