oxygen atom is oriented antiperiplanar to a C-OR bond. The stabilization would be gained through an electronic delocaliza- tion due to the overlap of an electron ...
rFOR
ERRATA
SEE
iF9.f!*.19...71.. P...17f.%,
I105
L.
1,7-Dioxaspiro[5.5]undecanes. An excellent system for the study of stereoelectronic effects (anomeric and exo-anomeric effects) in acetalsl ERRATA AND
JOHNK. SAUNDERS
Laboraroire de Synrhese Organique, DPparremenr de Chimie, FaculrP des Sciences, UniuersirP de Sherbrooke, Sherbrooke (QuP.), Canada Jl K 2Rl Received September 3, 1980 PIERREDESLONGCHAMPS, DARYLD. ROWAN,NORMAND POTHIER,TILLESSAUVE,and JOHNK. SAUNDERS. Can. J. Chem. 59, 1105 (1981). Several isomeric compounds derived from the spiro systems 5 to 9 (Scheme 4) were obtained from the acid cyclization of the appropriate dihydroxy ketone precursor. The configuration and the conformation of the products obtained was determined by I3C nmr analysis and equilibration studies. The experimental results can be rationalized by taking into account the anomeric and the exo-anomeric effects and the usual steric interactions. POTHIER,TILLESSAUVEet JOHN K. SAUNDERS. Can. J . Chem. PIERREDESLONGCHAMPS, DARYLD. ROWAN,NORMAND 59, 1105 (1981).
Plusieurs composes isomeres derives des systemes spiranniques 5 a 9 (Schema 4) furent obtenus par cyclisation en milieu acide des precurseurs dihydroxycetoniques appropries. La configuration et la conformation des produits obtenus ont ete dkterminees par la rmn du I3C et par des etudes d'equilibration. Les resultats exptrimentaux sont expliques en tenant compte de I'effet anomere, de I'effet exo-anomtre et des interactions steriques habituelles.
Stereoelectronic effects have been recognized for a long time to influence the configuration and the conformation of acetals, particularly in carbohydrates where these effects were first discovered and discussed in terms of the anomeric and exoanomeric effects (I).,,, a- And P-glycosides can theoretically take conformations A , , A,, A, and E,, E,, E, respectively (Scheme 1). The relative proportions of these various conformers in a and P-glycosides should be influenced by the usual steric interactions and by stereoelectronic effects. For instance, if stereoelectronic effects (anomeric and exo-anomeric effects) are important, the following predictions can be made: (a) conformer A, has only one anomeric effect and conformers A , and A, have two each,4 and since A, must be eliminated because of strong 'This work has been presented at the 8th Natural Products Symposium, University of West Indies, Mona, Jamaica, January 1980, and at the 1st International Symposium on Stereoelectronic Effects, University of St. Andrews, Scotland, July 1980. 2The preference for an alkoxy group to be axially oriented is due to the anomeric effect, whereas the preference for the R group of the side chain at the anomeric center to be in the A , or the E, conformation in a and P-glycosides respectively is due to the exo-anomeric effect (Scheme 1). 3The anomeric (or the exo-anomeric) effect is considered to be a stabilizing effect which occurs when an electron pair of an oxygen atom is oriented antiperiplanar to a C-OR bond. The stabilization would be gained through an electronic delocalization due to the overlap of an electron lone pair orbital of an oxygen with the antibonding orbital of a C-OR sigma bond (2, 3). 41n this article, we use the term anomeric effect to describe either an anomeric or an exo-anomeric effect, assuming that both effects are of the same order of magnitude.
steric interactions, A , must correspond to the most stable conformer of an a-glycoside; (b) conformer E, has no anomeric effect whereas E l and E, have one each, and since E2 has an extra steric interaction (one gauche form of butane ==0.9kcallmol) by comparison with EI, P-glycosides should exist as a mixture of conformers E, and E, in which E l should predominate. The validity of the above conclusion depends on the importance of the anomeric effect. Efforts have been made to evaluate the anomeric effect by undertaking equilibration studies between equatorial and axial isomers at the anomeric center in carbohydrates (4), and in monosubstituted 2alkoxytetrahydropyrans (5) as well as in more rigid systems (6). The anomeric effect has been evaluated to be of the order of 1.2 to 1.8 kcallmol from these studies. These evaluations cannot, however, be very precise because the orientation of the OR group in the axial and in the equatorial isomer was not considered, and the influence of the exoanomeric effect was consequently neglected. The evaluation of the anomeric effect could be achieved by determining the relative proportions of conformers in equatorial (El,E,, and E,) and axial (A and A,) 2-alkoxytetrahydropyrans respectively. This analysis, which could be done in principle by a study at low temperature by nmr spectroscopy, does not seem to be realizable because the energy barrier of rotation between conformers is presumably too small.5
,
analysis is also impossible if equatorial and axial isomers exist in only one preferred conformation.
0008-40421811071105-17$01.00/0 0 1 9 8 1 National Research Council of CanadaIConseil national de recherches du Canada
CAN. J. CHEM. VOL. 59, 1981
The analysis could also be done by nmr at room temperature provided that the various conformers have sufficiently different coupling constants. This method has the disadvantage that small percentages of some conformers will be difficult to detect. Using this method, in an attempt to assess the relative abundance of conformers E l and E, in P-glycosides, Lemieux (7) was unable to detect conformer E,. Thus, E l and E, would be separated by over 2 kcallmol. It was suggested that this rather unexpected situation would be mainly the result of a short C(1)-O(1) bond which would amplify the steric interaction in E,. Also, by comparison of bond length (X-ray) in a and P-glycosides, Lemieux et al. (8) further suggested that the exoanomeric effect would be stronger in the p-anomer. The fact remains that there exists no experimental evidence, including X-ray (9) and dipole moment studies (lo), that a and P-glycosides exist in conformations other than A, and E, respectively. The above results indicate that Zalkoxytetrahydropyrans are not very appropriate models for a precise evaluation of the anomeric and the exo-
anomeric effect. There is, however, a very interesting experiment on the evaluation of the anomeric effect which has been described by Descotes et al. (11). They have studied the acid catalyzed isomerization of cis and trans bicyclic acetals 1 and 2 (Scheme 2) and found, at equilibrium, a mixture of 57% cis and 43% trans. The cis isomer 1 corresponds to conformer E, (or A,) which has one anomeric effect, whereas the trans isomer 2 corresponds to conformer E, which has none. It was possible to estimate the steric effects in cis acetall (one gauche interaction = 0.85 kcallmol and one interaction for an axial OR group to cyclohexane = 0.8 kcallmol) and, by taking into account an entropy factor (0.42 kcallmol at 80°C) caused by the fact that cis acetal 1 exists as a mixture of two conformations (cis decalin system), they arrived at
DESLONGCHAMPS ET AL.
5a (0 kcallmol)
5b (2.4 kcallmol)
5c (4.8 kcal/mol)
SCHEME 4
1
'
a value of 1.4 kcallmol for the anomeric effect. We Results and Discussion have recently studied the equilibration of cis and spire system 5 trans tricyclic acetals 3 and 4 and have arrived at a ~~~~~~~d 5 can exist theoretically in the three value of 1.5 kcal/mol(12), which confirms the result conformations 5a, 5b, and 5c (Scheme 4). ConforDescotes et The 'e4-lo5 kcal m ~ ' mation 5a has two oxygens having each an electron must, however, be considered a minimum value pair oriented antiperiplanar to a polar C-0 bond, because, as suggested by Lemieux et (81, the conformation 56 has only one, whereas conformavalue for the steric interactions might be larger, tion 5c has none. consequently, sa has two anobeing amplified by a shortened C-0 bond.6 meric effects, 56 has only one, whereas 5c has We have mdertaken a study On the conforma- none. Accepting the value of 1.4 kcal/mol for one tional and on the acid hydrolysis of the anomeric effect, conformations 5a and 56 should 1,7-dioxas~iro[5.5l-undecane system 5 (Scheme 3) be more stable than conformation 5c by 2.8 and 1.4 in order to obtain results on the evaluation of both kcal/mol respectively on that basis.7 the anomeric and the exo-anomeric effects. We ~ h next , task concerns the evaluation of steric wish to report these results. effects in these three conformations. In conformaWe envisaged that the Viro Vstem be a tion 5a ,the two oxygens are oriented axial to a ring. very convenient one for the study of stereoelec- 1, conformation sc, there are two methylene tronic effects in the acetal function for the following groups oriented axial to a ring. conformation 5b, reasons: (a) 5 can take three different conforma- there are one oxygen and one methylene group tions which correspond to either conformer EI (or axially oriented to a ring. When a rnethylene group and P-2-a1k0xytetrah~dr0- is axially oriented, it corresponds to two gauche Or pyrans; (b) with 5, it appeared possible to under- forms of butane evaluated at 0.9 kcal/mol each take a conformational analysis by low temperature (14). when an oxygen is axially oriented, it c o r e nmr spectroscopy, because the energy barrier for spends to two gauche forms of n-propylether each conformational change which involves a chair ( O - ~ H , - ~ ~ , - ~ H , ) we have evaluated inversion should be high enough; (c) analogously to at 0.4 kcalImol each (15). On that basis, the steric the system of Descotes et al., the steric effects effect for conformations 5a, 56, and 5c should should be easily evaluated; and (d) by adding correspond to 1.6 (4 x 0.4), 2.6 (2 x 0.4 + 2 x 0.9), appropriate a l k ~ substituents l to the spire system and 3.6 (4 x 0 . 9 kcalImol respectively (Table 1). 5, it appeared possible to isolate isomeric cornIf the stabilizing anomeric and the destabilizing pounds which would differ by existing in one ofthe ,teric effects are taken together, conformation 5a above conformations. should be more stable than conformations 56 and We have studied the parent 5, the 5, by 2.4 and 4.8 kcal/mol respectively (Table I). methyl substituted derivatives 6 and 7, the tricyclic This analysis leads to the prediction that the spire Vstem 8, as as the corresponding compound 5 must exist essentially in conformation substituted derivatives 9 (Scheme 4). 5a only. E39
6Jeffrey et a / . (13) were the first t o carry out molecular orbital calculations on the anomeric effect, and suggested that a s much a s 4 to 6 kcallmol of stabilization can be involved.
'We make the assumption that when there are two anomeric effects in the same conformation, they are additive.
CAN. J . CHEM. VOL. 59, 1981
TABLE1. Evaluation of steric and stereoelectronic effects* Effects, compound 5
Total Relative to 5a
-1.2 0
1.2 2.4
3.6 4.8
Effects, compound 14
2 ae = -2.8 4 c o = 1.6
Total Relative to 14u
I ae = -1.4 2 c o = 0.8 2 cc = 1.8
- 1.2 0
4 cc = 3.6 1 6cc = 4.0
1.2 2.4
1 ae=-1.4 2 c o = 0.8 2 cc = 1.8 1 6cc = 4.0
7.6
5.2
8.8
6.4
Effects, compound 15
Total Relative to 14a
2 ae = -2.8 3 c o = 1.2 1 c c = 0.9 1 6co = 2.4
1 ae = - 1.4 1 c o = 0.4 3 c c = 2.7 1 6co = 2.4
1.7 2.9
4.1 5.3
4cc=3.6
1 a e = -1.4 2 c o = 0.8 2 c c = 1.8
3.6 4.8
1.2 2.4
Effects, compound 21
Total Relative to 21a
2 ae = -2.8 6 co = 2.4 2 cc = 1.8
1 ae=-1.4 4 co = 1.6 1 cc = 0.9 2 Scc = 8.0
4 co = 1.6 6 cc = 5.4
1.4 0
9.1 7.7
7.0 5.6
Effects, compound 22
Total Relative to 21a
DESLONGCHAMPS ET AL.
TABLE1. (Continued) Effects, compound 23
2 6 1 1
ae = -2.8 co = 2.4 cc = 0.9 6cc = 4.0
1 ae = -1.4 5 co = 2.0 5 cc = 4.5
Total
4.5
5.1
11.5
8.7
Relative to 21a
3.1
3.7
10.1
7.3
2 co = 0.8 3 cc = 2.7 2 6cc = 8.0
1 3 1 2
ae=-1.4 co = 1.2 cc = 0.9 6cc = 8.0
Effects, compound 34
Total Relative to 34a Effects, compound 35
Total Relative to 34a Effects, compound 43
Total Relative to 43b Effects, compound 44 44a
Total Relative to 43b
44b
C A N . J. CHEM. VOL. 59, 1981
TABLE1 . (Concluded) Effects, compound 46 46a
46b
2 ae = -2.8 4 c o = 1.6
I a e = -1.4 2 co = 0.8 2 c c = 1.8 1 Scc = 4.0
Total Relative to 46a
-1.2
5.2
0
6.4
Effects, compound 47
1 ae = -1.4 1 co = 0.4 3 cc = 2.7 1 Scc = 4.0
4 cc = 3.6
Total
5.7
3.6
Relative to 46a
6.9
4.8
I ae = one anomericeffect; I co = one gauche form ofOCH,CHICHl; 1 cc = one gauche form ofn-butane; I 6co = CH, and oxygen in a 1.3 diaxial arrangement; I 6cc = two CH,'s in a 1.3 diaxial arrangement.
I
,
The spiro compound 5 was prepared by the method (10 11 + 12 + 13 + 5) described in Scheme 5.8 The 13C nmr spectra of 5 at room temperature or at low temperature (= - 130°C, CHFC1,) are virtually identical and they show five peaks only.9 This result indicates that 5 exists in only one conformation which can either be 5a or 5c. Due to symmetry, conformations 5a and 5c should show five peaks only, whereas conformation 5b should exhibit eleven peaks. Conformation 5b is therefore eliminated. Conformation 5a has two anomeric effects whereas 5c has none, and on that basis, 5c must be eliminated. Rigorous evidence confirming this conclusion has been obtained by X-ray analysis (vide infra). Consequently, 5a corresponds to the stable conformation of 5 as predicted. Interestingly, compound 5 does not yield the corresponding dihydroxyketone precursor upon acid hydrolysis; however, in the presence of deuterated water, it incorporated four deuterium atoms (at C(5) and C(11)). This result shows that 5 undergoes hydrolysis, but the equilibrium lies toward the spiro ketal 5 in preference to the dihydroxy ketone precursor.
+
Spiro System 6 The spiro system 6 was considered next. With 6, 'A shorter synthesis of 5 has been recently published, see ref.
16. 9A detailed account of the 13C nmr spectral analysis is reported in the accompanying publication.
two isomers, 14 and 15 (Scheme 6), are possible and each can exist in principle in four different conformations (14a-d and 15a -d respectively). Furthermore, the two isomers 14 and 15 are theoretically interconvertible under acidic conditions (14 can be converted into the mirror image of 15 by opening and reclosure of the acetal function). The evaluation of the anomeric and the steric effects in the eight conformations of isomers 14 and 15 is described in Table 1. When a methyl group was found to be in a 1,3-diaxial arrangement with another methyl (or methylene) group (6 C, C) or with an oxygen atom (6 C, 0 ) we have taken the values of 4.0 and 2.4 kcallmol respectively for the corresponding steric interactions (17, 18). The relative stability of the four conformers (14a-d and 15a-d) for each of the two isomers 14 and 15 is shown in Scheme 6. This analysis shows that isomer 14 should exist in conformation 14a (0 kcallrnol) only, whereas isomer 15 should exist as a mixture of a major (15d, 2.4 kcallmol) and a minor (15a, 2.9 kcallmol) conformer. However, since isomers 14 and 15 are interconvertible, and since conformer 14a is more stable than conformer 15d by 2.4 kcallmol, this analysis leads to the prediction that under thermodynamically controlled conditions, only isomer 14 should be formed and that it should exist in conformation 14a only. The preparation of the spiro system 6 (10 16, 17 6) is described in scheme 5. we have isolated only one isomer (14) and analysis by nmr shows that 14 exists in only one conforma-
,,
+
DESLONGCHAMPS ET AL.
.
. .. . . . . . .. . . . . . . . . . . .. . .. . .. . .. . .. .. .. .... .... .... ... . .,.... ... ... . .. .. . .. . . .. . . . ... .. .. . . . .. . . . . . . . . . . . . . . .
SCHEME 5
tion which corresponds to 1 4 ~Upon . ~ hydrolysis (2.3 M DCl in 60% D,O/DME), compound 14 did not hydrolyse but incorporated fair deuterium atoms. This result shows that hydrolysis of 14 takes place but the equilibrium lies toward the cyclic form 14 in preference to the corresponding dihydroxyketone. This result further proves that under thermodynamic conditions, the isomer 15 should not be observed, a result in accord with our prediction. Spiro System 7 We will now consider the spiro system 7 which has two methyl groups. With this system, there are three possible isomers; two of them, 21 and 22, are formed from the cyclization of the dl dihydroxyketone 19 (Scheme 7), whereas the third isomer 23 comes from the cyclization of the isomeric meso
dihydroxyketone 20. Under acidic conditions, 21 and 22 should be readily interconvertible and if these acidic conditions afe strong enough to allow epimerization of the two dihydroxyketones 19 and 20, the three isomeric compounds 21, 22, and 23 should be interconvertible. Molecular models show that isomer 21 can exist in the three conformations, 21a-c (Scheme 8), isomer 22 in the three conformations, 22a-c, and isomer 23 in the four conformations, 23a-d. The relative stabilities of these various conformers of the three isomers 21, 22, and 23 are indicated in Scheme 8 and the detailed analysis is described in Table 1. Isomer 21 should therefore exist in conformation 21a only (0 kcallmol), isomer 22 should also exist in only one conformation (22a, 1.8 kcallmol), whereas isomer 23 should exist as a mixture of a
CAN. J . CHEM. VOL. 59, 1981
H-c-CH,
I
HO-C-H
H-c-CH,
I
H-C-OH
I
I
19 (dl)
1
H-c-CH, +
I
HO-C-H
I
DESLONGCHAMPS ET AL.
major (23a, 3.1 kcallmol) and a minor (236, 3.7 kcallmol) conformer. This analysis leads to the prediction that, under thermodynamic conditions, the dl precursor 19 should yield a 2.97 :3 mixture of isomers 21 and 22 which will exist in conformations 21a and 2242 respectively, whereas the meso precursor 20 should yield 23 existing as a mixture of conformers 23a and 236. However, if the acidic conditions used allow the equilibration of the isomeric precursors 19 and 20, isomer 23 which is at least 3.1 kcallmol less stable than isomer 21 should not be observed, and a -97:3 mixture of isomers 21 and 22 should be isolated. The preparation of a mixture of dl and meso dihydroxy ketones 19 and 20 (24 + 25 + 26 + 27 + 28 29 + 19 20) is described in Scheme 5. Cyclization of this mixture under mild acidic conditions (PTSAICHCl,) gave a mixture of the three isomeric spiroketals 21, 22, and 23 which were separated. These products were identified by their spectral data, equilibration experiments, and behavior under hydrolysis conditions; 13Cnmr spectroscopy further showed that 21 and 22 exist in conformations 21a and 22a respectively. We have also been able to show by low temperature study (CHFCI,, 160 K, 250 MHz), that 23 exists as a mixture of conformations 23a and 236, as predi~ted.~
+
+
Treatment of 21 under aqueous acid conditions (0.1 N HCI in H,O/acetone) did not yield the precursor dl dihydroxyketone 19, but gave a 2197 :3 mixture of 21 and 22. Repeating the above experiment with deuterated water, compound 21 was shown to incorporate two deuterium atoms. Treatment of 23 under the same acidic conditions gave also a 97:3 mixture of 21 and 22. Under milder acidic conditions (0.01 N HC1 in 20% H,O/acetone) 23 produced a mixture of 21, 22, and the meso dihydroxyketone 20, which was isolated as the corresponding meso ketodiacetate 29.1° These results are again completely consistent with our predictions based on the evaluation of the steric and the anomeric effects. Spiro System 8
With the tricyclic spiro system 8, two isomers, 34 and 35, are possible from the cyclization of the dihydroxyketone 33 (Scheme 9) and they can exist 1°The structure of meso ketodiacetate 29 was proven in the following way. Upon reduction of the ketone function, 29 can give the two isomers 30 and 31 whereas the dl ketodiacetate 28 can give the isomer 32 only. The ketodiacetate obtained (29) was reduced (NaBH,, MeOH); "C nmr analysis showed the presence of two signals for a carbon bearing a secondary alcohol indicating that a mixture of 30 and 31 was obtained. The product of the reduction of a 1 : l mixture of 28 and 29 showed three different signals for a carbon bearing a secondary alcohol, indicating that a mixture of 30.31, and 32 was obtained.
CAN. J . CHEM. VOL. 59, 1981
in two conformations each, which are 34a-b and 35a-b respectively. The detailed analysis of the relative stability of these four structures is described in Table 1. Conformer 34a (0 kcallmol) is more stable than 34b (2.4 kcallmol); isomer 34 should therefore exist in conformation 34a only. Similarly, conformer 35a (2.4 kcallmol) is more stable than 35b (4.8 kcallrnol); isomer 35 should exist in conformation 35a only. However, since conformer 34a is more stable than conformer 35a by 2.4 kcallmol, and since the isomers 34 and 35 can be interconverted by equilibration under acidic conditions, only isomer 34 should be observed under thermodynamically controlled conditions. The preparation of the tetrahydropyranyl derivative 38 of monocyclic dihydroxyketone 33 (36 11 + 37 + 38) is described in Scheme 10. Treatment of 38 under acidic conditions (0.1 N HC1/CH30H) gave only the tricyclic ketal product 34 which was shown by 13C nmr to exist in conformation 34a only.9 Under aqueous acidic conditions (1 N DC1, acetone), compound 34 did not hydrolyse or equilibrate with 35 but incorporated four deuterium atoms. We have also prepared the monocyclic dihydroxyketone 33 (38 + 39 + 40 + 41 + 33, Scheme 10) and this product was cyclized under mild acid conditions (catalyst p- TSOH in CHCl,); the reaction was stopped before completion and the
+
reaction mixture was acetylated ((CH3C0)20,pyridine) before isolation. This procedure gave a mixture of tricyclic acetal 34 and ketodiacetate 41 as well as a very small quantity of tricyclic acetal 35. Compound 35 was obtained pure (= 1.5 mg) and characterized by infrared, 'H nmr, and mass spectrometry. Upon treatment under acidic conditions (1 N HCl in acetone), tricyclic acetal 35 was irreversibly transformed into the more stable isomer 34. These results are again in complete agreement with our prediction. Spiro System 9 This spiro system can theoretically give the four isomers 43, 44, 46, and 47 (Scheme 11). The two isomers 43 and 44 come from the cyclization of the dihydroxyketone precursor 42, whereas the two isomers 46 and 47 come from the cyclization of the isomeric dihydroxyketone precursor 45. In this case, 42 and 45 cannot be interconverted by epimerization. The isomers 43 and 44 which are interconvertible under acidic conditions can exist in two conformations each, which are 43a, b and 442, b, respectively (Scheme 12). Similarly, the isomers 46 and 47 which are also interconvertible under acidic conditions can exist in two conformations each which are 46a, b and 47a, b, respectively.
11 15
DESLONGCHAMPS ET AL.
ditions, the acid cyclization of a mixture of the isomeric dihydroxyketones 42 and 45 should yield a mixture of the three isomers 43, 44, and 46. The preparation of a mixture of the tetrahydropyranyl derivatives 49 and 50 of the dihydroxyketones 42 and 45 (36 16 += 48 += 49 50) is described in Scheme 10. Cyclization of 49 and 50 under acidic conditions (1 N HCl, acetone), yielded as expected a mixture of 43,44, and 46 which were separated by chromatography. Low temperature 13Cnmr study confirms that isomers 44 and 46 are conformationally rigid and exist in conformations 44a and 46a respe~tively.~ Contrary to our analysis, isomer 43 exists in conformation 436 only; steric effects might have been underestimated in 43a, especially the 1,3 diaxial interaction between the oxygen and the methyl group. Furthermore, under acidic conditions, isomer 43 (or 44) was converted into a = I : 1 mixture of isomers 43 and 44. It was also shown that isomer 46 does not isomerize under acidic conditions, indicating that under thermodynamically controlled conditions the formation of 47 cannot compete with that of 46.
+
OR 39 R = CH3C0, R' = THP 40 R = C H 3 C 0 , R f = H 41 R = CH3C0, R' = C H 3 C 0 33 R = H , R'=H
CH3
I
The analysis of the relative stabilities of the eight conformers of the four isomeric compounds 43,44, 46, and 47 is described in detail in Table 1 and shown in Scheme 12. Isomer 43 should exist as a mixture of a major (436 0 kcallmol) and a minor conformer (43a, 0.5 kcallmol). Isomer 44 should exist only in conformation 44a (0 kcallmol). However, isomers 43 and 44 are interconvertible under acid conditions; a = 1: 1 mixture of isomers 43 and 44 should therefore be isolated from the cyclization of the precursor 42. The isomer 43 should, however, slightly predominate at equilibrium due to an entropy factor, because 43 can exist in two conformations (43a and 436) whereas 44 can exist in only one (44a). Isomer 46 should exist in conformation 46a (0 kcallmol) only, whereas isomer 47 should exist as a mixture of conformers 47a (6.9 kcallmol) and 476 (4.8 kcallrnol). However, since isomers 46 and 47 are interconvertible under acidic conditions, only isomer 46 existing in conformation 46a should be isolated under thermodynamically controlled conditions. Thus, under thermodynamically controlled con-
+
1116
CAN. J. CHEM. VOL. 59, 1981
Results from the Literature Compound 51, a masked tetrahydroxyketone (Scheme 13), which can theoretically give the isomers 52 and 53, was found to yield the isomer 52 exclusively (19). The structure of 52 was proven by X-ray analysis. Similarly, dibromodihydroxyketone 54 can theoretically give either isomer 55 or 56. Upon cyclization, the isomer 55 was the product formed (20), and its structure was also established by X-ray analysis (21). The recently reported total synthesis of ionophore A-23187 (22), a poly-
ether antibiotic which can be considered as a substituted 1,7-dioxaspiro[5.5]undecane system, i.e. 5, confirms these results. Thus, these results described in the literature rigorously established that conformer 5c of 5 is much less stable than conformer 5a , as predicted. Conclusion These results constitute very strong evidence concerning the importance of the anomeric (and the exo-anomeric) effect. The value of 1.4 kcallmol for
DESLONGCHAMPS ET AL.
an anomeric effect must, however, be considered as a minimum value, because the steric interactions might be larger than those observed in a simple cyclohexane (8). These results demonstrate clearly that the basic spiro system 5 exists in conformation 5a only; 5 can therefore be considered as a conformationally rigid system." Experimental
I
I
Vapor-phase chromatographic (vpc) analyses and separations were carried out on a Varian Aerograph instrument, model 2800 equipped with a thermal conductivity detector. The infrared (ir) spectra were recorded in chloroform on a Perkin-Elmer 257 spectrophotometer. Proton nuclear magnetic resonance ('H nmr) spectra were recorded in deuterochloroform on a Bruker WP-60 instrument with TMS as an internal standard. The I3C nrnr spectra were recorded on a Bruker HX-90 spectrometer equipped with a Nicolet 1083 computer (8K memory for data) operating in the Fourier transform mode. Spectra were recorded in deuterochloroform with a sweep width of 5000 Hz. Mass spectra were obtained on Hitachi-Perkin-Elmer RMU-6-A and Micromass ZAB-2F machines. Microanalyses were carried out by Guelph Chemical Laboratories Ltd., Guelph, Ontario. Bicyclic lactone 36 was obtained by Baeyer-Villiger oxidation (23) of trans-hydrindanone (24). The abbreviation plc (x% E/H) refers to preparative thin layer chromatography eluting with x% ether in hexane. The following abbreviations are also used: R T (room temperature); s (singlet); bs (broad singlet); d (doublet); t (triplet); q (quartet); quin (quintet); m (multiplet); W/2 (peak width at half peak height). Acetylene Z Z T o dihydropyran (84 g, 1.0 mol) cooled in an ice bath was added 3-butyn-1-01 (50 g, 0.70 mol) and then concentrated hydrochloric acid (2 drops). After 3 h at RT, potassium carbonate (1 g) was added and after 15 min stirring the solution was filtered and distilled to give pure compound 11 (99 g, 90%); bp 72-78"C/20 Torr; ir: 3280, 1124, 1108, 1053, and 1017 cm-I; lH nrnr 6: 1.63 (6H, m), 1.95 ( l H , t, J = 2.5 Hz, HC-C), 2.48 (2H, t of d, J = 7.0 Hz, 2.5 Hz, CH2C=C), 3.30-4.15 (4H, m, CH20), 4.64 (IH, bs, OCHO). Acetylene 16 A small quantity of propargyl bromide was added to magnesium (9.2 g, 0.38 mol) and mercuric chloride (catalytic quantity) under ether (50 mL). Once the reaction had been initiated by gentle heating, the solution was cooled to O°C and the remainder of the propargyl bromide (47.6 g, 0.40 mol) in ether (100 mL) was slowly added. After 30 min, acetaldehyde (19.8 g, 0.45 moll in ether (100 mL) was slowly added and the reaction stirred at room temperature for a further 30 min. The solution was acidified with 1 N hydrochloric acid and the organic phase was removed. The aqueous phase was extracted with ether (3 x 50 mL) and the combined ether phases were then washed with brine ( l x ) , dried (Na2S04),and evaporated. The residue was added to dihydropyran (42 g, 0.50 mol) maintained at WC. Two drops of concentrated hydrochloric acid were then added and the solution was left at R T for 3 h. Potassium carbonate (1 g) was added and after 15 min stirring, the reaction "The basic spiro system 5 can therefore be used to develop a new strategy for the synthesis of aliphatic chains containing several asymmetric centers and functional groups. Work is now in progress in our laboratory to demonstrate the validity of this new strategy.
1117
was filtered and distilled to give pure compound 16 (19 g, 30%); bp90-9S0C/20 Torr; ir: 3310,1110, 1053,1000, and973 cm-I; IH nrnr 6: 1.24 and 1.32 (3H, d, J = 10.5 Hz, isomeric CH,), 1.62 (6H, m), 2.00 ( l H , m, HC=C), 2.20-2.60 (2H, m, CH2C=C), 3.30-4.20 (3H, m, CHOR), 4.75 ( l H , bs, OCHO). 1.7-Dioxaspiro[5.5]undecane (5) T o a solution of compound 11 (3.08 g, 20 mmol) in tetrahydrofuran (25 mL) at -78°C was added slowly n-butyllithium (1.6 M in hexane, 20 mmol). After 30 min, 6-valerolactone (2.00 g, 20 mmol) in tetrahydrofuran (25 mL) was rapidly added and the reaction was allowed to warm to RT. The solution was poured into water (50 mL) and theorganic phase was separated. The aqueous phase was extracted with ether (3 x 50 mL) and the combined organic phases were then dried (Na2S04) and evaporated. The oily residue was taken up in dry methanol (50 mL) and hydrogenated (40 psi over PtO,). After filtration through silica gel, concentrated hydrochloric acid (2 drops) was added and the solution was left at R T overnight. Evaporation of the methanol gave a residue which was taken up in ether and dried (Na2S04 and some K,C03). Evaporation, followed by chromatography on silica gel gave, on elution with 5% EIH, spiroketal5 (1.10 g, 33%) as a clear oil; ir: 1164, 1076, 1046, and 966 cm-I; lH nmr 6: 1.60 (12H, m), 3.3-4.0 (4H, m, CH20); I3C nrnr 6: 18.6 (t), 25.4 (t), 35.8 (t), 60.3 (t), 94.9 (s); ms mle: 156 (M+). 2-Methyl-l,7-dioxaspiro[5.5]undecane14 (6) T o a solution of acetylene 16 (3.53 g, 20 mmol) in tetrahydrofuran (20 mL), cooled to -78OC, was slowly added n butyllithium (21 mmol of 1.6 M solution in hexane). After 30 min, a solution of 6-valerolactone (2.0 g, 20 mmol) in tetrahydrofuran (40 mL) was rapidly added and the solution was then allowed to warm to RT. The reaction was quenched in water (50 mL), the organic phase was removed, and the aqueous phase was ether extracted (3x). The combined organic phases were dried (Na2S04)and evaporated togive an oily residue which was hydrogenated (40 psi) over platinum oxide in methanol (50 mL). The catalyst was removed by filtration through silica gel, concentrated hydrochloric acid (2 drops) was added and the solution was left at R T overnight. The solvent was removed under reduced pressure and the residue was taken up in ether and dried (MgS041K2C03). Evaporation and chromatography on silica gel gave, on elution with 5% EIH. methvl sviroketal 14 (900 mg,?!6%) as.a clear oil; ir: 1384, 1216, 1093; 1064, and 994 cm-I; ' H nmr6: 1.14(3H, d, J = 10.5 Hz, CH,), 1.54(12 H, m), 3.60 (3H, m, CHOR); 13Cnrnr 6: 18.6 (t), 19.0 (t), 21.8 (q), 25.4 (t), 32.7 (t), 35.1 (t), 35.9 (t), 60.2 (t), 65.1 (d), 95.5 (s); ms mle: 170 (M+). Deuteration of Spiroketals 5 and 14 The spiroketals (100-300 mg) in dimethoxyethane (3.0 mL), deuterium oxide (3.0 mL), and 35% deuterium chloridelD20(1.5 mL) were maintained at R T overnight. The reaction was diluted with water (10 mL) and ether extracted (3 x 20 mL). Drying (MgS04) and evaporation of solvent gave the deuterated ketals; d4-acetal 5: I3C nmr 6: 18.3, 25.3, 60.4, anomeric carbon not observed; d4-acetal 14: 13C nmr 6: 18.4, 18.7, 21.8, 25.4, 32.7, 60.3,65.2, anomeric carbon not observed. Keto-ester 24 A suspension of sodium hydride (4.22 g, 50% dispersion, 88 mol, washed with pentane (2x)) in tetrahydrofuran (200 mL) was cooled in an icelsalt bath under nitrogen and ethyl-apropionyl propionate (12.6 g, 9.64 mL, 80 mmol) was added dropwise with rapid stirring. Ten minutes after gas evolution ceased, n-butyllithium (81 mmol, 1.6 M in hexane) was added and, after afurther 10 min, allyl bromide(8.0 mL, 92 mmol). The
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CAN. J. CHEM. VOL. 59, 1981
cooling bath was removed and, after 10 rnin, the reaction was quenched (10% hydrochloric acid, 50 mL) and diluted with ether (2.200 mL). 'The aqueous phase and a first brine washing of the organic phase were combined and further extracted with ether. The combined ether phases were then washed with brine, brine - sodium bicarbonate to remove colour, and then brine again until neutral. Drying (MgSO,) and evaporation of the solvent gave the keto-ester24(14.8g, 94%) sufficiently pure for the next reaction. Distillation (86-88"C/4 Torr) and vpc (5 ft x in; 10% SE-30 on Chromosorb W, 160°C) gave an analytical sample; ir: 3070,1745, 1716, 1643,1222, 1180,973, and 898cm-I; IHnmr6: 1.11 (3H, d, J = 7 Hz, yCH,), 1.25 (3H, t, J = 7 HZ, CH2CH3), 1 . 3 2 ( 3 H , d , J = 8 H z , c r C H 3 ) , 1.9-3.1(3.5H,m),3.63and3.67 (IH, 2 q, J = 7 Hz, isomeric aH), 4.17 (2H, q, J = 7 Hz, OCH,), 4.80-6.10 (3H, olefinic m); ms mle: 198 (Mf), 152, 129, 97. Keto-ester 25 A solution of dimethylformamide (70 mL) and benzene (40 mL) was dried in a Dean-Stark apparatus (17 ml removed), cooled under nitrogen, and the major part added to sodium hydride (3.66 g, 50% dispersion, 76.3 mmol, washed with pentane ( 2 ~ ) )and stirred in an icelsalt bath under nitrogen. Keto-ester 24 (13.7 g, 69.2 mmol) was added dropwise followed by the remainder of the solvent. After 15 min, ally1 bromide (7.1 mL, 82 mmol) was added and the system was allowed to warm to R T over 15 rnin. After 50 min at 40°C, the reaction was quenched (10% hydrochloric acid, 40 mL), diluted with water (600 mL), and extracted with ether (3x). The combined organic fractions were washed with water until neutral, dried (MgSO,), and evaporated to give keto-ester 25 (14.2 g, 86%) sufficiently pure for the next reaction. An analytical sample was prepared by vpc (5 ft. x f in., 10% SE-30 on Chromosorb W, 170°C); ir: 3065, 1735, 1713, 1642, 1220, 1135,977, and 897 cm-I; ' H nmr6: 1.06 (3H, d, J = 7 Hz, CH,), 1.26 (3H, t, J = 7 Hz, CH,), 1.32 and 1.34(3H, twos, isomeric CH,'s), 2.0-3.1 (6H, m), 4.17 (2H, q, J = 7 Hz), 4.80-6.07 (6H, olefinic m); ms m/e: 238 (M+), 210, 193, 142. Ketone 26 Keto-ester 25 (14.2 g, 59.7 mmol) in methanol (200 mL) and water (10 mL) was refluxed with sodium hydroxide (5.0 g, 125 mmol) with vigorous stirring for 3f h. The solvent was largely removed under reduced pressure and the residue was diluted with water and adjusted to neutral pH. Ether extraction (3x), drying (MgSO,), and evaporation of the solvent followed by distillation (76-8O0C/6 Torr) gave ketone 26 (7.08 g, 71.5%). An analytical sample was prepared by vpc (5 ft. x t in., 10% SE-30 on Chromosorb W, 130°C); ir: 3065, 1713, 1642, 977, and 893 cm-I; 'H nmr 6: 1.04 and 1.07 (6H, two d, J = 7 Hz, isomeric CH,), 1.73-3.02 (6H, m), 4.75-6.02 (6H, olefinic m); I3C nmr 6: 16.1 and 16.2 (q, isomeric CH,), 37.0 and 37.2 (t), 45.0 (d), 1 16.8, 135.9,216.5; ms m/e: 166 (M+), 97, 69. Dibromide 27 The ketone 26 (2.39 g, 14.4 mmol) in pentane (500 mL) was placed in a water-cooled uv apparatus, cooled with ice, and purged with nitrogen for 15 min. Anhydrous hydrogen bromide was then bubbled gently into the solution with irradiation from a 450 W Hanovia mercury lamp for 15 rnin. The solution was again purged with nitrogen and the pentane solution was washed with 5% sodium bicarbonate containing some sodium thiosulfate (2x1, then water ( I x ) . Drying (MgS04) and evaporation gave the dibromide 27 (4.21 g, 85%) as a rapidly blackening oil which was used directly for the next step; plc (50% E/H) gave an analytical sample; ir: 1713, 1243, and 995 cm-I; lH nmr 6: 1.08 and 1.09 (6H, two d, J = 7 Hz, isomeric CH,), 1.4-2.1 (8H, m), 2.63 (2H, deformed quin, J = 6.5 Hz), 3.39(4H, t, J = 6 Hz); ms m/e: 330,328,326 (M+, 1 :2 : I), 249,247 (M+ - Br, 1 : I), 179, 177 (M+ - CSHloBr,1 : 1).
Diacetates 28 a n d 29 Sodium acetate (2.70 g, 32.9 mmol) was dissolved in hexamethylphosphoramide (60 mL) and water (12 mL). To this warm solution was added the dibromide 27 (3.87 g, 11.8 mmol) and hexamethylphosphoramide (5 mL). After 21 h at 3S°C the solution was diluted with water (600 mL) and ether extracted (3x). The combined ethereal phases were washed with brine (2x), dried (MgSO,), and evaporated. Chromatography on silica (140 g) with increasing proportions of ether in hexane gave keto-diacetates 28 and 29 (2.27 g, 70.7%) as an inseparable mixture; plc (60% E/H) gave an analytical sample; ir: 1735, 1237, and 1017 cm-I; ' H nmr 6: 1.06 and 1.O8 (6H, two d, J = 7 Hz, isomeric CH,), 1.3-1.8 (8H, m), 2.04 (6H, s, OAc), 2.4-2.9 (2H, m), 4.04 (2H, deformed t); I3C nmr 6: 16.6, 20.9, 26.5, 28.9,29.1,44.6,64.2, 170.9,216.7,216.8; ms mle: 226, 186,166, 157. Anal. calcd. for C,,H,,O,: C 62.91, H 9.15; found: C 62.81, H 9.35. Spiroketals 21, 22, a n d 23 Diacetates 28 and 29 (3.31 g, 11.6 mmol) in methanol (90 mL), triethylamine (10 mL), and water (5 mL) were maintained at 50°C for 3 days. Evaporation of the solvent gave the diols 19 and 20 (3.06 g, 100%); ir: 3420, 1710, 1040, and 973 cm-I; l H nmr 6: 0.96 (6H, d, J = 7 Hz), 2.30-2.85 (2H, m), 3.40 (4H, deformed t, W/2 = 4 Hz, CH,O), 4.51 (2.5 H , variable s, OH); ms m/e: 184, 115. Cyclization was effected in chloroform (12 mL) withconsecutive additions of p-toluenesulfonic acid (total 2.50 mg) as the reaction was followed by nmr and vpc (5 ft x t in., 5% FFAPon Chromosorb W, 105°C). The reaction occurred suddenly giving spiroketals 21,23, and 22 in a ratioof 100:59:4 (Rf 3.6,6.0, and 7.2 min respectively). The reaction was quenched with saturated sodium bicarbonate and the aqueous phase was extracted with chloroform. The combined organic phases were washed with sodium bicarbonate, dried (Na,S04), and evaporated to give the product (2.13 g 115%). Chromatography on Florisil(200 g), eluting with 2% E/H, gave a partial separation of the isomeric spiroketals. From these fractions, pure material was prepared by vpc, to give (from highest R f ) the following. Spiroketal21: ir: 1067, 1000, 958, and 913 cm-I; lH nmr 6: 0.86 (6H, d, J = 6 Hz), 1.3-2.0 (lOH, m), 3.38-3.70 (4H, m, W/2 = 10 Hz); I3C nmr 6: 16.2, 26.4,27.3, 34.5, 59.9, and 99.8; ms mle: 184 (M+). Anal. calcd. for CllH2002:C 71.69, H 10.94; found: C 71.94, H 11.39. Spiroketal23: ir: 1062,998, and 915 cm-I; ' H nmr6: 0.96(3H, d, J = 6 Hz), 1.08 (3H, d, J = 7 Hz), 1.17-2.10 (lOH, m), 3.59 (4H, m, W/2 = 8 Hz); 13Cnmr6: 16.8(q), 17.5 (q), 20.6(t), 24.9 (t), 26.6 (t), 29.2 (t), 35.9 (d), 36.0 (d), 59.4 (t), 60.6 (t), 100.0; ms mle: 184 (M+). Spiroketal22: ir: 1053, 1015,988,910, and 865 cm-'; 'H nmr 6: 1.01 ( 6 H , d , J = 7 H z ) , 1.13-2.42(10H,m),3.50-3.80(4H,m, W/2 = 11 Hz); I3C nmr 6: 13.6, 19.6, 25.4, 32.0, 60.7, and 99.4; ms m/e: 184 (M+). Equilibration of Spiroketal21 T o spiroketal 21 (264 mg, 1.43 mmol, 199.5% by vpc) in acetone (2 mL) was added hydrochloric acid (I N, 0.50 mL) and then sufficient acetone to give a homogeneous system. The reaction was complete within 2 days by vpc. After 8 days, the reaction was quenched with sodium carbonate, diluted with ether, and concentrated under reduced pressure. Dilution with ether, drying (Na2S04),and evaporation gave the product (242 mg, 91.7%) which by vpc, consisted of spiroketals 21 (96.8%), 23 (50.1%), and 22 (3.2%). Infrared and l H nmr confirmed the presence of acetal21. The presence of acetal22 was confirmed by I3C nmr. Deuteration of Spiroketal21 Spiroketal 21 (106 mg, 0.58 mmol) in dl-methanol (0.9 mL)
DESLONGCH.AMPS ET AL.
and I M deuterium chloride in deuterium oxide (0.1 mL) were maintained at R T for 6 days when lH nmr showed the exchange to be 50% complete. Additional 35% deuterium chloride solution (10 pL) and d,-methanol (0.1 mL) were added and after a further 8 days the reaction was almost complete. Complete deuteration was effected by dilution of the system with d l methanol (=2 mL) and addition of further acid (20 pL, 35% solution). After 3 more days, the system was quenched with saturated sodium bicarbonate solution, diluted with ether, and the organic phase dried (Na2S04).Evaporation of the solvent gave d,-acetal(21) (70 mg, 66%); vpc gave an analytical sample; ir: 1090, 1052, 1035, and 995 cm-I; 'H nmr 6: 0.86 (6H, s, CH,), 1.24-1.86 (8H, m), 3.44-3.76 (4H, m); 13C nmr 6: 16.1, 26.4, 27.2, 59.9, anomeric carbon not observed; ms mle: 186 (M+). Hydrolysis of Spiroketal22 T o spiroketal22 (4.0 mg) in acetone (0.3 mL) and water (0.15 mL) was added a solution of 1 M hydrochloric acid (50 pL). By tlc, the isomerization was almost complete in 1 h. Work-up, as for the isomerization of spiroketal21, gave spiroketal21 by vpc, tlc, 'H nmr, and ir; vpc analysis gave a ratio 21 :22 = 97 :3.
1
:
,
Hydrolysis of Spiroketal23 Spiroketal23 (7.9 mg) in acetone (250 pL) was treated with 1 N hydrochloric acid (100 pL) and the reaction was followed by vpc (=I5 min). After 18 h, the acetone was removed under reduced pressure at R T and the acid was quenched with sodium bicarbonate. Dilution with ether and adsorption of the aqueous phase with sodium sulfate gave, after evaporation, the product (11.7 mg) of composition 21 (97%), 22 (3%), 23 ( ~ 0 . 0 9 %byvpc. ) Drying with EtOH-benzene azeotrope gave acetal 21 (5.5 mg, 70%) by ir, ' H nmr, and tlc. Mild Acid Hydrolysis of Spiroketal23 T o spiroketal 23 (178 mg, 0.97 mmol, composition by vpc 21 (2%), 23 (95%), 22 (3%)) in acetone (2.4 mL) and water (0.57 mL) was added 1 M hydrochloric acid (30 pL) and the hydrolysis was followed by vpc. After 160 min, the reaction was quenched with sodium bicarbonate and then diluted with ether. After drying (Na2S04) and evaporation of the solvent, the residue was acetylated with pyridine (0.5 mL) and acetic anhydride (0.4 mL) for 2 h a t room temperature. Saturated sodium bicarbonate and ether were added.The ethereal phase was washed with sodium bicarbonate (1 x ) and then water (2x), dried, and evaporated to give the product (0.57 g). Chromatography with ether-hexane on Florisil (30 g) gave, on elution with 2% ether-hexane (i) spiroketal21 (33.6 mg, 18.9%) by ir and nmr; vpc analysis gave 21 (95%) and 23 (5%); (ii) a mixture of spiroketals (66.8 mg, 37.5%) consisting by vpc of 21 (67%), 23 (30%), and 22(3%); (iii) a fraction of starting material (9.9 mg, 5.6%) by ir and nmr and consisting, by vpc analysis, of 21 (3%), 23 (75%), and 22 (23%). Elution through to ether gave diacetate 29 (50 mg, 18%) as a ~ ; nmr 6: 1.08 (6H, d, J clear oil; ir: 1735, 1234, and 1 0 4 0 ~ m - lH = 7 Hz), 1.30- 1.90 (8H, m), 2.04 (6H, s), 2.37-2.90 (2H, m), 4.04 (4H, t, J = 6 Hz); 13C nmr 6: 16.6, 20.9, 26.4, 29.0.44.6, 64.3, 171.1, 217.1; ms mle: 226, 166, 157. Sodium Borohydride Reduction of Keto-acetate 29 T o diacetate 29 (70 mg, 0.24 mmol) in methanol (5 mL) was added sodium borohydride (10 mg). After 95 min, the reaction was concentrated cold under reduced pressure whereupon thin layer chromatography showed incomplete reduction. Additional sodium borohydride (=lo mg) and methanol (2 mL) were added and after 60 min the reaction was complete. The solution was again concentrated under reduced pressure, ether was added, and the organic phase was washed with saturated ammonium chloride ( l x ) and the brine ( l x ) . Drying (Na,S04) and evaporation gave alcohols 30 and 31 (54 mg, 77%). An analytical sample (18 mg, 26%) was obtained after plc (50% ethyl
1 1 19
acetate - hexane); ir: 3510,1733,1240, and 1022 cm-I; ' H nmr6: 0.92 (6H, d, J = 6 Hz), 1.30-2.87 (1 IH, m), 2.05 (6H, s), 3.00-3.30(1H, m),4.06(4H, t, J = 6Hz); 13C nmr6: 14.1, 16.5, 21.0,26.2,26.3,27.0,29.9,35.1,64.7,64.8,78.3,80.6,171.2;ms mle: 159, 99. Sodium Borohydride Reduction of Ketodiacetates 28 and 29 T o diacetates 28 and 29 (90 mg, 0.31 mmol) in methanol (10 mL) was added sodium borohydride (22 mg). After 80 min, saturated ammonium chloride and ether were added.The aqueous phase was diluted with enough water to dissolve precipitated salts and extracted with ether ( l x ) . The combined ether layers were washed with brine ( I x ) , evaporated, and then azeotroped with benzene-ethanol to give alcohol diacetates 30, 31, and 32 (92 mg, 102%); plc (80 mg, 50% ethyl acetate hexane) gave a sample (52 mg, 65%) pure by vpc (5 ft x f in., Apiezon L 10% on Chromosorb W, 230°C); ir: 3500,1733, 1240, and 1020 cm-I; 'H nmr 6: 0.85 and 0.91 (6H, two d , J = 6 Hz, meso and dl isomers respectively), 1.13-1.90 ( l l H , m), 2.04 (6H, s), 3.00- 3.30 (IH, m), 4.06 (4H, t, J = 6 Hz); 13C nmr 6: 12.5, 14.1, 15.9, 16.6, 21.0, 26.2, 26.3, 26.4, 27.0, 28.8, 29.9, 30.6,34.5,35.1,35.9,64.7,64.8,78.2,80.6, 171.2;msmle: 159, 99. Spiroketal34 To acetylene 11(1.40g, 9.1 mmol) in tetrahydrofuran (25 mL) at -78°C was added n-butyllithium (9.1 mmol of 1.6 M hexane solution). After 30 min, bicyclic lactone 36 (1.40 g, 9.1 mmol) in tetrahydrofuran (30 mL) was quickly added and the system was allowed to warm to RT. The reaction was quenched in water (50 mL), the organic phase was separated, and the aqueous phase was ether extracted (3x). The combined organic phases were dried (Na2S04) and evaporated and the resulting residue was taken up in methanol (50 mL) and hydrogenated (40 psi over PtO,). After filtration through silica gel, concentrated hydrochloric acid (2 drops) was added and the solution was left at R T overnight. The solvent was evaporated and the residue was taken up in ether, dried (MgS041K2C03),and again evaporated. Chromatography on silica gel gave on elution with 5% E/H, spiroketal 34 (1.18 g, 62%) as a clear oil; ir: 1164, 1150, 1132, 1020,997, and964cm-I; 'Hnmr6: 1.32(18H, m),3.3-4.0(4H,m, CH,O); 13C nmr6: 18.6,25.4,26.0,26.2,27.7,32.8,35.4,35.6, 41.8, 43.1, 60.4, 65.5, 96.0; ms mle: 210 (M+). Deuteration (as for spiroketals 5 and 14, but for 30 days reaction time) gave d 4 spiroketal 34. Exact Mass calcd. for C2,H,,D40: 214.1871; found (ms): 214.1872. THP-hydroxyketone 38 Compound 38 was produced, a s described above for spiroketal 34, and purified by chromatography on Florisil. Eluting with 40% E/H gave compound 38 (60-70%) a s a clear oil which crystallized on standing (mp 53-55°C crystallized from hexane); ir: 3595,3440, 1707 (weak), 1121, 1060,1048,1006~m-~; ' H nmr 6: 1.58 (24H, m), 2.10 (IH, variable s, OH), 3.15-4.03 (6H, m, CH,O), 4.56 ( l H , m, OCHO). THP-keto-acetate 39 Compound 38 (597 mg, 1.69 mmol) was treated with pyridine (2.0 mL) and acetic anhydride (2.0 mL) for 24 h at RT. Dilution with water (100 mL) and saturated sodium bicarbonate (100 mL) was followed by extraction with dichloromethane (3 x 30 mL). Washing with brine (1 x ), drying (MgSO,), and evaporation gave THP-keto-acetate 39 (658 mg, 97.2%) as a yellow oil. Chromatography on Florisil, eluting with 20% ethyl acetate - hexane gave analytical material; ir: 1728, 1237, 1010 cm-I; IH nmr 6: 1.0-1.9 (20H, m), 2.04 (3H, OAc), 2.42 (4H, m, W/2 = 20 Hz, CH,COR), 3.56 (4H, m, Wl2 = 33 Hz, CH,O), 3.97 (2H, deformed d, J = 6 Hz, CH20Ac), 4.56 (lH, m, OCHO); ms mle: 354 (M+), 294 (M+ - HOAc), 270,269,253.
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C A N . J. CHEM. VOL. 59, 1981
Alcohol 40 and Diacetate 41 Crystals ofp-toluenesulfonic acid were added successively to a solution of the THP-keto-acetate 39 (467 mg, 1.32 mmol) in 10% water-methanol (25 mL) and the reaction followed by tlc. After 4 h, sodium bicarbonate was added and the solution concentrated under reduced pressure. After the addition of ether (50 mL) and removal of the aqueous phase, drying (MgSO,) and evaporation gave compound 40 as a clear oil (370 mg, 104%). Pure hydroxy-acetate 40 (70% yield) could be obtained as a clear oil by chromatography on Florisil, eluting with 40% EIH; ir: 3480, 1733, 1240, and 1017 cm-l; lH nmr 6: 1.1-1.9 (14H, m), 2.05 (3H, s, OAc), 2.45 (4H, m, Wl2 = 20 Hz, CH2COR), 3.63 (2H, t, J = 6 Hz, CH20H), 3.97 (2H, d, J = 4 Hz, CH,OAc); ms mle: 252.1685 (M+ - H,O, C,,H,,O, requires 252.1725), 210 (M+ - HOAc). Alternatively the crude hydroxy-acetate 40 was acetylated with acetic anhydride (2.0 mL) and pyridine (2.0 mL) at R T for 17 h. Dilution with 3% sulfuric acid (150 mL), ether extraction (3x), and washing of the combined ether extracts with saturated sodium bicarbonate (I x ) and brine (1 x ) , followed by drying (MgSO,) and evaporation of the solvent gave a pale oil (556 mg). Chromatography on silica gel gave, on elution with 80% EIH, keto-diacetate 41 (190 mg, 46.1% as a clear oil. A midfraction, pure by tlc and vpc (5 ft x +in., Apiezon 10% on Chromosorb W, 230°C, R, 32 min) gave ir: 1733, 1238, 1016 cm-l; lH nmr 6: 1.0-1.8 (14H, m), 2.03 (6H, s, OAc), 2.42 (4H, m, Wl2 = 20 Hz, CH,COR), 3.99 (4H, m, Wl2 = 9 Hz, CH20Ac); ms mle: 252.1724 (M+ - HOAc, Cl5H2,O3 requires 252.1725), 192 (M+ - 2 HOAc), 158, 155, 137. Spiroketal35 Keto-diacetate 41 (148 mg, 0.47 mmol) in a mixture of methanol, triethylamine, and water (4:2: 1; 7 mL) was warmed at 70°C for 8 days, additional solvent (3.5 mL) being added after 5 days. Removal of the solvent gave keto-diol33 as a brown oil which crystallized on standing; mp 67-69°C; ir: 3400,1710 (weak), 1222, and 1040cm-I; msmle: 210(M+ - H,O), 165,155, 152, 137, 101. This material was immediately cyclized in chloroform (2 mL) by the successive addition of small crystals ofp-toluenesulfonic acid, the reaction being followed by tlc and vpc (5 ft x 4 in., 3% SE-30 on Chromosorb W, 175°C). Spiroketals 34 and 35 were initially present in a ratio of 7 :3 (R, 5.0 and 5.7 min respectively) which fell to 9: 1 after 5.5 h. Quenching with sodium carbonate, dilution with ether, and drying (Na,SO,) gave, after evaporation, a yellow oil (117 mg) which was immediately acetylated in pyridine (0.5 mL) with acetic anhydride (0.5 mL). After standing overnight at RT, the solution was diluted with ether (50 mL) and washed with saturated sodium bicarbonate (2x), brine ( l x ) , then dried (Na,SO,). Evaporation gave a yellow oil (155 mg) which was chromatographed on Florisil. Elution with 5% EIH gave spiroketal34 (27 mg, 27% from 41) pure by vpc, tlc, nmr, and ir. Elution with ether gave keto-diacetate 41 (74 mg, 50%). Recovery of intermediate fractions gave a sample of spiroketal 35 (14 mg, 14%) containing 9% of spiroketal 34 by vpc. Preparative vpc gave an analytical sample (=1.5 mg); ir: 1166, 1090, 1042, 1021, and 970 cm-I; l H nmr 6: 0.8-1.9 (17 H, m), 2.10-2.43 ( l H , m), 2.88-4.33 (4H, m); ms mle: 210 (M+), 155, 152, 137, 110, 101. Zsomerization of Compound 35 A sample of spiroketal35 (=1.5 mg, 56: 55 = 74: 26, spontaneous isomerization on sample recovery) in acetone (0.45 mL) was treated with 1 N hydrochloric acid (0.05 mL) at RT. Conversion to spiroketal34 was complete within 5 min by vpc. Evaporation of the solvent gave pure spiroketal34 by ir, nmr, tlc, and vpc.
Spiroketals 43, 44, and 46 T o acetylene 16 (18.5 g, 110 mmol) in tetrahydrofuran (100 mL) at -78°C was slowly added n-butyllithium (100 mmol of 1.6 M hexane solution). After 30 min, bicyclic lactone 36 (13.9 g, 90 mmol) in tetrahydrofuran (50 mL) was quickly added and the system was allowed to warm to RT. The reaction was quenched in water (50 mL), the organic phase separated,and the aqueous phase was ether extracted (3x). The combined organic phases were dried (Na,SO,), evaporated, and the resulting oil was taken up in methanol (50 mL) and hydrogenated (40 psi over PtO,). After filtration through silica gel, concentrated hydrochloric acid (2 drops) was added and the solution was left at RT overnight. The solvent was evaporated and the residue was taken up in ether, dried (MgSO,IK,CO,), and again evaporated. Chromatography on silica gel gave, on elution with 5% E/H, (i) spiroketal46: (6.80 g, 33.5%); ir: 1383, 1229, 1092, 1087, 1048, and 992 cm-l; lH nmr 6: 1.14 (3H, d, J = 10.5 Hz, CH,), 1.19 (18H, m), 3.1-4.1 (3H,m, CHOR); 13C nmr 6: 19.0, 21.9, 26.0, 26.2,27.7,32.7,32.8,35.1,35.4,41.9,43.2,65.2,65.4,96.6; ms mle: 224(M+); (ii) spiroketal44: (2.60g, 12.8%); ir: 1052and992 cm-I; 'H nmr 6: 1.12 (3H, d, J = 10.5 Hz, CH,), 1.30 (18H, m), 2.8-4.5 (3H, m, CHOR); 13Cnmr6: 18.4,22.2, 25.9,26.1,27.7, 28.0, 32.2, 33.0, 37.2, 41.9, 44.2, 66.4, 68.3, 97.9; ms mle: 224 (M+); (iii) spiroketal43: (3.40 g, 16.7%); ir: 1068 and 1006 cm-I; ' H nmr6: 1.21 (3H, d, J = 10.2Hz, CH,), 1.52(18H, m);2.8-4.3 (3H, m, CHOR); 13C nmr 6: 19.3, 21.9, 26.0, 26.3, 27.7, 32.4, 32.9, 35.0, 36.0, 37.3, 41.9, 66.3,68.6, 97.8; ms mle: 224 (M+). Zsomerization of Spiroketals 43, 44, and 46 Spiroketal 43 (224 mg, 1 mmol) in anhydrous methanol (25 mL) containing one drop of concentrated hydrochloric acid was left at R T for 20 h. The solvent was evaporated, ether was added, and the solution was dried (MgSO,), filtered, and evaporated to dryness. ' H and I3C nmr analysis showed that a = 1 : 1 mixture of spiroketals 43 and 44 was obtained. The same experiment was repeated starting with spiroketal44 and an identical result was obtained. However, spiroketal 46 was recovered unchanged when submitted to the same experimental conditions. Deuteration of a mixture of spiroketals 43 and 44 under the conditions described previously gave the spiroketals 43 and 44 containing two deuterium atoms in ring B as shown by 13C nmr analysis.
Acknowledgements Support for this work by the National Research Council of Canada, and by the Ministkre de 1'Education, Quebec, is gratefully acknowledged. One of us (P. Deslongchamps) is pleased to thank the John Simon Guggenheim Memorial Foundation for a Fellowship (1979-1980). 1. R. U. LEMIEUX and S. KOTO.Tetrahedron, 30,1933 (1974). 2. C. ALTONA.Ph.D. Thesis, University of Leiden, 1964; C. ROMERS,C. ALTONA,H. R. BUYS,and E. HAVINGA.In Topics in stereochemistry. Vol. 4. Edited by E. L. Elieland N. L. Allinger. Wiley-Interscience, New York, NY. 1969. p. 39. 3. S. DAVID,0 . EISENTEIN,W. J. HERE, L. SALEM,and R. HOFFMAN.J . Am. Chem. Soc. 95,3806 (1973). 4. C. T. BISHOPand F . P. COOPER.Can. J. Chem. 41, 2742 (1963). 5. C. B. ANDERSONand D. T. SEPP. Tetrahedron, 24, 1707 (1968). 6. J. T. EDWARDS,P. F. MORAND,and I. PUSKA.Can. J. Chem. 39,2069 (1961).
DESLONGCHAMPS E T AL.
16. R. BAKER,R. HERBERT,P. E . HOWSE,and 0. T . JONES.J. Chem. Soc. Chem. Commun. 52 (1980). 17. N. L . ALLlNGERand M. A. MILLER.J. Am. Chem. Soc. 83, anomeric effect. In Anomeric effect, origin and consequences. Edited by W. A. Szarek and D. Horton. ACS 2145 (1961); H. WERNER,G. MANN,M. M~~HLSTADT, and H.-J. KOHLER.Tetrahedron Lett. 3563 (1970). Symposium Series 87. Washington, DC. 1979. p. 17. H. M. BERMAN,S. S . CHU, and G. A. JEFFREY.Science, J. Org. Chem. 26,3504 18. E. L . ELIELand H. HAUBENSTOCK. (1961); G. CHIURDOGLU and W. MASSCHELEIN. Bull. Soc. 157, 1576 (1967). Chim. Belg. 70,782(1961); E. L . E L l E ~ a n dC. A. LUKACH. A. J. DE HOOG,H. R. BUYS,C. ALTONA,and E. HAVINGA. J. Am. Chem. Soc. 79, 5986 (1957). Tetrahedron, 25, 3365 (1969); A. J. DE HOOG and H. 19. D. E . EVANS,C. E . SACKS,R. A. WHITNEY,and N. G. R. BUYS.Tetrahedron Lett. 4175 (1969); M. GELIN, Y. MANDEL.Tetrahedron Lett. 727 (1978). BAHUREL,and G. DESCOTES.Bull. Soc. Chim. Fr. 3723 20. T . M. CRESP, C. L. PROBERY,and F. SONDHEIMER. (1970). Tetrahedron Lett. 3955 (1978). G. DESCOTES,M. LISSAC, J. DELMAU,and J. DUPLAU. 21. D. L . HUGHES.Tetrahedron Lett. 3959 (1978). C.R. Acad. Sci. Ser. C, 267, 1240 (1968). N. BEAULIEU, R. A. DICKINSON, and P. DESLONGCHAMPS. 22. D. A. EVANS, C. E . SACKS,W. A. KLESCHICK,and T.R.TABER.J. Am. Chem. Soc. 101, 6789 (1979). Can. J. Chem. 58,2531 (1980). and E . FRAUENGLASS. J. Am. Chem. Soc. G. A. JEFFREY,J. A. POPLE,and L. RADOM.Carbohydr. 23. J . MEINWALD 82,5235 (1960). Res. 25, 117 (1972). H. BOOTH and J. R. EVERETT. J. Chem. Soc. Chem. 24. G. A. HAGGISand L. N. OWEN.J. Chem. Soc. 389 (1953); E. ALI and L . N. OWEN.J. Chem. Soc. 2111 (1958); W. Commun. 278 (1976). HUCKELand W. EGERER.Ann. Chem. 645, 162 (1961). H. J. SCHNEIDER and V. HOPPEN.Tetrahedron Lett. 579 (1974).
7. R. U. LEMIEUX. Ann. N.Y. Acad. Sci. 222,915 (1973). 8. R. U. LEMIEUX,S. KOTO, and D. VOISIN. The exo
9. 10.
11. 12. 13. 14. 15.
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