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A novel method of ring formation with functionalized angular methyl groups. Limitations and MM2 calculations
Tetrahedron Letters,Vol.29,No.6,pp Printed in Great Britain
715-718,1988
A NOVEL METHOD OF RING FORMATION ANGULAR METHYL GROUPS. LIMITATIONS
0040-4039/88 $3.00 + .Oo Pergamon Journals Ltd.
WITH FUNCTIONALRED AND MM2 CALCULATIONS’
Alfred Hassner’ and Ananda S. Amarasekara Department of Chemistry, Bar-l/an University Ramat-Gan, Israel Albert Padwa’ and William H. Bullock Department of Chemistry, Emory University Atlanta, GA 30322 Intramolecular nitrile oxide-olefin cycloadditions (INOC) have been of considerable synthetic and mechanistic interest.2
When such reactions are to be employed in the construction of cyclic compounds with well defined stereochemistry as in natural product synthesis, it is most desirable to be able to predict stereoselectivity
and regioselectivity during ring formation.3
We report here a
new application of the INOC reaction and its limitation in the formation of fused rings possessing functionality in the angular methyl group. Furthermore, we show that molecular mechanics calculations have excellent predictive value regarding product formation and stereochemistry.4 We decided to test the feasibility of ring fusion during INOC reactions of the type l-2 leading to the synthesis of bifunctional compounds of type 3 (X=0 or NH), in spite of the fact that a previous attempt to effect the ring closure of 1 to 2 (n=m=l) was unsuccessful.6
As a general entry to compounds of type 1, we chose the sequence 4-4-6-l. step utilizes NaH in a modification of a monoalkylation using dibromoalkanes.6 reaction a nitro group was introduced by means of sodium nitrite (see 5-6). the nitrile oxide precursor.7 We found that spontaneous ring closure of l-2
The first
After the Wittig
The latter serves as occurred when the ring
in the methylene cycloalkane 1 was six-membered (n=2). Thus, we were able to readily form the fused ring systems 7 and 6. On the other hand, fusion to the methylenecylopentane system 1 (n=l) was unsuccessful and led to polymeric products without isolation of any products of type 9 where n=l and m=l , 2 or 3. We first thought that the difference in propensity to ring closure of 1 may be due to a large preference for an axial side chain in the cyclohexane system (see 10) vs. the corresponding more
716
BrCH2(CH2),CH2Br H,O+
I
1) CHwPh3
2) NaNO,
t
C”2
Et,N
6
2
q
q
flexible
cyclopentane
between
However,
system.
axial and equatorial
MM2 calculations8
show that the energy
side chains in 1 is similar in magnitude
regardless
difference
of the ring size (n=l
or 2).
;H2CH2C18C? lo-equatorial =
We then decided
lo-axial =
to perform molecular
obtain an insight into the different of 7 and 9.
Recently
tions on transition Interestingly,
available
behavior
mechanics exhibited
calculations
these calculations
for the process
1-2
state oxygen
reveal (see Table I) that both ground Although
admissable
to compare
differences
(see Table I) are consistent
Furthermore,
activation
energies
established
Raney nickel cleavage to be cis by ‘SC-NMR.
difference
at 37.75 (unambiguously
sistent with the cis fused structure. decalins
assigned
such energies,
it is
We find that these between
cis and trans
in 8 led to ketol 11 which was
A trans CH20H
from off-resonance
is not expected
and the additional
to significantly
The observed
decoupled
This reflects both the higher field position
(41.8 ppm in 9-methyl-cis-decalinf2)
state energies
Indeed only one isomer was isolated in
of the isoxazoline
affect the C-l 0 shift found at 46.1 ppm in trans 9-methyl-1-decalone.” absorption
for 2.
results.
reveal a large energy
fused rings in 7 and 8 in favor of the cis fused isomers. unambiguously
and transition
(ET6-EGS) for the ring closure.
with the experimental
MMX calcula-
comparisons
than for 9a, b and c for which
it is not realistic to directly compare
the MMX calculations
these INOC cyclizations.
permitted
and ground state energies
are lower for 7 and 8, which are formed readily in the INOC reaction, ring closure was not observed.
in order to
during the ring closure step to the fused rings
parameters 9116 for transition
state energies
on these systems
gamma-effect
spectra)
C-i 0 is fully con-
of C-10 in cis fused of an added cis
Table I. Molecular Mechanics Calculations of the INCC Reaction of Methylenecycloalkanes 1 Total Energy kcal/mole
cis-2 n=m=l
gsb tsc
53.13 29.07
tsss
43.02 20.04
tsss
50.66 30.70
n=2; m=l n=l ;m=2
n=m=2
tss”
n=l ;m=3
tsss n=2; m=3
36.47 22.45
trans-2
17.50 11.57 kcal 57.49
12.42 8.42 kcal 17.55 13.13 kcal
50.53
13.11 9.34 kcal
54.57 35.28 40.17 28.72
1
18.21 17.07 kcal 49.45
13.77
tss” 14.95 kcal _____________ a) difference in transition state energy of 2 and ground state energy of 1 b) ground state c) transition state
hydroxy group. Further transformation to cis 9-methyldecalone 12 confirmed the stereochemical structure assignment.13l14 The reason for the preferences observed during the ring closure of 1 to a hydrindane system apparently lies in the strain energy of 7 compared to 9b. This is a subtle effect which is not
&$.,m
7, m=l 8, m=2 =
+&
9,. m=O 9,, m=l gc, m=2 =
718
immediately obvious on inspection of molecular models but for which MMX calculations serve well to predict effective ring closures in such INOC reactions. The formation of cis-decalone 11 shows the utility of these cyclizations in the synthesis of certain bicyclic compounds with functionalized angular alkyl groups. Other aspects of the INOC reaction of methylenecycloalkanes
of type 1 and their application to natural product synthesis will
appear in forthcoming papers. Acknowledgment:
We are grateful to the US-Israel Binational Science Foundation for grant 84-
0001 7 in support of this work. A.P. would also like to thank the National Institutes of Health for their generous support. The authors thank Dr. Hugo Gottlieb for some help in the interpretation of the NMR data. References 1. 2.
3. 4.
5. 6. ::
9. 10.
11. 12. 13. 14.
and
Notes
Cycloadditions 36. For paper 35 see A. Hassner and K. S. K. Murthy Tetrahedron Lett. 4097 (1987). R. V. Stevens, C. G. Christensen, R. M. Cory and E. Thorsett J. Am. Chem. Sot. 97,594O (1975); A. P. Kozikowski Act. Chem. Res. 17, 410 (1984); P. N. Confalone, G. Pizzolato, D. L. Confalone and M. R. Uskokovic J. Am. Chem. Sot. 102,1954 (1980); P. N. Confalone and S. S. Ko Tetrahedron Lett. 947 (1984); T. Kametani, S. P. Huang and M. lhara Heterocycles 12, 1183 (1979); V. Jager, V. Buss and M. Schwab Tetrahedron Lett. 3133 (1978); D. P. Curran J. Am. Chem. Sot. 104, 4024 (1982). A few examples of stereoselectivity during intramolecular nitrile oxide-olefin cycloadditions have been described, see A. P. Kozikowski and Y. Y. Chen J. Org. Chem. 46,5248 (1981); A. P. Kozikowski and P. D. Stein J. Am. Chem. Sot. 107, 2569 (1985). For some MM2 calculations on bimolecular nitrile oxide cycloadditions, see K. N. Houk, S. R. Moses, Y. D. Wu, N. G. Rondan, V. Jager, R. Schohe and F. R. Fronczek J. Am. Chem. Sot. 106, 3880 (1984); K. N. Houk, H. Y. Duh, Y. D. Wu and S. R. Moses J. Am. Chem. Sot. 108, 2754 (1986). A. H. Hewson and D. T. McPherson J. Chem. Sot. Perkin I 2625 (1985). K. B. Becker Helv. Chim. Acta. 60, 68 (1977); K. S. K. Murthy and A. Hassner Tetrahedron Lett. 97 (1987). T. Hoshino and M. Mukaiyama J. Am. Chem. Sot. 62, 5339 (1960). U. Burket and N. L. Allinger, “Molecular Mechanics”, American Chemical Society: Washington, 1982; N. L. Allinger J. Am. Chem. Sot. 99, 8127 (1977). We wish to thank Professor Kosta Steliou of the University of Montreal for providing a copy of the extensively rewritten Still Model program which was used for the MM2 calculations. MMX 86 is available from Serena Software, 489 Serena Lane, Bloomington, IN 47401. Calculations were performed on a VAX/785 (version 4.5). We are indebted to Professor J. Gajewski of the University of Indiana for a prerelease version of this program. The relative energy differences of these transition states were estimated by calculating the transition state total energy. This program is parameterized for transition state carbon (C$,C#,c’) as well as transition state oxygen (O#). Transition-state bond orders of 0.3 were entered which gave transition state bond lengths and torsional angles very similar to those obtained from the more rigorous nitrile oxide calculations.4 S. H. Grover, D. H. Marr, J. B. Stothers and C. T. Tan Can. J. Chem. 53, 1351 (1975). D. K. Dalling, D. M. Grant and E. G. Paul J. Am. Chem. Sot. 95, 3718 (1973). A. J. Sisti and A. C. Vitale J. Org. Chem. 37, 4090 (1972). Complete spectroscopic and degradative details will be given in our full publication. (Received
in UK 3 December
1987)
715-718,1988
A NOVEL METHOD OF RING FORMATION ANGULAR METHYL GROUPS. LIMITATIONS
0040-4039/88 $3.00 + .Oo Pergamon Journals Ltd.
WITH FUNCTIONALRED AND MM2 CALCULATIONS’
Alfred Hassner’ and Ananda S. Amarasekara Department of Chemistry, Bar-l/an University Ramat-Gan, Israel Albert Padwa’ and William H. Bullock Department of Chemistry, Emory University Atlanta, GA 30322 Intramolecular nitrile oxide-olefin cycloadditions (INOC) have been of considerable synthetic and mechanistic interest.2
When such reactions are to be employed in the construction of cyclic compounds with well defined stereochemistry as in natural product synthesis, it is most desirable to be able to predict stereoselectivity
and regioselectivity during ring formation.3
We report here a
new application of the INOC reaction and its limitation in the formation of fused rings possessing functionality in the angular methyl group. Furthermore, we show that molecular mechanics calculations have excellent predictive value regarding product formation and stereochemistry.4 We decided to test the feasibility of ring fusion during INOC reactions of the type l-2 leading to the synthesis of bifunctional compounds of type 3 (X=0 or NH), in spite of the fact that a previous attempt to effect the ring closure of 1 to 2 (n=m=l) was unsuccessful.6
As a general entry to compounds of type 1, we chose the sequence 4-4-6-l. step utilizes NaH in a modification of a monoalkylation using dibromoalkanes.6 reaction a nitro group was introduced by means of sodium nitrite (see 5-6). the nitrile oxide precursor.7 We found that spontaneous ring closure of l-2
The first
After the Wittig
The latter serves as occurred when the ring
in the methylene cycloalkane 1 was six-membered (n=2). Thus, we were able to readily form the fused ring systems 7 and 6. On the other hand, fusion to the methylenecylopentane system 1 (n=l) was unsuccessful and led to polymeric products without isolation of any products of type 9 where n=l and m=l , 2 or 3. We first thought that the difference in propensity to ring closure of 1 may be due to a large preference for an axial side chain in the cyclohexane system (see 10) vs. the corresponding more
716
BrCH2(CH2),CH2Br H,O+
I
1) CHwPh3
2) NaNO,
t
C”2
Et,N
6
2
q
q
flexible
cyclopentane
between
However,
system.
axial and equatorial
MM2 calculations8
show that the energy
side chains in 1 is similar in magnitude
regardless
difference
of the ring size (n=l
or 2).
;H2CH2C18C? lo-equatorial =
We then decided
lo-axial =
to perform molecular
obtain an insight into the different of 7 and 9.
Recently
tions on transition Interestingly,
available
behavior
mechanics exhibited
calculations
these calculations
for the process
1-2
state oxygen
reveal (see Table I) that both ground Although
admissable
to compare
differences
(see Table I) are consistent
Furthermore,
activation
energies
established
Raney nickel cleavage to be cis by ‘SC-NMR.
difference
at 37.75 (unambiguously
sistent with the cis fused structure. decalins
assigned
such energies,
it is
We find that these between
cis and trans
in 8 led to ketol 11 which was
A trans CH20H
from off-resonance
is not expected
and the additional
to significantly
The observed
decoupled
This reflects both the higher field position
(41.8 ppm in 9-methyl-cis-decalinf2)
state energies
Indeed only one isomer was isolated in
of the isoxazoline
affect the C-l 0 shift found at 46.1 ppm in trans 9-methyl-1-decalone.” absorption
for 2.
results.
reveal a large energy
fused rings in 7 and 8 in favor of the cis fused isomers. unambiguously
and transition
(ET6-EGS) for the ring closure.
with the experimental
MMX calcula-
comparisons
than for 9a, b and c for which
it is not realistic to directly compare
the MMX calculations
these INOC cyclizations.
permitted
and ground state energies
are lower for 7 and 8, which are formed readily in the INOC reaction, ring closure was not observed.
in order to
during the ring closure step to the fused rings
parameters 9116 for transition
state energies
on these systems
gamma-effect
spectra)
C-i 0 is fully con-
of C-10 in cis fused of an added cis
Table I. Molecular Mechanics Calculations of the INCC Reaction of Methylenecycloalkanes 1 Total Energy kcal/mole
cis-2 n=m=l
gsb tsc
53.13 29.07
tsss
43.02 20.04
tsss
50.66 30.70
n=2; m=l n=l ;m=2
n=m=2
tss”
n=l ;m=3
tsss n=2; m=3
36.47 22.45
trans-2
17.50 11.57 kcal 57.49
12.42 8.42 kcal 17.55 13.13 kcal
50.53
13.11 9.34 kcal
54.57 35.28 40.17 28.72
1
18.21 17.07 kcal 49.45
13.77
tss” 14.95 kcal _____________ a) difference in transition state energy of 2 and ground state energy of 1 b) ground state c) transition state
hydroxy group. Further transformation to cis 9-methyldecalone 12 confirmed the stereochemical structure assignment.13l14 The reason for the preferences observed during the ring closure of 1 to a hydrindane system apparently lies in the strain energy of 7 compared to 9b. This is a subtle effect which is not
&$.,m
7, m=l 8, m=2 =
+&
9,. m=O 9,, m=l gc, m=2 =
718
immediately obvious on inspection of molecular models but for which MMX calculations serve well to predict effective ring closures in such INOC reactions. The formation of cis-decalone 11 shows the utility of these cyclizations in the synthesis of certain bicyclic compounds with functionalized angular alkyl groups. Other aspects of the INOC reaction of methylenecycloalkanes
of type 1 and their application to natural product synthesis will
appear in forthcoming papers. Acknowledgment:
We are grateful to the US-Israel Binational Science Foundation for grant 84-
0001 7 in support of this work. A.P. would also like to thank the National Institutes of Health for their generous support. The authors thank Dr. Hugo Gottlieb for some help in the interpretation of the NMR data. References 1. 2.
3. 4.
5. 6. ::
9. 10.
11. 12. 13. 14.
and
Notes
Cycloadditions 36. For paper 35 see A. Hassner and K. S. K. Murthy Tetrahedron Lett. 4097 (1987). R. V. Stevens, C. G. Christensen, R. M. Cory and E. Thorsett J. Am. Chem. Sot. 97,594O (1975); A. P. Kozikowski Act. Chem. Res. 17, 410 (1984); P. N. Confalone, G. Pizzolato, D. L. Confalone and M. R. Uskokovic J. Am. Chem. Sot. 102,1954 (1980); P. N. Confalone and S. S. Ko Tetrahedron Lett. 947 (1984); T. Kametani, S. P. Huang and M. lhara Heterocycles 12, 1183 (1979); V. Jager, V. Buss and M. Schwab Tetrahedron Lett. 3133 (1978); D. P. Curran J. Am. Chem. Sot. 104, 4024 (1982). A few examples of stereoselectivity during intramolecular nitrile oxide-olefin cycloadditions have been described, see A. P. Kozikowski and Y. Y. Chen J. Org. Chem. 46,5248 (1981); A. P. Kozikowski and P. D. Stein J. Am. Chem. Sot. 107, 2569 (1985). For some MM2 calculations on bimolecular nitrile oxide cycloadditions, see K. N. Houk, S. R. Moses, Y. D. Wu, N. G. Rondan, V. Jager, R. Schohe and F. R. Fronczek J. Am. Chem. Sot. 106, 3880 (1984); K. N. Houk, H. Y. Duh, Y. D. Wu and S. R. Moses J. Am. Chem. Sot. 108, 2754 (1986). A. H. Hewson and D. T. McPherson J. Chem. Sot. Perkin I 2625 (1985). K. B. Becker Helv. Chim. Acta. 60, 68 (1977); K. S. K. Murthy and A. Hassner Tetrahedron Lett. 97 (1987). T. Hoshino and M. Mukaiyama J. Am. Chem. Sot. 62, 5339 (1960). U. Burket and N. L. Allinger, “Molecular Mechanics”, American Chemical Society: Washington, 1982; N. L. Allinger J. Am. Chem. Sot. 99, 8127 (1977). We wish to thank Professor Kosta Steliou of the University of Montreal for providing a copy of the extensively rewritten Still Model program which was used for the MM2 calculations. MMX 86 is available from Serena Software, 489 Serena Lane, Bloomington, IN 47401. Calculations were performed on a VAX/785 (version 4.5). We are indebted to Professor J. Gajewski of the University of Indiana for a prerelease version of this program. The relative energy differences of these transition states were estimated by calculating the transition state total energy. This program is parameterized for transition state carbon (C$,C#,c’) as well as transition state oxygen (O#). Transition-state bond orders of 0.3 were entered which gave transition state bond lengths and torsional angles very similar to those obtained from the more rigorous nitrile oxide calculations.4 S. H. Grover, D. H. Marr, J. B. Stothers and C. T. Tan Can. J. Chem. 53, 1351 (1975). D. K. Dalling, D. M. Grant and E. G. Paul J. Am. Chem. Sot. 95, 3718 (1973). A. J. Sisti and A. C. Vitale J. Org. Chem. 37, 4090 (1972). Complete spectroscopic and degradative details will be given in our full publication. (Received
in UK 3 December
1987)