Tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes. 10. Trans-2-(1-methyl-1-phenylethyl)cyclohexanol as a new auxiliary

Full text of DOI:10.1021/jo960912c

J . Org. Chem. 1996, 61, 6727-6729
6727
Ta n d em [4 + 2]/[3 + 2] Cycloa d d ition s of
Nitr oa lk en es. 10.
tr a n s-2-(1-Meth yl-1-p h en yleth yl)cycloh exa n ol
a s a New Au xilia r y
Scott E. Denmark* and Atli Thorarensen
F igu r e 1. Chiral auxiliaries employed in the tandem [4 +
2]/[3 + 2] cycloadditions of nitroalkenes.
Roger Adams Laboratory, Department of Chemistry,
University of Illinois, Urbana, Illinois 61801
Sch em e 1
Received May 17, 1996
The asymmetric variant of the tandem [4 + 2]/[3 + 2]
cycloaddition of nitroalkenes with chiral vinyl ethers has
been extensively explored in recent years.1 To date, the
chiral vinyl ethers that have been utilized in the tandem
sequence are derived from bornane-2,3-diol, 1, trans-2-
phenylcyclohexanol, 2, and 2,2-diphenylcyclopentanol, 3,
Figure 1. These auxiliaries have served admirably in
many aspects of the cycloaddition process, but some
limitations still exist, such as the following: (1) length
of synthesis, (2) low selectivity in exo mode cycloadditions
or (3) unavailability in both enantiomeric series.
Sch em e 2
In the course of a number of total synthesis projects
that employ the tandem sequence, we were forced to
consider alternatives that addressed some of the limita-
tions noted above.2 In particular, material through-put
became an important issue since the critical unmasking
of the nitroso acetals to R-hydroxy lactams involves up
to a 50% mass loss due to the size of the chiral auxiliaries
employed. Thus, it is of critical importance that the
auxiliaries be easily prepared and inexpensive. Comins
has recently disclosed the use of an easily prepared
auxiliary, trans-2-cumylcyclohexanol, 4 (TCC), for the
diastereoselective addition of Grignard reagents to alkoxy-
pyridines.3 The preparation of TCC by Comins is con-
siderably more simple than that previously reported by
Whitesell, making this auxiliary an interesting alterna-
tive for use in the nitroalkene cycloaddition chemistry.4
By analogy with the preparation of the vinyl ethers
derived from phenylcyclohexanol, 2, and 2,2-diphenylcy-
clopentanol, 3, the transetherification of 4 with a vinyl
ether was explored.5 TCC is a very sterically crowded
auxiliary, since the 1-methyl-1-phenylethane presents a
larger steric bulk than the phenyl group in 2-phenylcy-
clohexanol. Therefore, a higher boiling vinyl ether was
required for the trans-etherification. n-Butyl vinyl ether
was found to be the vinyl ether of choice as was also the
case for 2,2-diphenylcyclopentanol.6 Optimized reaction
conditions employed two portions of 0.6 equiv of mercury-
(II) acetate in a dilute solution of n-butyl vinyl ether as
solvent, Scheme 1. The vinyl ether, (-)-5, was isolated
in 62% yield along with 33% of recovered alcohol, (-)-4.
To evaluate the utility of this new auxiliary in the
tandem [4 + 2]/[3 + 2] cycloaddition, the nitroalkene 6
was selected as the model substrate since it had been
used previously with all the other chiral vinyl ethers.6
Furthermore, it was imperative to deduce the sense of
asymmetric induction exercised by this new auxiliary.
We, therefore, needed to establish to which enantiomeric
series the final R-hydroxy lactam belonged. Accordingly,
slow addition of the nitroalkene 6 to a cold solution of
methylaluminum bis(2,6-diphenylphenoxide) (MAPh)7
and vinyl ether (+)-5 afforded the nitroso acetal 7 in 85%
yield, Scheme 2. By 1H NMR analysis of HC(6) the
product composition was estimated to be a 145/1.8/1.0
(exo/exo/endo) mixture of diastereomeric nitroso acetals.
The major diastereomer was assumed to have a trans
relationship between HC(4a) and HC(6) on the basis of
the documented preference of MAPh to promote exo-mode
[4 + 2] cycloadditions.8 The nitroso acetal 7 was then
unmasked under the standard hydrogenolysis conditions
(Raney nickel/1 atm H2/rt/MeOH). The R-hydroxy lac-
tam, (-)-8, isolated in 76% yield (along with an
(1) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137.
(2) Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J . Org. Chem.
1995, 60, 3574.
(3) (a) Comins, D. L.; Salvador, J . M. J . Org. Chem. 1993, 58, 4656.
(b) Comins, D. L.; Salvador, J . M. Tetrahedron Lett. 1993, 34, 801. (c)
Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1994, 35, 7343.
(4) Whitesell, J . K.; Lawrence, R. M. Chimia 1986, 40, 318.
(5) The vinyl ether of phenmenthol has been prepared earlier in a
two-step procedure, by the preparation of the acetylenic ether followed
by a partial reduction. Denmark, S. E.; Senanayake, C. B. W.; Ho, G.
D. Tetrahedron 1990, 46, 4857.
(7) (a) Maruoka, K.; Itoh, T.; Yamamoto, H. J . Am. Chem. Soc. 1985,
107, 4573. (b) Nonoshita, K.; Banno, H.; Maruoka, K.; Yamamoto, H.
J . Am. Chem. Soc. 1990, 112, 316. (c) Maruoka, K.; Ooi, T.; Yamamoto,
H. J . Am. Chem. Soc. 1990, 112, 9011. (d) Maruoka, K.; Itoh, T.;
Shirasaka, T.; Yamamoto, H. J . Am. Chem. Soc. 1988, 110, 310.
(8) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. J . Org.
Chem. 1993, 58, 1859.
(6) (a) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. J .
Org. Chem. 1993, 58, 1859. (b) Denmark, S. E.; Schnute, M. E.; Marcin,
L. R.; Thorarensen, A. J . Org. Chem. 1995, 60, 3205.
S0022-3263(96)00912-7 CCC: $12.00 © 1996 American Chemical Society

6728 J . Org. Chem., Vol. 61, No. 19, 1996
Notes
Sch em e 3
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. See ref 6.
(1R, 2S)-tr a n s-[[2-(1-Meth yl-1-p h en yleth yl)cycloh exyl]-
oxy]eth en e ((-)-(5)). (-)-4 (4.00 g, 18.3 mmol, 1.0 equiv) was
dissolved in n-butyl vinyl ether (260 mL), and Hg(OAc)2 (3.50
g, 11.0 mmol, 0.6 equiv) was added. The solution was heated
to reflux for 12 h. An additional portion of Hg(OAc)2 (3.50 g,
11.0 mmol, 0.6 equiv) was added, and the solution was heated
to reflux for an additional 12 h. The reaction mixture was
allowed to cool to approximately 40 °C, and the mixture was
diluted with (500 mL) MTBE and washed with saturated
aqueous Na2CO3 (3 × 150 mL), and brine (1 × 150 mL). The
aqueous layers were back-extracted with CH2Cl2 (1 × 500 mL).
The combined organic layers were dried (K2CO3) and concen-
trated in vacuo. The crude product was purified by column
chromatography on basic alumina activity II (pentane/MTBE (1/
0, 1/1/ 0/1)) and distillation to afford 2.77 g (62%) of vinyl ether
(-)-5 and 1.34 g (33%) of recovered alcohol (-)-4. For (-)-5: 1H
NMR (CDCl3) 7.31-7.25 (m, 4H), 7.17-7.13 (m, 1H), 6.15 (dd,
J ) 6.6, 14.2 Hz, 1H), 4.16 (dd, J ) 1.2, 14.2 Hz, 1H), 3.94 (dd,
J ) 1.4, 6.6 Hz, 1H), 3.54 (dt, J d ) 4.2, J t ) 10.2 Hz, 1H), 2.05-
2.08 (m, 1H), 1.88-1.82 (m, 1H), 1.69-1.65 (m, 1H), 1.57-1.53
(m, 1H), 1.44-1.40 (m, 1H), 1.39 (s, 3H), 1.31 (s, 3H), 1.29-
1.22 (m 1H), 1.18-1.09 (m, 2H), 0.91-0.81 (m, 1H); 13C NMR
(CDCl3) 150.53, 150.15, 127.68, 125.86, 125.02, 87.65, 81.10,
51.92, 40.51, 32.89, 29.00, 27.43, 25.92, 24.94, 24.67; IR (neat)
1630 (m), 1601 (w), 1496 (w); MS (FAB) 245 (M+ + H, 3), 244
(M+, 9); [R]25D -27.9 (CH2Cl2, c ) 1.78); TLC Rf ) 0.13 (hexane).
Anal. Calcd for C17H24O (244.37): C 83.55; H, 9.89. Found:
C, 83.81; H, 9.90.
(2S,2a S,4a S,6R,7a R,7b R)-6-[[(1S,2R)-tr a n s-2-(1-Met h yl-
1-p h en yleth yl)cycloh exyl]oxy]octa h yd r o-7b-m eth yl-1,7-d i-
oxa -7a -a za cyclop en t[cd ]in d en e-2-ca r boxylic Acid Meth yl
E st er ((-)-(7)). To a solution of 2,6-diphenylphenol (3.33 g,
13.55 mmol, 6.0 equiv) in CH2Cl2 (18 mL) was added trimethy-
laluminum (2.0 M in toluene, 2.3 mL, 4.51 mmol, 3.0 equiv).
Gas evolution was observed, and the resulting light yellow
solution was stirred at rt for 30 min.
F igu r e 2. Comparison of auxiliaries used in MAPh promoted
cycloadditions (the enantiomer (-)-5 is depicted for consis-
tency).
The Lewis acid was cooled to -65 °C (internal temperature).
A solution of vinyl ether ((+)-5) (1.10 g, 4.51 mmol, 3.0 equiv)
in CH2Cl2 (2.6 mL) was added followed by a dropwise addition
of 6 (0.300 g, 1.50 mmol, 1.0 equiv) in CH2Cl2 (2.6 mL) at a rate
keeping the internal temperature below -63 °C. The brown
solution was stirred for additional 55 min and then was
quenched with MeOH (5.6 mL), poured into CH2Cl2 (300 mL),
and washed with water (2 × 100 mL) and brine (1 × 100 mL).
The aqueous phases were back-extracted with CH2Cl2 (2 × 100
mL), the combined organic extracts were dried (Na2SO4) and
filtered through Celite. The resulting solution was stored at rt
for 12 h to ensure complete [3 + 2] cycloaddition and then
concentrated in vacuo. The crude product was purified by silica
gel column chromatography, eluting with hexane/EtOAc (1/0,
8/1, 6/1, 4/1, 2/1, 1/1). The first fractions contained 2,6-
diphenylphenol, which was recrystallized from hexane (80 mL)
to afford 2.83 g (85%) of recovered phenol. The second fraction
afforded 0.570 g (85%) of a white foam the composition of which
was estimated by 1H NMR to be a 1/1.8/145 (endo/exo/exo)
mixture of diastereomers (-)-7. For (-)-7: mp 48-51 °C
(hexane/EtOAc); 1H NMR (CDCl3) 7.30-7.24 (m, 4H), 7.14-7.10
(m, 1H), 4.84-4.78 (m, 2H), 3.76 (s, 3H), 3.37(dt, J d ) 4.2 Hz, J t
) 10.2 Hz, 1H), 2.68-2.65 (m, 1H), 2.44-2.40 (m, 1H), 1.95-
1.73 (m, 7H), 1.69-1.62 (m, 1H), 1.55-1.51 (m, 1H), 1.48-1.39
(m, 3H), 1.34 (s, 3H), 1.28 (s, 3H), 1.26 (s, 3H), 1.21-0.87 (m,
3H); 13C NMR (CDCl3) 170.35, 151.51, 127.72, 125.54, 124.85,
100.05, 87.20, 85.20, 81.67, 56.92, 52.33, 52.17, 43.02, 40.41,
35.36, 31.60, 28.76, 28.49, 27.76, 26.85, 26.52, 26.12, 25.08, 23.67;
88% recovery of (+)-4), was levorotatory ([R]25 -35.6
D
(CH2Cl2, c ) 1.15)) and, therefore, belonged to the 1S
configurational series.5 To determine the enantiomeric
enrichment, (-)-8 was converted to the 3,5-dinitrophenyl
carbamate 9, which was shown to be highly enantiomeri-
cally enriched (98.0% ee) by chiral HPLC.9
These results allow formulation of the transition state
geometry in the [4 + 2] cycloaddition. To obtain the 1S
configuration of the R-hydroxy lactam, the vinyl ether
must approach the re-face of the nitroalkene, Scheme 3.10
Furthermore, assuming that MAPh is promoting an exo-
selective cycloaddition, the vinyl ether must be reacting
through an exo-oriented, s-trans conformation where the
aryl moiety shields the si-face of the vinyl ether.
The vinyl ether derived from TCC is a very useful
addition to the arsenal of vinyl ethers employed in
tandem [4 + 2]/[3 + 2] cycloadditions. The selectivity
obtained with (+)-5 in MAPh-promoted cycloaddition is
equal to that of vinyl ether 1, Figure 2. At the same time
this new auxiliary does not suffer from a lengthy and
difficult preparation as in the case of 1. Furthermore,
since both enantiomers of TCC are readily available this
new auxiliary complements the use of 1 and (-)-2 for
asymmetric nitroalkene cycloaddition reactions in syn-
thesis. The use of (-)-5 in total synthesis projects
highlighting the tandem [4 + 2]/[3 + 2] cycloaddition will
be reported in due course.
IR (KBr) 1757 (s), 1741 (m); MS (FAB) 444 (M+ + H, 3); [R]25
D
-25.5 (CH2Cl2, c ) 1.16); TLC Rf ) 0.58 (hexane/EtOAc, 4/1).
Anal. Calcd for C26H37NO5 (443.58): C, 70.40; H, 8.40; N, 3.15.
Found: C, 70.35; H, 8.35; N, 3.12.
(1S,3R,5a S,7a S,7b R)-Oct a h yd r o-1-h yd r oxy-7b -m et h yl-
2H-cyclop en ta [gh ]p yr r olizin -2-on e ((-)-8). To a solution of
nitroso acetal (-)-7 (490 mg, 1.10 mmol) in methanol (80 mL)
was added a catalytic amount of Raney nickel (W-2). The
suspension was stirred for 24.5 h under 1 atm of hydrogen
pressure at rt and then was filtered through Celite. The catalyst
was washed with MeOH (100 mL), and the combined washes
(9) (a) Pirkle, W. H.; Mahler, G.; Hyun, M. H. J . Liq. Chromatogr.
1986, 9, 443. (b) Pirkle, W. H.; Pochapsky, T. C.; Burke, J . A.; Deming,
K. C. In Chiral Separations; Stevenson, D., Wilson, I. D., Eds.;
Plenum: New York, 1988; p 23.
(10) The re and si faces of the diene are defined with respect to
nitrogen.

Notes
J . Org. Chem., Vol. 61, No. 19, 1996 6729
were filtered through Celite and then concentrated in vacuo. The
residue was purified by column chromatography (hexane/EtOAc
(1/1, 1/2, 0/1)) to afford 152 mg (76%) of R-hydroxy lactam (-)-8
as a white solid along with 213 mg (88%) of recovered alcohol
(+)-5. For (-)-8: mp 91-101 °C (hexane/EtOAc); 1H NMR
(CDCl3) 4.69 (dd, J ) 2.0, 7.1 Hz, 1H), 3.87 (ddd, J ) 3.7, 8.4,
11.8 Hz, 1H), 3.74 (d, J ) 3.3 Hz, 1H), 2.90 (ddt, J d ) 1.1, 11.8
Hz, J t ) 7.9 Hz, 1H), 2.60 (q, J ) 7.5 Hz, 1H), 2.26-2.21 (m,
1H), 2.15-2.05 (m, 1H), 1.78-1.68 (m, 3H), 1.51-1.42 (m, 1H),
1.28 (s, 3H), 1.27-1.19 (m, 1H); 13C NMR (CDCl3) 176.44, 75.63,
72.82, 51.10, 49.19, 42.10, 31.45, 31.00, 24.80, 22.86; IR (KBr)
product was purified by column chromatography (hexane/EtOAc
(4/1, 2/1, 1/1, 1/2, 0/1)) to afford 76 mg (88%) of 9 as a slightly
yellow solid. For 9: 1H NMR (CDCl3) 10.50 (s, 1H, NH), 8.58
(s, 1H), 8.52 (s, 2H), 5.96 (d, J ) 7.2 Hz, 1H), 3.93 (ddd, J ) 3.6,
8.4, 12.0 Hz, 1H), 3.08 (dt, J d ) 11.9 Hz, J t ) 7.8 Hz, 1H), 2.80
(q, J ) 7.2 Hz, 1H), 2.39-2.37 (m, 1H), 2.28-2.21 (m, 1H), 1.91-
1.79 (m, 2H), 1.74-1.66 (m, 1H), 1.55-1.47 (m, 1H), 1.44 (s, 3H),
1.41-1.23 (m, 1H); 13C NMR (CDCl3) 172.20, 152.49, 148.52,
141.21, 118.00, 112.31, 76.10, 74.69, 49.41, 42.37, 31.61, 30.95,
25.77, 22.61; IR (KBr) 1744 (m), 1686 (s); HPLC (Pirkle covalent
L-naphthylalanine (250 × 4.5 mm, 5 m (Regis)), (hexane/EtOAc,
7/3, 1.5 mL/min)) tR (1R,3S,5aR,7aR,7bS)-9, 6.6 min (0.98%); tR
(1S,3R,5aS,7aS,7bR)-9, 18.4 min (99.01%).
1694 (s), 1464 (w); [R]25 -35.6 (CH2Cl2, c ) 1.15).
D
(1S,3R,5aS,7aS,7bR)-1-[N-(3,5-Din itr oph en yl)car bam oxy]-
7b-m eth yloctah ydr o-2H-cyclopen ta[gh ]pyr r olizin -2-on e (9).
A solution of 3,5-dinitrobenzoyl azide (58 mg, 0.24 mmol, 1.1
equiv) in toluene (10.0 mL) was heated to reflux for 5 min, and
then a solution of R-hydroxy lactam (-)-8 (40 mg, 0.22 mmol,
1.0 equiv) in toluene (2.0 mL) was added. The solution was
heated to reflux for 95 min and then was allowed to cool to rt.
The reaction mixture was concentrated in vacuo, and the crude
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM-30938) for financial support.
A.T. thanks the University of Illinois for a Graduate
Fellowship.
J O960912C