Studies of intramolecular Diels-Alder reactions of nitroalkenes for the stereocontrolled synthesis of trans-decalin ring systems

Article abstract of DOI:10.1016/j.tetlet.2010.11.012

Studies of thermal IMDA cyclizations of (1E,7E)-1-nitro-deca-1,7,9-trienes and (1E,3Z,7E)-1-nitro-deca-1,3,7,9-tetraenes have been examined. Reactions of these nitroalkenes proceed via transition states featuring characteristics of asymmetric stretch asyn

Full text of DOI:10.1016/j.tetlet.2010.11.012

Tetrahedron Letters 52 (2011) 2120–2123
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Tetrahedron Letters
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Studies of intramolecular Diels–Alder reactions of nitroalkenes for the
stereocontrolled synthesis of trans-decalin ring systems
⇑
David R. Williams , J. Cullen Klein, Nicholas S. C. Chow
Department of Chemistry, Indiana University, Bloomington, IN 47405, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 11 November 2010
Studies of thermal IMDA cyclizations of (1E,7E)-1-nitro-deca-1,7,9-trienes and (1E,3Z,7E)-1-nitro-deca-
1,3,7,9-tetraenes have been examined. Reactions of these nitroalkenes proceed via transition states fea-
turing characteristics of asymmetric stretch asynchronicity and result in stereoselective formation of
trans-fused decalin products. Substantial rate acceleration is observed for IMDA cyclizations exemplified
by triene 14 due to steric repulsions of substituents in the tethering chain which promote facile stereo-
controlled formation of trans-fused 26.
Dedicated in honor of Professor Harry
Wasserman on the occasion of his 90th
birthday.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Intramolecular Diels–Alder reaction
1-Nitro-deca-1,3,7,9-tetraenes
1-Nitro-deca-1,7,9-trienes
trans-Decalins
Asynchronous transition states
The intramolecular Diels–Alder reaction (IMDA) has been
extensively utilized as a powerful strategy for the efficient con-
struction of polycyclic systems.1 Applications of transannular ver-
sions of IMDA reactions, as well as a number of creative IMDA
strategies, have been featured for natural product synthesis.2 Nev-
ertheless, there are surprisingly few examples of IMDA processes
which describe the use of nitroalkenes as dienophilic components.
An early precedent illustrated the thermal cyclizations of 1-nitro-
1,6,8-decatrienes for the synthesis of hexahydroindenes,3 and
Kunesch and Tillequin described the cycloaddition of a 1,1-dini-
troalkene with a tethered furan to produce 3,7-dinitro-11-oxatri-
cycloundec-9-ene.4 In 2000, we reported the first study of IMDA
reactions of (E)-1-nitro-1,7,9-decatrienes leading to substituted
decalins as a preliminary investigation toward the synthesis of
the AB ring system of norzoanthamine.5 Alternatively, the use of
the nitroalkene moiety as a heterodiene in formal [4 + 2] cycliza-
tions leading to nitronates has been extensively exploited by Den-
mark and coworkers as an effective strategy for the synthesis of
alkaloids.6 In this communication, we describe studies of IMDA
reactions of nitroalkenes which detail factors affecting the relative
reactivity of these substrates as well as the observed stereoselec-
tivity of the cyclization process.
tivity in the production of nearly equal amounts of trans-fused
and cis-fused decalins 2a and 3a.7 Four concerted synchronous
transition state arrangements stemming from 4–7 are feasible in
which the staggered conformations of the tethering carbon chain
are compatible with a minimization of ring strain in the developing
chair-like B-ring. Thus cis-fused decalins are derived from arrange-
ments 5 and 6 in which the transition state positions the diene
in an axial orientation with respect to the developing cyclohexane
of the tether. The incorporation of the ester in methyl (E,E)-
undeca-2,8,10-trienoate (1b) does not significantly alter the
product distribution even though this electron-withdrawing func-
tionality increases the relative rate of the IMDA process.8 Further
enhancement of the rate of the reaction is observed by the inclusion
of the terminal nitro group in 1c and 1d, and these examples display
a modest improvement in stereoselectivity which favors the trans-
fused products 2c and 2d.5 Finally, the precoordination of Lewis
acids results in powerful electron-withdrawing effects which
dramatically alter the LUMO of the dienophile in 1e, and result in
high trans-stereoselectivity (2e:3e ratio 97:3).9 These aspects of
stereocontrol appear to correlate with a change from a concerted
and highly synchronous reaction to a concerted, asynchronous
pathway with increasing polarization of the dienophile. Indeed,
Houk and Brown first described asymmetric stretch asynchronici-
ty10 as a relevant concept leading to internal compression of the
reacting C2 and C7 loci which proceeds to a greater preference for
the trans-fused endo-transition states from 4 and 7.
A comparative summary is compiled in Table 1 for reports of
thermal IMDA cyclizations of several representative decatrienes
1a–d. Houk has previously noted that the unactivated and unsub-
stituted (E)-deca-1,3,9-triene (1a) displays very little stereoselec-
Our recent studies have examined the intramolecular [4
P + 2P]
cycloaddition of the 1-nitro-deca-1,3,6,8-tetraene system
8
⇑
Corresponding author. Tel.: +1 812 855 6629; fax: +1 812 855 8300.
E-mail address: williamd@indiana.edu (D.R. Williams).
(Scheme 1).11
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.012

D. R. Williams et al. / Tetrahedron Letters 52 (2011) 2120–2123
2121
Table 1
A comparison study of the formation of trans- and cis-decalins via thermal IMDA cyclizations
EWG
EWG
1
H
H
H
H
2
R
R
R
EWG
9
+
4
5
7
8
6
1
2
3
Entry
Triene
Conditions
Yield (%) (ratio 2:3)
Literature reference
1
2
3
4
1a EWG = H; R = H
220 °C/cyclohex
155 °C/toluene
85 °C/benzene
85 °C/benzene
92 (48:52)
92 (51:49)
63 (73:27)
80 (73:27)
Ref. 7
Ref. 8
Ref. 5
Ref. 5
1b EWG = COOMe; R = H
1c EWG = NO2; R = H
1d EWG = NO2; R = CH3
O
O
O
N
1e EWG =
; R = H
5
Me2AlCl (1.4 equiv) À30 °C/CH2Cl2
88 (97:3)
Ref. 9
Bn
Ring Flip
(Tether)
H
H
R
H
H
R
H
H
EWG
EWG
Dienophile
Flip
H
H
H
H
4
5
Diene
Flip
Diene
Flip
H
R
Ring Flip
(Tether)
H
H
R
H
H
EWG
EWG
H
Dienophile
Flip
H
H
H
H
6
7
Investigations of IMDA reactions of related tetraenes have not
been previously explored. However, the incorporation of the
(Z)-C3–C4 double bond in 8 was expected to provide an important
element of conformational constraint which, in addition to the
presence of the fully substituted C6 carbon, would facilitate the
cyclization process. One caveat is posed by the potential for ther-
mal (Z) ? (E) isomerization in 8. Mulzer and coworkers have re-
cently addressed this issue by the design of an exo-selective
transannular Diels–Alder reaction yielding cis-decalin products.12
In the event, we have observed slow cyclizations of 8 proceed-
ing to 50% conversion upon heating at 90 °C under argon atmo-
sphere in toluene (or xylenes) over a period of 12–15 h. Small
quantities of BHT are added to curtail radical decomposition pro-
cesses, but longer reaction times lead to side products from
destruction of the starting tetraene. In practice, we have routinely
isolated a 50% yield of the substituted decalins 9 and 10 as a 88:12
ratio of diastereomers with the recovery of 45% yield of the starting
material. In this fashion, approximately 72% yield of the trans-
decalins 9 and 10 can be achieved after one recycle of starting
tetraene.
Purification by flash silica gel chromatography afforded com-
plete characterizations of 9 and 10, and NMR studies showed key
NOESY correlations as depicted in Figure 1, which led to the assign-
ments of relative stereochemistry.
Under basic conditions, product 9 underwent isomerization to
give a separable mixture of C1 epimers (99%, dr 5:1) in which the
axial diastereomer 11 was identified as the major component. A
number of bases produced the same unanticipated result. Indeed,
our calculations confirm that 11 is less stable than the starting
equatorial 9 by approximately 2.0 kcal/mol. This outcome suggests
that the accumulation of 11 is the result of an unanticipated kinetic
effect. Removal of the PMB ether and esterification yielded a highly
crystalline sample of 12 (mp 111–112 °C), and X-ray diffraction
studies of 12 provided an unambiguous stereochemical assign-
ment.13 In addition, selective reduction with zinc in methanolic
HCl yields the amino-substituted trans-decalins, such as 13 (70%)
for further derivations.
O2N
1
O2N
1
3
6
H
H
H
2
7
4
CH3
CH3
CH3
O2N
9
Toluene
2
90 °C
12–16 h
(50%)
OPMB
OPMB
OPMB
H
H3C
CH3
CH3
[dr 88:12]
8
9 (major)
10
Based on the cyclization results, we postulate that features of
extended conjugation in tetraene 8, which lower the LUMO energy
of the nitroalkene dienophile, have very little effect on the rate of
O2N
H
H
DBU
Zn; MeOH/HCl
CH3
THF
1) DDQ
O2N
H2N
H
CH2Cl2; H2O
(70%)
H
CH3
CH3
1
2
O
12
COOH
HB
CH3
2)
HC
HA
CH3
CH3
NO2
O
OPMB
OPMB
H
H
CH3
CH3
NO2
O2N
H
Br
Br
11
13
CH3
OPMB
EDCI; DMAP
CH2Cl2
(98%)
NO2
HA
HC
dr 5:1
for 11:9
H
H
OPMB
HB
H
9
10
Scheme 1. Studies of tetraene 8.
Figure 1. Key NOESY correlations for 9 and 10.

2122
D. R. Williams et al. / Tetrahedron Letters 52 (2011) 2120–2123
this IMDA reaction. However, geometrical constraints imposed by
the additional C@C benefit the asynchronous, endo-transition state
affording higher trans-selectivity as compared with corresponding
exo-transition states leading to cis-decalins as seen in Table 1.
The observed stereochemical preference favoring the produc-
tion of trans-fused decalins provided encouragement for studies
of increasing structural complexity within the tethering chain as
a prelude for efforts toward biologically significant natural prod-
ucts. In this regard, Scheme 2 illustrates a pathway of general util-
ity which has led to the Diels–Alder nitroalkene precursors 14 and
15. The optically active (Z)-allylic alcohol 16 affords nearly quanti-
tative esterification with (+)-3-methylnonanoic acid (17) to yield
18 as a single, nonracemic diastereomer.14
A Claisen rearrangement protocol, featuring the slow addition
of 18 into a THF solution of LDA and freshly distilled TMS-Cl, pro-
vides for conversion to an intermediate (E)-silylketene acetal
which is heated to reflux in toluene (12 h). The methyl ester 19
is obtained in 86% yield following an aqueous workup and esterifi-
cation. Subsequent cleavage of the silyl ether gave a primary alco-
hol and mesylation provided an unstable homoallylic mesylate for
elimination, yielding the desired diene 19 (91% yield; three-steps).
Elongation of the carbon chain via an aldol condensation of the
enolate of tert-butylacetate with aldehyde 20 leads to 21 (dr
approximately 1:1) in excellent overall yield. However, further
manipulations incorporating the (E)-nitroalkene dienophile re-
quired a selection of conditions to avoid b-elimination of the C-4
MOM ethers. This is accomplished by DIBAL reduction of 21 at
À78 °C and buffered Dess–Martin oxidation of the resulting pri-
mary alcohols to give the aldehydes 22. Finally, Henry reactions15
with nitromethane are effectively achieved using KF in isopropanol
at 22 °C (98% yields) and resulted in the isolation of the diastereo-
meric b-hydroxy-nitroalkane adducts. Subsequently, mild dehy-
drations are accomplished with methanesulfonyl chloride and
Et3N to produce the triene precursors 14 and 15, respectively, as
unstable species which readily undergo the IMDA reaction.
Based upon our mechanistic analysis of these IMDA cycliza-
tions, we anticipated a transition state B-ring anchored by the
branched alkyl group at C5 as an equatorial substituent of a pre-
ferred chair arrangement. The protected hydroxyl functionality
was viewed as less significant although there were initial concerns
about the propensity for elimination reactions under the thermal
conditions. These fears proved to be unwarranted since the IMDA
reaction of triene 23, as described in our previous efforts toward
norzoanthamine, proceeded at 80 °C in refluxing benzene over
65 h to yield 24 and 25 in 92% yield [dr 91:9] (Scheme 3).5 On
the other hand, we were surprised to observe a remarkable rate
enhancement in studies of the trienes 14 and 15 which resulted
in the production of small amounts of cyclization products at room
temperature during silica gel chromatography of the IMDA precur-
sors. Upon heating to reflux in benzene (containing BHT), the triene
14 was completely converted to 26 (85% yield) and 27 (4% yield)
within 4 h (Scheme 4).16 Under identical conditions, the C-4 diaste-
reomer 15 yielded three cyclization products (dr 25:55:20). The
more polar, minor component was readily separated by flash
chromatography and identified as cis-fused 29.17 Preparative HPLC
led to the separation and purification of the trans-fused decalin 28
as the major product,17 and an additional isomer, which is assumed
to be the alternative trans-fused system based on previous
trends. Unfortunately, an unambiguous assignment of this third
diastereomer was not feasible because key 1H signals were over-
lapping and insufficiently resolved for correlations in 2D-COSY
and 2D-NOESY spectra.
The presence of the branched C-5 alkyl substituent in trienes 14
and 15 leads to a substantial IMDA rate acceleration as a conse-
quence of a Thorpe–Ingold effect from which steric repulsions of
C-5 and C-6 substituents result in the compression of internal
C-2 and C-7 loci in the Diels–Alder endo-transition states. The
presentation of an axial OMOM substituent in the transition state
from 15 destabilizes the B-ring chair arrangement owing to the
1,3-diaxial interaction with the C-6 methyl group and diminishes
trans-selectivity in this IMDA example.
In conclusion, investigations of IMDA reactions using nitro-
alkene dienophiles have demonstrated the production of trans-
fused decalin systems with high stereoselectivity. Our mechanistic
O2N
H
OMOM
CH3
O
24
H3C
O
H
H3C
17
OPMB
CH3
H
CH3
H13C6
OH
HO
OPMB
CH3
H13C6
O
MOMO
EDCI: DMAP
NO2
RO
PhH; 80 °C
OPMB
H
RO
18 (R = SitBuPh2)
CH2Cl2 (98%)
16 (R = SitBuPh2)
H3C
O2N
65 h (92%)
[dr 91:9]
H3C
OMOM
Li+ –
O
O
CH3
OPMB
H
1) LDA; THF
TMSCl
tBuO
25
23
R
C6H13
OPMB
H3C
H
CH3
then: toluene; Δ
THF; –78 °C
CH3
then: MOM-Cl
DMAP
2) CN2N2
(83%; 2 steps)
3) TBAF
4) Ms2O; pyr
then: K+ –OtBu
(91%; 3 steps)
OPMB
1) LAH
ether
–20 °C
2) DMP
NaHCO3
(91%)
CH2Cl2
(90%)
19 R = OMe
20 R = H
Scheme 3. IMDA cyclization of 23.
MOMO
CH3
MOMO
CH3
H
H
CH3
MOMO
H
benzene
C6H13
OPMB O2N
C6H13
OPMB
OMe
H
H
H
4
14
15
3
2
C6H13
OPMB
5
O2N
80 °C
4 h (90%)
6
O
O
CH3
1
CH3
H
CH3
1) H3CNO2
H
CH3
KF; i-PrOH
O2N
8
R
C6H13
OPMB
26 (major)
27
(98%)
14
CH3
10
MOMO
CH3
MOMO
CH3
2) MsCl; Et3N
MOMO
4
CH3
H
H
H
CH2Cl2 at 0 °C
benzene
C6H13
OPMB O2N
C6H13
OPMB
C6H13
OPMB
H
H
H
5
1) DIBAL
–78 °C
21 R = OtBu
22 R = H
O2N
80 °C
4 h (92%)
H
CH3
CH3
2) DMP
CH3
O2N
NaHCO3
28 (major)
(85%; 2 steps)
15
29
Scheme 2. Preparation of trienes 14 and 15.
Scheme 4. IMDA cyclizations of trienes 14 and 15.

D. R. Williams et al. / Tetrahedron Letters 52 (2011) 2120–2123
2123
12. Felzmann, W.; Arion, V. B.; Mieusset, J.-L.; Mulzer, J. Org. Lett. 2006, 8, 3849–
3851.
rationale considers the benefits of geometrical constraints and ste-
ric repulsions within the tethering carbon chain which facilitate
asynchronous, endo-transition states. Applications for the synthe-
sis of natural products are underway.
13. Colorless monoclinic crystals of 12 (space group P21) were submitted for X-ray
diffraction and the structure 12 was solved using SIR-2004 and refined with
SHELLXL-97. The final full matrix least squares refinement converged to
R1 = 0.0225 and wR2 = 0.0560 (F2, all data). Crystallographic data (excluding
structure factors) have been deposited with the Cambridge Crystallographic
Data Centre (No CCDC-796539) and can be obtained free of charge upon
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax (+44) 1223
336 033; e-mail: deposit@ccdc.cam.ac.uk).
14. Preparation of (+)-3-methylnonanoic acid (17) is accomplished via an
asymmetric conjugate addition using N-acyloxazolidinone iv and subsequent
hydrolysis of v. For a general reaction protocol and examples: Williams, D. R.;
Kissel, W. S.; Li, J. Tetrahedron Lett. 1998, 39, 8593–8596; The chiral acid 17 has
been previously described: Meyers, A. I.; Kamata, K. J. Am. Chem. Soc. 1976, 98,
2290–2294
Acknowledgments
We thank Indiana University, Faculty Research Support Pro-
gram, and the National Institutes of Health (GM041560) for partial
support of this research.
Supplementary data
CH3
O
O
O
O
CH3
BrMg
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.012.
CH3
O
N
CH3
O
N
CuBr•DMS
THF (–50 °C)
iv
Ph
Ph
BF3•OEt2 (1 equiv)
References and notes
LiOH
THF
H2O
v (83%)
then: add iv at –78 °C
1. For a review: Takao, K.-i.; Munakata, R.; Tadano, K.-i. Chem. Rev. 2005, 105,
4779–4807.
17 (98%)
2. For a tutorial review: Juhl, M.; Tanner, D. Chem. Soc. Rev. 2009, 38, 2983–2992.
3. (a) Kurth, M. J.; O’Brien, M. J.; Hope, H.; Yanuck, M. J. Org. Chem. 1985, 50, 2626–
2632; (b) Retherford, C.; Knochel, P. Tetrahedron Lett. 1991, 32, 441–444.
4. Sader-Bakaouni, L.; Charton, O.; Kunesch, N.; Tillequin, F. Tetrahedron 1998, 54,
1773–1782.
15. For a review of the Henry reaction: Luzzio, F. A. Tetrahedron 2001, 57, 915–945.
16. Key observed NOESY cross peaks for 26 and 27 from 2D NMR are summarized
below:
PMB
H
H
H
H
H
O
H
O
MOM
R
5. Williams, D. R.; Brugel, T. A. Org. Lett. 2000, 2, 1023–1026.
6. For a leading publication in this area, see: (a) Denmark, S. E.; Seierstad, M. J.
R
MOMO
O2N
H
Org. Chem. 1999, 64, 1610–1619; For
a review of tandem [4 + 2]/[3 + 2]
H
OPMB
H
H
cycloaddition reactions of nitroalkenes, see: (b) Denmark, S. E.; Thorarensen, A.
Chem. Rev. 1996, 96, 137–166.
NO2
H3C
CH3
H
H
H
7. Lin, Y.-T.; Houk, K. N. Tetrahedron Lett. 1985, 26, 2269–2272.
8. Roush, W. R.; Hall, S. E. J. Am. Chem. Soc. 1981, 103, 5200–5211.
9. Evans, D. A.; Chapman, K. T.; Bisaha, J. Tetrahedron Lett. 1984, 25, 4071–4074.
10. Brown, F. K.; Houk, K. N. Tetrahedron Lett. 1985, 26, 2297–2300.
11. Synthesis of optically active tetraene 8 utilized the terminal alkyne i which was
prepared by sequential execution of an Eschenmoser–Claisen rearrangement,
DIBAL reduction and Seyferth–Gilbert homologation beginning with the
enantiomeric allyl alcohol of 16. Acylation followed by the syn-addition of
dimethylcuprate produced the Z-unsaturated ester ii for the subsequent Henry
reaction of iii and dehydration. A full description will be incorporated in the
complete account of these studies.
26 (R = C8H17
)
27 (R = C8H17)
17. Key NOESY cross peaks observed in the 2D NMR spectra of 28 and 29 are
shown below:
PMB
H
H
H
H
H
O
H
H
H
H
H
R
H
R
O2N
H
OPMB
H
O
NO2
H3C
CH3
MOM
MOMO
H
H
H
CH3NO2
TBAF/THF
TMSCl; NEt3
1) nBuLi
TMEDA; THF
ClCOOEt (70%)
28 (R = C8H17
)
29 (R = C8H17)
H3C
O
8
R
quench: Ms2O
THF; NEt3
2) Me2CuLi
60% based
on one recycle
of iii
THF (–78 °C)
quench MeOH
at –78 °C
H3C
OPMB
H3C
OPMB
i
ii R = OEt (68%)
iii R = H (60%)
DIBAL
–78 °C