Radical-induced cyclopentannulation of Henry (nitroaldol)-derived intermediates

Article abstract of DOI:10.1021/jo0605546

Tributyltin hydride-mediated cyclizations of 1-nitro-2-acetoxy-5-hexenes 7a-g having multiple substitutions on carbons 1 and 6 result in 2,3-substituted-1-acetoxycyclopentanes 1a-g. The substrates were prepared by nitroaldol reactions of silyloxyaldehydes

Full text of DOI:10.1021/jo0605546

SCHEME 1. Tin Hydride-Mediated Pathways for Radical
Reduction or 5-Hexenyl Cyclization
Radical-Induced Cyclopentannulation of Henry
(Nitroaldol)-Derived Intermediates1
Frederick A. Luzzio,* Joel P. Ott, and Damien Y. Duveau
Department of Chemistry, UniVersity of LouisVille,
2320 South Brook Street, LouisVille, Kentucky 40292
faluzz01@gwise.louisVille.edu
ReceiVed March 13, 2006
SCHEME 2. Multistep Synthesis of Cyclization Precursors and
Cyclized Productsa
Tributyltin hydride-mediated cyclizations of 1-nitro-2-ac-
etoxy-5-hexenes 7a-g having multiple substitutions on car-
bons 1 and 6 result in 2,3-substituted-1-acetoxycyclopentanes
1a-g. The substrates were prepared by nitroaldol reac-
tions of silyloxyaldehydes followed by acetylation, desily-
lation, and oxidation to the acetoxynitroaldehydes 6a-e.
Wittig olefination of aldehydes 6a-e then afforded substrates
for the radical cyclizations. The overall scheme gave a di-
verse array of cyclopentanes, including gem-disubstituted
cyclopentanes having substitution on three contiguous car-
bons.
The versatility of the Henry reaction in joining sensitive
molecular fragments together is multifold as exemplified by the
concomitant creation of a new multiply reactive center, the
â-nitroalkanol group.2a-e In turn, the nitroalkanol group may
then serve as a convenient starting point for further conversion
to a number of diverse functional groups. The most frequently
employed nitro alcohol conversions include in situ dehydration
to the corresponding nitroolefin, reduction to the corresponding
amino alcohol, or oxidation to the corresponding nitro ketone.
In addition, the complete replacement or removal of the nitro
group by the many variants of the Nef reaction has been utilized
extensively in organic synthesis.3 The less commonly employed
transformations include removal of the nitro group by radical
reduction and includes replacement with hydrogen (radical
denitrohydrogenation)4a,b or concomitant inter- or intramolecular
carbon-carbon bond formation depending on suitably disposed
unsaturation (Scheme 1).4c-f The radical 5-hexenyl cyclizations
have been reported in a few isolated cases and have included
both the formation of tetrahydrofurans from allyl or propargyl
ethers bearing nitro substituents4a,d,e and the preparation of a
tricyclic cedrene intermediate through a radical cascade cy-
clization of a homoallylic â-nitro alcohol.5a,b To demonstrate
substrate generality, we evaluated â-nitroalkanols or Henry-type
intermediates as substrates for radical cyclization to highly
substituted cyclopentanes. The cyclopentane ring system con-
stitutes the structural core of numerous natural products and
biologically active compounds; therefore, new and general
approaches to diverse cyclopentanoids continue to prove valu-
a Reagents and conditions: (a) N,N,N′,N′-tetramethylguanidine/THF/rt; (b)
Ac2O/pyr/rt; (c) TFA/H2OCH2Cl2/rt; (d) PCC/SiO2/CH2Cl2; (e) R,RCdPPh3; (f)
HSnBu3/AIBN/toluene/110 °C.
able in total synthesis.6 Our approach to five-membered rings
employs a radical cyclization of substrates which possess both
a nitro group and a suitably disposed olefinic unit (Scheme 2).
The nitro group, which is susceptible to radical replacement, is
introduced through a Henry reaction giving a nitro alcohol, while
the olefinic unit is introduced at a later stage through a Wittig
reaction. Generation of the double bond at the later stage, or
after the Henry reaction, is preferable since many nitroaldols
on intermediate aldehydes having conjugated olefinic units will
suffer competing nitronate Michael addition. Although the indi-
vidual reactions are commonplace, the overall scheme represents
a novel sequence utilizing Henry intermediates and thereby tests
the tolerances of the derivatized nitro alcohol function.
The scheme commences with the 4-tert-butylsilyloxy (TB-
DMS) aldehydes 2a-c (Figure 1). The aldehydes are then
(4) (a) Ono, N.; Miyake, H.; Kamimiura, A.; Hamamoto, I.; Tamura,
R.; Kaji, A. Tetrahedron 1985, 41, 4013-4023. (b) Tanner, D. D.;
Blackburn, B. B.; Diaz, G. E. J. Am. Chem. Soc. 1981, 103, 1557-1559.
(c) DuPuis, J.; Giese, B.; Hartung, J.; Leising, M. J. Am. Chem. Soc. 1985,
107, 4332-4333. (d) Vankar, Y. D.; Bawa, A.; Kumaravel, G. Tetrahedron
1991, 47, 2027-2040. (e) Vankar, Y. D.; Chauduri, N. C. Synth. Commun.
1991, 21, 885-899. (f) Crich, D.; Shirai, M.; Rumthao, S. Org. Lett. 2003,
5, 3767-3769.
(5) (a) Chen, Y.-J.; Lin, W. Y. Tetrahedron Lett. 1992, 33, 1749-1750.
(b) Chen, Y.-J.; Chang, W.-H.; Lin, W.-Y. Tetrahedron Lett. 1993, 34,
2961-2962. (c) Chen, Y.-J.; Chang, W.-H. J. Org. Chem. 1996, 61, 2536-
2539. (d) Chen, Y.-J.; Chang, W.-H.; Lin, W.-Y. Tetrahedron 1996, 52,
13181-13188.
(6) Corey, E. J.; Cheng, X. M. The Logic of Chemical Synthesis; Wiley:
New York, 1989; pp 373, 250-307.
* Corresponding author. Tel: (502) 852-7323. Fax: (502) 852-8149.
(1) Presented at the 226th National Meeting of the American Chemical
Society, New York, Sep 7 and 8, 2003; ORGN 131.
(2) (a) Seebach, D.; Colvin, E. W.; Leher, F.; Weller, T. Chimia 1979,
331; (b) Rosini, G. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon: Oxford, 1991; Vol. 2. (c) Rosini, G.; Ballini, R. Synthesis
1988, 833-847. (d) Luzzio, F. A. Tetrahedron 2001, 57, 915-945. (e)
Ono, N. The Nitro Group in Organic Synthesis; Wiley: New York, 2001.
(3) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017-1047.
10.1021/jo0605546 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/02/2006
J. Org. Chem. 2006, 71, 5027-5030
5027

TABLE 2. Acetylation/Desilylation/Oxidation of Nitroalkanols
3a-e to Aldehydes 6a-e through Nitroacetoxysilyl Ethers 4a-e and
Nitroacetoxy Alcohols 5a-e
FIGURE 1. Selected aldehydes for the Henry reactions (R ) tert-
butyldimethylsilyl).
TABLE 1. Henry Reaction of Silyloxyaldehydes 2a-c with
Selected Nitro Compounds
a R ) TBDMS. b Unstable to purification due to retro-Henry process
and was used directly in the next step.
tetra-N-butylammonium fluoride (TBAF)/THF, which we se-
lected for the initial attempts, with TFA for removal of the
TBDMS group and noted that unwanted elimination of the
acetate in 5a, 5d, and 5e was facilitated by TBAF under all
conditions. After removal of the TBDMS group, the alcohols
5a-e were then oxidized to the corresponding aldehydes 6a-e
with pyridinium chlorochromate (PCC)/silical gel. To our
satisfaction, the relatively polar acetoxynitroaldehydes were
easily removed from the granular reduced chromium byproducts
during the purification process, an operation which has been
problematic when using PCC to oxidize other substrates bearing
both nitro and nitroalkanol groups.
Although the 4-acetoxy-5-nitropentanals 6a-e easily survived
the protocol of the PCC oxidation, they proved to be unstable
on storage, and the best results were obtained when they were
used immediately in the olefination step. The isolated yields of
aldehyde products 6a-e ranged from 67 to 98% (Table 2). The
4-acetoxy-5-nitropentanals 6a-e were then directly treated with
several types of Wittig reagents of varying structure and reac-
tivity (Table 3). The Wittig reagent employed for the preparation
coupled with nitroethane, 2-nitropropane, or nitrocyclopentane
in the presence of N,N,N′,N′-tetramethylguanidine (TMG) or
potassium tert-butoxide (KO-t-Bu) to produce nitro alcohols
3a-e in isolated yields of 89-41% (Table 1). The coupling of
the 4-silyloxyaldehydes with the primary nitro compounds was
easily facilitated with TMG; however, the more sluggish Henry
reactions required KO-t-Bu. Typically, both protocols yielded
chromatographically inseparable mixtures of erythro and threo
isomers. Although there are methods available for gaining high
erythro or threo selectivity in the nitroaldol reaction,7 such
modes of selectivity were not an issue in our multistep scheme
whereby the nitro group would be lost in the cyclization step.
Immediately following the isolation of the nitroalkanols 3a-e,
they were acetylated with acetic anhydride in pyridine to furnish
the corresponding silyloxynitroacetates 4a-e in yields of 75-
96% (Table 2). Derivatization of the nitro alcohol function in
3a-e as the nitroacetate both protects the hydroxyl group during
the oxidation step and deactivates these sensitive compounds
to the usual retroaldol processes that plague the use of â-
nitroalkanols as synthetic intermediates. Next, the removal of
the TBDMS group was accomplished with aqueous trifluoro-
acetic acid (TFA) to furnish the corresponding 4-acetoxy-5-
nitropentanols 5a-e in 71-88% yield (Table 2). We compared
(7) Barrett, A. G. M.; Robyr, C.; Spilling, C. D. J. Org. Chem. 1989,
54, 1233-1234. (b) Eyer, M.; Seebach, D. J. Am. Chem. Soc. 1985, 107,
3601-3606.
5028 J. Org. Chem., Vol. 71, No. 13, 2006

TABLE 3. Wittig Olefination of Acetoxynitroaldehydes 6a-e
TABLE 4. Tri-n-butyltin Hydride-Mediated 5-Hexenyl
Cyclizations of 7a-h to 1a-g
troacetates 7a-h were then treated with tri-n-butyltin hydride
(Bu3SnH) and azobisisobutyronitrile (AIBN) in toluene at 108-
110 °C.8 The Bu3SnH-mediated reactions resulted in smooth
5-exo-trig radical closure and thus provided the title tri- and
tetrasubstituted cyclopentanes in isolated yields ranging from
43 to 82% (Table 4). Although the progress of the radical
closures was conveniently monitored by analytical TLC, the
cyclized products were chromatographically inseparable mix-
tures of cis and trans diastereoisomers as determined by 1H and
of 7a,b,f-h was ethoxycarbonylmethylidenetriphenylphosphorane.
Benzylidenetriphenylphosphorane was used for the preparation
of 7c, while treatment of 6b with the more stable R-triph-
enylphosphoranylideneacetophenone gave olefin 7d. Finally,
treatment of aldehyde 6b with cyclopentylidenetriphenylphos-
phorane afforded olefin 7e. The aldehydes 6a-e responded to
the Wittig reagents quite well although the reaction conditions,
particularly the mode of addition, temperature, and equivalents
of reagent, were critical since the Wittig reagents possessed
sufficient basicity to promote unwanted elimination in the
acetoxynitroaldehydes 6a and 6d. In all cases except for 7c and
7e, the acetoxynitroolefins were obtained as the chromato-
graphically pure E isomers and were used directly in the cycli-
zation study. Olefin 7c was used as a mixture of E and Z isomers
(2:1), while E/Z stereochemistry was not an issue with the
cyclopentylidene olefin 7e (Table 3). The olefinic acetoxyni-
1
13C NMR analysis. While routine H NMR was inconclusive
in confirming the stereochemistry of each diastereoisomer in
the mixture, a chemical expedient combined with NMR analysis
led to the positive assignment of each diastereoisomer.9 The
(8) An excess of HSnBu3 (3 equiv) was required for total consumption
of 7a-g, although products 1a-g were easily separable from the tin
byproducts by chromatography. Organotin waste disposal was done in
accordance with: Prudent Practices in the Laboratory: Handling and
Disposal of Chemicals; National Academy Press: Washington D.C., 1995;
pp 412-413.
J. Org. Chem, Vol. 71, No. 13, 2006 5029

SCHEME 3. Hydrolysis and Lactonization of the cis-Acetoxy
both the employment of chiral or bulky controller groups to
direct stereoselectivity and the use of organocatalytic tin hydride
systems.
Ester 1ba
Experimental Section
General Experimental Procedures. See the Supporting Infor-
mation.
Cyclization of Ethyl 6-Acetoxy-7-methyl-7-nitrooct-2-enoate
(7b). cis- and trans-Ethyl (3-Acetoxy-2,2-dimethylcyclopentyl)-
acetate (1b). To a solution of the nitroolefin 7b (56.0 mg, 0.195
mmol) in dry toluene (1.5 mL) were added tributyltin hydride (165
µL, 0.595 mmol) and AIBN (6.4 mg, 0.039 mmol). The clear
solution was stirred at 110 °C for 1.5 h and then allowed to cool
to room temperature. The solvent was removed under high vacuum,
and the residue was purified by flash chromatography (hexanes/
ethyl acetate, 5:1) giving 1b (38.7 mg, colorless oil) as a mixture
of diastereoisomers (1:1, cis/trans) in 82% yield: Rf 0.27 (hexanes/
ethyl acetate, 3:1); IR 2963, 2874, 1740, 1734; 1H NMR 4.82 (dd,
J ) 1.8 Hz, 6.9 Hz, 0.5 × 1H, trans), 4.72 (t, J ) 7.9 Hz, 0.5 ×
1H, cis), 4.14 (m, 2H), 2.36-2.42 (m, 1H), 1.88-2.18 (m, 4H),
2.06 (s, 0.5 × 3H), 2.04 (s, 0.5 × 3H), 1.32-1.62 (m, 2H), 1.27
(m, 3H), 0.97 (s, 1.5H), 0.95 (s, 1.5H), 0.79 (s, 3H); 13C NMR
173.5, 173.2, 170.8, 170.7, 83.7, 82.1, 60.65, 60.60, 44.26, 44.23,
42.9, 42.80, 42.75, 35.5, 35.0, 29.3, 28.1, 27.4, 26.73, 26.70, 25.4,
21.2, 21.1, 20.3, 15.5, 14.2; HRMS (CI, MNH4+) calcd for C13H26-
NO4 260.1861, found 260.1869.
a Reagents and conditions: (a) LiOH/THF/MeOH/20 °C/18 h (quant); (b)
TsOH/CH2Cl2/20 °C/35 h (quant); (c) Ac2O/pyr/20 °C/23 h, 77%.
50/50 cis/trans mixture of acetoxy esters 1b was hydrolyzed
(0.5 M LiOH in THF/MeOH, 1:1; rt, 18 h) giving the cis- and
trans-hydroxy esters 8a and 8b (Scheme 3). The mixture was
then treated with p-toluenesulfonic acid monohydrate in CH2-
Cl2 (rt/18 h), which led to both quantitative conversion of the
cis-diastereoisomer 8a to apocamphor lactone 9 and leaving the
chromatographically separable trans-hydroxy ester 8b unreacted.
The unreacted hydroxy ester 8b was separated and then
acetylated with acetic anhydride/pyridine (rt/24h) to afford ester
10. An 1H NMR correlation with the acetoxy CH (dd, 4.82 ppm)
was then made, thereby establishing the more downfield
absorptions as those representing the trans diastereoisomers in
products 1b-f (Scheme 3). Acetoxy ester 1a and indan 1g were
also obtained as chromatograpically inseparable mixtures of
diastereoisomers.
However, the stereochemical correlation described above
together with that made by Normant10 for cis- and trans-1-
acetoxy-2-methylcyclopentanes led to the assignment of the
trans,cis and the cis,cis as the most downfield pair, respectively,
followed by the more upfield cis,trans and trans,trans, respec-
tively (see the Supporting Information). Substrates 7b-f gave
somewhat higher yields (see 1b-f, Table 4) than substrates 7a
and 7g, presumably due to the greater ease in developing the
radical derived from the tertiary nitro carbon as opposed to that
formed from a secondary carbon. Substrate 7h (Table 3) failed
to cyclize but instead provided only 11. Presumably, unfavorable
Cyclization of Ethyl 6-Acetoxy-6-(1-nitrocyclopentyl)hex-2-
enoate (7f). cis- and trans-Ethyl (4-Acetoxyspiro[4.4]non-1-yl)-
acetate (1f). To a solution of the nitroolefin 7f (15.9 mg, 0.051
mmol) in dry toluene (1.0 mL) were added tributyltin hydride (40
µL, 0.149 mmol) and AIBN (1.7 mg, 0.010 mmol). The clear
solution was stirred at 110 °C for 1 h and then allowed to cool to
room temperature. Following removal of the solvent under high
vacuum, the residue was purified by flash chromatography (hexanes/
ethyl acetate, 4:1) affording 1f (10.8 mg, colorless oil) as a mixture
of diastereoisomers (40:60, cis/trans) in 79% yield: Rf 0.52 (hexane/
ethyl acetate, 3:1); IR 2963, 2874, 1741, 1733; 1H NMR 4.86 (dd,
J ) 4.7 Hz, 6.7 Hz, 0.6 × 1H, trans), 4.82 (d, J ) 5.6 Hz, 0.4 ×
1H, cis), 4.14 (m, 2H), 2.23-2.48 (m, 2H), 2.04 (s, 3H), 1.90-
2.20 (m, 3H), 1.33-1.74 (m, 9H), 1.26 (m, 3H); 13C NMR 173.7,
173.6, 170.9, 170.8, 82.1, 81.8, 60.4, 60.3, 55.9, 55.6, 42.8, 41.3,
37.3, 36.9, 35.1, 30.4, 29.6, 29.1, 28.2, 28.1, 27.7, 25.6, 25.5, 25.3,
24.9, 21.4, 21.3, 14.3; HRMS (CI, MNH4+) calcd for C15H28NO4
286.2018, found 286.2031.
Acknowledgment. Financial support by the National Cancer
Institute and the University of Louisville (Assistantships to
J.P.O. and D.Y.D.) is gratefully acknowledged.
geometry together with the competing reductive denitrohydro-
genation process conspired to give 11 as the sole product. With
respect to the design of substrate 7g, which leads to the
formation of indan 1g, we noted a related radical cyclization of
12 having a carbohydrate-based chiral controller group. The
cyclization was tin hydride-mediated and gave an indanyl acetic
ester similar to 1g.11 In conclusion, 5-hexenyl radical cycliza-
tions of substrates having both esterified nitroalkanol groups
(Henry nitro esters) and suitably disposed double bonds offer
an expedient to highly substituted cyclopentanes. The cyclization
affords most notably esters of cyclopentanols and cyclopenty-
lacetic esters having quaternary spiro or gem-dialkyl substitution
as well as substituted indans. The diversity of the nitro com-
pounds available for construction of the pivotal â-nitroacetoxy-
aldeydes together with the variation of Wittig reagents available
for introducing the 5-hexenyl subunit allows for versatility in
the structure of the cyclized products. Current studies include
Supporting Information Available: Experimental procedures
1
for the preparation of all new compounds and H NMR and 13C
NMR spectra of 1a,c-e,g, 3a,b,d,e, 4a-e, 5a-e, 6a-d, 7a-h,
8a/b, 8b, and 9-11. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO0605546
(9) Wu, Y.; De Clercq, P.; Vandewalle, M.; Bouillon, R.; Verstuyf, A.
Bioorg. Med. Chem. Lett. 2002, 12, 1633-1636.
(10) Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J.-F. Tetrahedron
1994, 50, 11665-11692.
(11) Enholm, E. J.; Cottone, J. S.; Allais, F. Org. Lett. 2001, 3, 145-
147.
5030 J. Org. Chem., Vol. 71, No. 13, 2006