Study on the base-catalyzed reverse vinylogous aldol reaction of (4aβ,5β)-4,4a,5,6,7,8-hexahydro-5-hydroxy-1,4a-dimethylnaphthalen- 2(3H)-one under Robinson annulation conditions

Article abstract of DOI:10.1021/jo0520036

We have proposed a pathway for the base-catalyzed reverse vinylogous aldol reaction of (-)-(4aβ,5β)-4,4a,5,6,7,8-hexahydro-5-hydroxy-1,4a- dimethylnaphthalen-2(3H)-one [(-)-8] under Robinson annulation conditions. For confirmation, 4-(2,6-dimethyl-3-oxocy

Full text of DOI:10.1021/jo0520036

SCHEME 1
Study on the Base-Catalyzed Reverse Vinylogous
Aldol Reaction of
(4aâ,5â)-4,4a,5,6,7,8-Hexahydro-
5-hydroxy-1,4a-dimethylnaphthalen-2(3H)-one
under Robinson Annulation Conditions
Joshua N. Payette, Tadashi Honda,* Hidenori Yoshizawa,†
Frank G. Favaloro, Jr., and Gordon W. Gribble*
Department of Chemistry, Dartmouth College,
6128 Burke Laboratory, HanoVer, New Hampshire 03755
th9@dartmouth.edu; ggribble@dartmouth.edu
ReceiVed September 23, 2005
SCHEME 2
We have proposed a pathway for the base-catalyzed reverse
vinylogous aldol reaction of (-)-(4aâ,5â)-4,4a,5,6,7,8-
hexahydro-5-hydroxy-1,4a-dimethylnaphthalen-2(3H)-one [(-)-
8] under Robinson annulation conditions. For confirmation,
4-(2,6-dimethyl-3-oxocyclohex-1-enyl)butanal (11) and 4-(2,6-
dimethyl-5-oxocyclohex-1-enyl)butanal (12), both of which
potentially produce enolate I, were synthesized regioselec-
tively. Unexpectedly, 11 gave a complex mixture, including
only a trace amount of (()-8 (less than 5% yield), under
these basic conditions. To the contrary, 12 cleanly afforded
(()-8 in 66% yield. This result provides evidence for our
proposed mechanism of the above reaction.
4, produced by a base-catalyzed vinylogous retro-aldol reaction
(Scheme 1).3
In connection with the synthesis of optically active tricyclic
compounds having cyano-bis-enone functionalities [e.g., (-)-6
and (-)-7], which represent a series of novel and orally active
anti-inflammatory and cancer-chemopreventive agents,4,5 we
have found that hydroxy enone (-)-85,6 [96% enantiomeric
excess (ee); [R]26 -170° (c 1.2, CHCl3)] is racemized and
D
epimerized under Robinson annulation conditions [ethyl vinyl
ketone and sodium methoxide in methanol (reflux, 12 h)] to
afford (+)-9 [51% yield; 56% ee; [R]27D +50° (c 2.0, CHCl3)],
10 (<5% yield), and recovered 8 in racemic form [33% yield,
[R]28 +2.4° (c 8.6, CHCl3), Scheme 2].5 We speculate that
D
racemization and C-5 epimerization of (-)-8 occur via an
interesting base-catalyzed reVerse vinylogous aldol reaction
shown in Scheme 3. It is reasonable that enolate I, potentially
derived from conjugated and/or deconjugated aldehydes 11 and
12 (Scheme 4), is a common intermediate for this reverse
vinylogous aldol reaction, although we were not able to isolate
these aldehydes from the reaction mixture. Therefore, for
confirmation of this pathway, we now describe the regioselective
It is well-known that racemic hydroxy enone 1, which is
derived from a Wieland-Miescher ketone, gives polymeric
products via the proposed enolate 2 under base-catalyzed
benzylation conditions.1 Enolate 2 is presumed to arise from 1
by a vinylogous retro-aldol reaction. Moreover, 1 cannot be
ketalized because of a similar acid-catalyzed vinylogous retro-
aldol reaction.2 Also, it has been reported that hydroxy enone
3 gives the ring-enlargement product 5 via the presumed enolate
(3) Swaminathan, S.; John, J. P.; Ramachandran, S. Tetrahedron Lett.
1962, 729-734.
* To whom correspondence should be addressed. Phone: 603-646-1591
(T.H.); 603-646-3118 (G.W.G.). Fax: 603-646-3946 (T.H.); 603-646-3946
(G.W.G.).
(4) Favaloro, F. G., Jr.; Honda, T.; Honda, Y.; Gribble, G. W.; Suh, N.;
Risingsong, R.; Sporn, M. B. J. Med. Chem. 2002, 45, 4801-4805.
(5) Honda, T.; Favaloro, F. G., Jr.; Janosik, T.; Honda, Y.; Suh, N.; Sporn,
M. B.; Gribble, G. W. Org. Biomol. Chem. 2003, 1, 4384-4391.
(6) Dutcher, J. S.; Macmillan, J. G.; Heathcock, C. H. J. Org. Chem.
1976, 41, 2663-2669.
† Visiting scholar from Shionogi & Co., Ltd.
(1) Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746-
1757.
(2) Los, M.; Mighell, A. D. Tetrahedron 1965, 21, 2297-2303.
10.1021/jo0520036 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/11/2005
416
J. Org. Chem. 2006, 71, 416-419

SCHEME 3
SCHEME 5
SCHEME 4 a
enone 19 in 98% yield. In contrast, deketalization of 18 using
PPTS in aqueous acetone8 produced deconjugated enone 20
(64% yield) and 19 (11% yield),9 which were separable by flash
column chromatography. Oxidation of 19 and 20 with CrO3 and
10
pyridine in CH2Cl2 afforded 11 and 12 in 77 and 68% yield,
respectively.
Interestingly, we found that 12 gave (()-86 in 66% yield
under the same Robinson annulation conditions used for 9, while
11 gave a complex product mixture including only trace amounts
of (()-8 and 11 (each less than 5% yield). We rationalize these
results in Scheme 5. Although the conjugated aldehyde 11 forms
two enolates, I and II, under basic conditions, we believe that
the formation of II is kinetically preferable to I. Because II
cannot give the vinylogous aldol condensation product (()-8,
it affords a complex mixture, including only a trace amount of
(()-8. However, because the deconjugated aldehyde 12 is
predominantly enolized to produce enolate I, which then cyclizes
to (()-8, 12 is cleanly converted to (()-8 in good yield.11
This result provides evidence for our proposed mechanisms
on the base-catalyzed reverse vinylogous aldol reaction of (-)-8
under Robinson annulation conditions that the common inter-
mediate is the enolate I.
a
Key: (a) aqueous NaOH, 82%; (b) H2SO4, MeOH, 71%; (c) p-TsOH,
ethylene glycol, PhH, 54%; (d) LiAlH4, Et2O, 89%; (e) aqueous HCl,
MeOH, 98%; (f) PPTS, aqueous acetone, 64%; and (g) CrO3, pyridine,
CH2Cl2, 77% for 11 and 68% for 12.
synthesis of unknown aldehydes 11 and 12 and their behavior
under these reaction conditions.
Because aldehydes 11 and 12 would presumably be unstable
under both basic and acidic conditions, we adopted the sequence
shown in Scheme 4 in which neutral oxidation conditions were
employed. In this fashion, both aldehydes 11 and 12 were
synthesized regioselectively by this sequence.
(9) GC-MS indicated that the ratio of 20 and 19 at the end of the reaction
was 85:15.
(10) Ratcliffe, R.; Rodehorst, R. J. Org. Chem. 1970, 35, 4000-4002.
(11) For confirmation of our speculation about the different outcomes
from 11 and 12, we envisioned an enolate trapping experiment under kinetic
enolate formation conditions using 21, which was prepared from 19 with
TBSCl in the presence of imidazole in DMF (85% yield). Enone 21 was
treated with LDA and TMSCl in THF at -78 °C for 1 min to give silyl
ether 22 (92% yield).12 This result shows that enolate III is produced
kinetically from 21 and supports our belief that aldehyde 11 gives a complex
product mixture via kinetic enolate II (Scheme 5).
Methyl ester 15 was prepared from known acid 147 under
sulfuric acid-methanol conditions, which in turn was derived
from diketone 136 with a 2% aqueous NaOH solution (58%
yield from 13). Ketalization of 15 with ethylene glycol in the
presence of pyridinium p-toluenesulfonate (PPTS) in benzene8
gave an inseparable mixture of 16 and 17 in 53% yield.
Interestingly, the use of p-TsOH gave only ketal 16 in 54%
yield. The structure of 16 was confirmed by the observation of
an NOE between the ketal protons and the C-6 methyl group
(NOESY one-dimensional experiment). Reduction of 16 with
LiAlH4 in Et2O afforded alcohol 18 in 89% yield. Deketalization
of 18 with aqueous HCl conditions gave only the conjugated
(7) Becker, D.; Birnbaum, D. J. Org. Chem. 1980, 45, 570-578.
(8) Sterzycki, R. Synthesis 1979, 724-725.
(12) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 495-498.
J. Org. Chem, Vol. 71, No. 1, 2006 417

3-(4-Hydroxybutyl)-2,4-dimethylcyclohex-3-enone (20). A so-
lution of 18 (87.5 mg, 0.36 mmol) and PPTS (42 mg, 0.17 mmol)
in acetone (5.0 mL) and water (0.6 mL) was stirred at reflux for 2
h. After the removal of acetone, the resultant mixture was diluted
with a mixture of Et2O and CH2Cl2 (2:1; 35 mL) and then worked
up according to the standard method to give an oil (66.3 mg). This
was purified by flash column chromatography [hexanes/EtOAc (1:
2)] to give 20 as a colorless oil (45.6 mg, 64%) and 19 (8.0 mg,
11%). 20: 1H NMR (CD3OD) δ 3.57 (2H, t, J ) 6.22 Hz), 2.74
(1H, m), 1.76 (3H, s), 1.21 (3H, d, J ) 7.2 Hz); 13C NMR (CD3-
OD) δ 217.0, 134.2, 128.6, 62.8, 47.7, 37.5, 33.5, 32.4, 31.3, 25.7,
19.1, 17.1. HREIMS calcd for C12H20O2: 196.1463. Found:
196.1460. Anal. Calcd for C12H20O2‚1/8H2O:13 C, 72.60; H, 10.28.
Found: C, 72.78; H, 10.26.
4-(2,6-Dimethyl-3-oxocyclohex-1-enyl)butanal (11). To a stirred
solution of anhydrous CH2Cl2 (20 mL) and anhydrous pyridine (1.25
mL) was added CrO3 (763 mg, 7.63 mmol). The deep burgundy
solution was stirred for 15 min at rt. At this time, a solution of 19
(261 mg, 1.33 mmol) in a small amount of CH2Cl2 was added.
After stirring for an additional 15 min, the solution was decanted
and the remaining tarry black residue was washed with a mixture
of Et2O and CH2Cl2 (2:1; 3 × 10 mL). The combined organic
extracts were washed with a 5% aqueous NaOH solution (3 × 10
mL) and a 5% aqueous HCl solution (3 × 10 mL) and then worked
up according to the standard method to give an oil (233 mg). This
was purified by flash column chromatography [hexanes/EtOAc (1:
1)] to give 11 (200 mg, 77%) as a colorless oil. 1H NMR (CDCl3)
δ 9.80 (1H, t, J ) 1.28 Hz), 1.76 (3H, s), 1.18 (3H, d, J ) 7.33
Hz); 13C NMR (CDCl3) δ 201.7, 199.3, 162.0, 131.0, 43.8, 33.8,
33.5, 32.5, 29.6, 20.3, 18.0, 11.2. HREIMS calcd for C12-
H18O2: 194.1307. Found: 194.1311. Anal. Calcd for C12H18O2‚
1/4H2O:13 C, 72.51; H, 9.38. Found: C, 72.40; H, 9.19.
Experimental Section
Methyl 4-(2,6-Dimethyl-3-oxocyclohex-1-enyl)butyrate (15).
To a solution of 4-(2,6-dimethyl-3-oxocyclohex-1-enyl)butyric acid
(14)7 (4.12 g, 19.6 mmol) in MeOH (170 mL) was added concd
H2SO4 (10.7 mL) dropwise. The resultant mixture was stirred at
reflux for 45 min. After the removal of the solvent (ca. 100 mL),
the reaction mixture was diluted with water (150 mL) and extracted
with a mixture of Et2O and CH2Cl2 (2:1; 3 × 80 mL). The combined
organic extracts were worked up according to the standard method
to give a yellow oil (4.26 g). This was purified by flash column
chromatography [hexanes/EtOAc (2:1)] to give 15 as a yellow oil
1
(3.10 g, 71%). H NMR (CDCl3) δ 3.65 (3H, s), 2.34 (2H, t, J )
7.32 Hz), 1.73 (3H, s), 1.16 (3H, d, J ) 6.95 Hz); 13C NMR (CDCl3)
δ 199.3, 173.6, 162.1, 130.9, 51.7, 33.9, 33.7, 33.5, 32.6, 29.6,
23.1, 17.9, 11.0. HREIMS calcd for C13H20O3: 224.1412. Found:
224.1417. Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found:
C, 69.78; H, 9.13.
Methyl 4-(6,8-Dimethyl-1,4-dioxaspiro[4,5]dec-7-en-7-yl)-
butyrate (16). A mixture of 15 (1.22 g, 5.44 mmol), p-TsOH (188
mg, 0.99 mmol), and ethylene glycol (11 mL) in anhydrous benzene
(65 mL) was heated under reflux with a Dean-Stark apparatus
overnight. The benzene and ethylene glycol layers were separated.
To the ethylene glycol layer was added water (15 mL), and this
was extracted with a mixture of Et2O and CH2Cl2 (2:1; 3 × 15
mL). The extracts were combined with the original benzene layer.
The organic mixture was worked up according to the standard
method to give an oil (1.63 g) that was purified by flash column
chromatography [hexanes/EtOAc (2.5:1)] to give 16 as a yellow
oil (790.8 mg, 54%). 1H NMR (CD3OD) δ 3.93 (4H, m), 3.65 (3H,
s), 2.31 (2H, t, J ) 7.14 Hz), 1.60 (3H, s), 1.03 (3H, d, J ) 6.96
Hz); 13C NMR (CD3OD) δ 176.0, 133.7, 127.0, 112.0, 65.5, 65.2,
52.1, 42.2, 34.3, 31.9, 31.4, 28.0, 24.8, 18.9, 17.0. HREIMS calcd
for C15H24O4: 268.1675. Found: 268.1675. Anal. Calcd for
C15H24O4: C, 67.14; H, 9.01. Found: C, 67.10; H, 9.13.
4-(6,8-Dimethyl-1,4-dioxaspiro[4,5]dec-7-en-7-yl)butan-1-ol (18).
To a solution of 16 (301 mg, 1.12 mmol) in anhydrous Et2O (40
mL) was added LiAlH4 (372 mg, 9.54 mmol) with cooling to 0
°C. The resultant mixture was stirred for 2 h at rt. To the reaction
mixture was added successively water (0.9 mL), a 40% aqueous
NaOH solution (0.3 mL), and water (0.9 mL). After the formation
of a white precipitate, the reaction mixture was decanted and dried
over MgSO4. Removal of the solvent in vacuo gave 18 (240.4 mg,
89%) as a colorless oil, which was used for the next reaction without
further purification. An analytically pure sample was obtained by
flash column chromatography [hexanes/EtOAc (1:2)] as a colorless
oil. 1H NMR (CD3OD) δ 3.94 (4H, m), 3.53 (2H, t, J ) 6.41 Hz),
1.62 (3H, s), 1.04 (3H, d, J ) 6.95 Hz); 13C NMR (CD3OD) δ
134.4, 126.0, 111.9, 65.3, 65.1, 62.9, 42.1, 33.6, 32.0, 31.7, 27.9,
25.8, 18.8, 16.9. HREIMS calcd for C14H24O3: 240.1725. Found:
240.1720. Anal. Calcd for C14H24O3: C, 69.96; H, 10.07. Found:
C, 69.83; H, 10.18.
3-(4-Hydroxybutyl)-2,4-dimethylcyclohex-2-enone (19). To a
solution of 18 (148.1 mg, 0.62 mmol) in MeOH (26 mL) was added
a 1 N aqueous HCl solution (9.9 mL) dropwise. The resultant
mixture was stirred at reflux for 45 min. After the removal of
MeOH, the reaction mixture was diluted with water (35 mL) and
extracted with a mixture of Et2O and CH2Cl2 (2:1; 3 × 15 mL).
The combined organic extracts were worked up according to the
standard method to give 19 (118.7 mg, 98%) as a yellow oil, which
was used for the next reaction without further purification. An
analytically pure sample was obtained by flash column chroma-
tography [hexanes/EtOAc (1:2)] as a colorless oil. 1H NMR (CDCl3)
δ 3.65 (2H, t, J ) 6.0 Hz), 1.73 (3H, s), 1.16 (3H, d, J ) 6.96
Hz); 13C NMR (CDCl3) δ 199.6, 163.6, 130.4, 62.5, 33.7, 33.6,
33.1, 33.0, 29.6, 24.3, 17.9, 11.0. HREIMS calcd for C12H20O2:
196.1463. Found: 196.1455. Anal. Calcd for C12H20O2‚1/10H2O:13
C, 72.76; H, 10.28. Found: C, 72.96; H, 10.30.
4-(2,6-Dimethyl-5-oxocyclohex-1-enyl)butanal (12). The title
compound was prepared from 20 according to the same procedure
followed for 11, resulting in a colorless oil (68%). 1H NMR (CDCl3)
δ 9.78 (1H, t, J ) 1.5 Hz), 2.72 (1H, m), 1.73 (3H, s), 1.22 (3H,
d, J ) 7.2 Hz); 13C NMR (CDCl3) δ 214.4, 202.3, 132.3, 128.4,
46.6, 43.7, 36.7, 31.7, 30.1, 20.9, 19.2, 17.2. HREIMS calcd for
C12H18O2: 194.1307. Found: 194.1307. Anal. Calcd for C12H18-
O2‚1/2H2O:13 C, 70.90; H, 9.42. Found: C, 70.70; H, 9.20.
Conversion of 4-(2,6-Dimethyl-5-oxocyclohex-1-enyl)butanal
(12) into (()-(4aâ,5â)-4,4a,5,6,7,8-Hexahydro-5-hydroxy-1,4a-
dimethylnaphthalen-2(3H)-one [(()-8]. To 12 (39.0 mg, 0.20
mmol) was added a 1.28 M solution of sodium methoxide in MeOH
(0.39 mL). The resultant mixture was stirred at reflux for 20 min.
The reaction mixture was diluted with water (20 mL) and extracted
with a mixture of Et2O and CH2Cl2 (2:1; 3 × 15 mL). The combined
organic extracts were then washed with a saturated aqueous NH4-
Cl solution (10 mL) and brine (10 mL), dried over MgSO4, and
filtered. Removal of the solvent in vacuo gave an oil (30.7 mg)
that was purified by flash column chromatography [hexanes/EtOAc
(1:2)] to give (()-86 (25.9 mg, 66%) as a colorless oil. 1H and 13
C
NMR, IR, UV, and MS spectra of this compound were identical
with those of the authentic sample.
3-[4-(tert-Butyldimethylsilyloxy)butyl]-2,4-dimethylcyclohex-
2-enone (21). A solution of 19 (62.5 mg, 0.32 mmol), tert-
butyldimethylsilyl chloride (TBSCl) (72 mg, 0.48 mmol), and
imidazole (65 mg, 0.95 mmol) in anhydrous DMF (0.6 mL) was
stirred at rt overnight. The reaction mixture was diluted with water.
The aqueous mixture was extracted with a mixture of Et2O and
CH2Cl2 (2:1; 3 × 15 mL). The extract was washed with a saturated
aqueous NH4Cl solution (twice) and brine (twice), dried over
MgSO4, and filtered. Removal of the solvent in vacuo gave an oil
(122 mg) that was purified by flash column chromatography
[hexanes/EtOAc (5:1)] to give 21 (83.7 mg, 85%) as a colorless
(13) Extensive drying did not remove the water present in the sample.
418 J. Org. Chem., Vol. 71, No. 1, 2006

1
oil. H NMR (CDCl3) δ 3.62 (2H, t, J ) 5.86 Hz), 2.51 (2H, m),
(1H, m), 1.90 (1H, m), 1.86 (3H, s), 1.53 (4H, m), 1.03 (3H, d, J
) 6.95 Hz), 0.98 (9H, s), 0.19 (9H, s), 0.07 (6H, s); 13C NMR
(C6D6) δ 150.5, 141.5, 125.3, 97.9, 63.4, 33.6, 32.44, 32.38, 30.2,
26.5, 26.4, 18.9, 17.3, 12.8, 0.6, -4.8. HRMS (ESI+) calcd for
C21H42O2Si2 + H: 383.2802. Found: 383.2801.
2.34 (2H, m), 2.06 (2H, m), 1.75 (1H, m), 1.74 (3H, s), 1.55 (4H,
m), 1.17 (3H, d, J ) 7.3 Hz), 0.87 (9H, s), 0.03 (6H, s); 13C NMR
(CDCl3) δ 199.4, 163.6, 130.4, 62.7, 33.7, 33.6, 33.12, 33.08, 29.7,
26.1, 24.3, 18.4, 17.9, 11.0, -5.2. HRMS (ESI+) calcd for
C18H34O2Si + H: 311.2406. Found: 311.2409
1-[4-(tert-Butyldimethylsilyloxy)butyl]-2,6-dimethyl-3-(tri-
methylsilyloxy)-cyclohexa-1,3-diene (22). To a solution of 2 M
LDA (0.16 mL, 0.32 mmol) in dry THF (0.42 mL) was added a
solution of TMSCl (257 mg, 2.37 mmol) in THF (0.47 mL),
followed by the dropwise addition of a solution of 21 (73.7 mg,
0.237 mmol) in THF (0.47 mL) in a dry ice-2-propanol bath. After
1 min, dry Et3N (0.47 mL) was added followed by quenching with
a saturated aqueous NaHCO3 solution. The mixture was extracted
with a mixture of Et2O and CH2Cl2 (2:1; 3 × 10 mL). The extract
was washed with water (twice) and a 0.1 N aqueous citric acid
solution (once), dried over MgSO4, and filtered. Removal of the
solvent in vacuo gave 22 (83.2 mg, 92%) as an oil. 1H NMR (C6D6)
δ 4.78 (1H, dd, J ) 2.75 and 6.41 Hz), 3.55 (2H, t, J ) 5.86 Hz),
2.48 (1H, ddd, J ) 2.93, 7.32, and 16.11 Hz), 2.30 (1H, m), 2.03
Acknowledgment. We thank Dr. Steven Mullen (University
of Illinois) for the mass spectra, Dr. Dennis L. Wright
(Dartmouth College) for the GC-MS data, and Mr. Wayne Casey
(Dartmouth College) for the NOESY one-dimensional experi-
ment. This investigation was supported by funds from NIH
Grant 5R03-CA105294.
Supporting Information Available: General experimental
procedures, UV, IR, and MS spectra for 11, 12, 15, 16, and 18-
22, and 1H and 13C NMR spectra for 11, 12, and 19-22.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0520036
J. Org. Chem, Vol. 71, No. 1, 2006 419