Bicyclic Lactams as Chiral Homoenolate Equivalents: Synthesis of (-)-Penienone

Full text of DOI:10.1021/jo000860y

7240
J . Org. Chem. 2000, 65, 7240-7243
Sch em e 1
Bicyclic La cta m s a s Ch ir a l Hom oen ola te
Equ iva len ts: Syn th esis of (-)-P en ien on e
Alex G. Waterson and A. I. Meyers*
Department of Chemistry, Colorado State University, Fort
Collins, Colorado 80523
aimeyers@lamar.colostate.edu.
Received J une 5, 2000
The synthesis of substituted chiral 2-cyclohexenones
remains a challenging objective in organic chemistry.
Often, when such compounds are needed as building
blocks, they are derived from naturally occurring sources,
such as carvone,1 pinene,2 pulegone,3 or quinic acid.4 In
recent years, however, several methods for the synthesis
of chiral 2-cyclohexenones in enantiomerically pure form
have been reported.5 Chiral 2-cyclohexenones with sub-
stituents in the 5-position are particularly difficult to
construct stereoselectively. Indeed, very few methods are
available which can be considered at all general. Among
the most useful comes from the work of Sato,6 which
involves the addition of a cuprate to an optically active
siloxy-substituted cyclohexenone. The latter is prepared
from a chiral, nonracemic starting material. Also useful
is the method of Takano, which involves the desym-
metrization of Diels-Alder cycloadducts.7
Sch em e 2a
Bicyclic lactams have been shown over the past 10
years to be powerful tools for the construction of optically
active carbocycles and heterocycles.8 Recently, we have
reported the utilization of R-cyanoenamines, prepared
from chiral, nonracemic bicyclic lactams, as homoenolate
equivalents, via a diastereoselective alkylation.9 These
alkylated lactams may then be employed for the prepara-
tion of a number of 5-substituted 2-cyclohexenones or
functionalized piperidines.10 Herein, we wish to report
the further application of this methodology to the asym-
metric synthesis of (-)-penienone (1), which was first
isolated in 1997 and was shown to exhibit regulatory
activities concerning plant growth.11 Only one previous
synthesis of penienone has been reported to date; an
efficient synthesis (26% overall yield) by Sato using a
cuprate addition to a siloxy-containing chiral 2-cyclohex-
enone.6
a
Conditions: (a) LiTMP, HMPA, THF, -78 °C; (b) ethereal
formaldehyde, -78 °C; (c) THF/1 M HCl, 65 °C.
of lactam 3, which would be available from a homoenolate
alkylation of the bicyclic lactam-derived cyanoenamine
4. We have previously reported cyanoenamine 4,9 and it
was efficiently prepared for this synthesis using the
published method, from a commercially available bicyclic
lactam.12
Initially, we planned to install the dienyl side chain of
lactam 3 via a Horner-Emmons olefination, using an
aldehyde (6a ) formed from the direct formylation of
cyanoenamine 4. However, the γ-anion of the cyano-
enamine proved to be unreactive toward a variety of
standard formylating reagents, including DMF, various
formates, and the pyridine-based “Meyers-Comins re-
agent”.13 Reasoning that the desired aldehyde 6a might
be obtained from oxidation of the corresponding alcohol
6b, we attempted hydroxymethylation of the cyano-
enamine. Treatment of cyanoenamine 4 with lithium
tetramethylpiperidine (LiTMP) in the presence of HMPA
at -78 °C resulted in a dark orange solution of the R,γ-
delocalized anion. This anion was then treated with cold
ethereal formaldehyde (Scheme 2).14 Upon attempted
acidic hydrolysis or silica gel purification of the crude
product 5b, the desired lactam 6b was not observed.
Retrosynthetically, penienone (1) was envisioned as
arising from the 5-substituted 2-cylcohexenone 2 (Scheme
1). This compound, in enantiomerically pure form, would
in turn be constructed from the reduction and hydrolysis
(1) Srikrishna, A.; Redy, T. J .; Kumar, P. P. J . Chem. Soc., Perkin
Trans. 1 1998, 3143.
(2) Chapuis, C.; Brauchli, R.; Thommen, W. Helv. Chim. Acta 1993,
76, 535.
(3) Chen, C. Y.; Nagumo, S.; Akita, H. Chem. Pharm. Bull. 1996,
44, 2153.
(4) Barros, M. T.; Maycock, C. D.; Ventura, M. R. J . Org. Chem.
1997, 62, 3984.
(5) (a) Amino acid-catalyzed aldol-type reactions: Terishima, S.;
Sato, S.; Koga, K. Tetrahedron Lett. 1979, 3469. (b) Asymmetric Diels-
Alder reactions: Wada, E.; Yasuoka, H.; Kanemasa, S. Chem. Lett.
1994, 1637. Kozmin, S. A.; Rawal, V. H. J . Am. Chem. Soc. 1997, 119,
7165. (c) Enantioselective deprotonations: O’Brien, P.; Poumelle, P.
Tetrahedron Lett. 1996, 37, 8057.
(6) (a) Hareau, G. P-J .; Koiwa, M.; Hikichi, S.; Sato, F. J . Am.
Chem. Soc. 1999, 121, 3640. (b) Hareau, G.; Koiwa, M.; Hanazawa,
T.; Sato, F. Tetrahedron Lett. 1999, 40, 7493.
(7) Takano, S.; Higashi, Y.; Kamikubo, T.; Moriya, M.; Ogasawara,
K. Synthesis 1993, 948.
(8) Meyers, A. I.; Brengel, G. P. J . Chem. Soc., Chem. Commun.
1997, 1. Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503.
(9) Schwarz, J . B.; Devine, P. N.; Meyers, A. I. Tetrahedron 1997,
53, 8795.
10.1021/jo000860y CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/27/2000

Notes
J . Org. Chem., Vol. 65, No. 21, 2000 7241
Sch em e 3a
Sch em e 4a
a
Conditions: (a) DiBAL-H‚n-BuLi, THF, -78 °C; (b) p-TsOH,
a
Conditions: (a) LiTMP, HMPA, THF, -78 °C; (b) trans-2-
heptenal, -78 °C; (c) THF/1 M HCl, 25 °C; (d) PhSCl, Et3N, THF,
25 °C; (e) THF, 65 °C.
THF/H2O, ∆.
Sch em e 5a
Instead, lactone 7 was isolated in very low yield. It was
found that the lactone product 7 could be obtained in an
improved 44% yield if the crude product 5b was heated
to reflux for 12 h in a 1:1 mixture of THF and 1 M HCl.
It is unclear whether lactone formation is the result of
initial hydrolysis of the cyanoenamine to lactam 6b
followed by rearrangement or if rearrangement proceeds
directly from the hydroxymethylated cyanoenamine 5b.
Similar bicyclic lactams, bearing subtituents adjacent to
the hydroxyl group, have previously been prepared in our
group without competition from lactone formation.9 At
present, we choose not to suggest a possible pathway
leading to 7 until more information becomes available.
On the basis of this unexpected difficulty in synthesiz-
ing the desired aldehyde 6a , we sought an alternative
method for the construction of the dienyl side chain. The
method that eventually proved useful involved the direct
installation of the entire seven carbon chain present in
penienone (1) by treatment of the anion of cyanoenamine
4 with commercially available trans-2-heptenal (Scheme
3). Without purification, the crude product was hydro-
lyzed at room temperature, affording lactam 8 in good
yield as the exclusively endo alkylated compound. The
reaction furnished a readily separable 1.4:1 mixture of
diastereomeric alcohols. The lack of selectivity at this
position has been previously observed9 and was of no
concern in the present synthesis since the alcohol was
to be eventually transformed into an olefin. Attempts to
directly eliminate the hydroxyl group in conjugate fashion
failed to deliver the desired diene 3 in good yield. Thus,
transposition of the alkene was carried out by reaction
of the alcohol 8 with benzene sulfenyl chloride. The
resulting sulfenate ester underwent spontaneous [2,3]-
sigmatropic rearrangement to give sulfoxide 9 directly.
As dictated by the cyclic transition state of the rear-
rangement, the sulfoxides 9 were formed in a 1.4:1 ratio
of two inseparable diastereomers, as observed by proton
NMR integration. This ratio is identical to the ratio
observed with the alcohols 8. Indeed, when only a single
hydroxyl isomer was used, a single sulfoxide diastere-
omer was obtained. Complete selectivity for the trans-
alkene was also observed in all cases, again as a result
of the cyclic transition state. Thermal elimination of
sulfoxide 9 then produced the desired diene 3 in 93%
yield as a 9.5:1 mixture of E,E and E,Z isomers. These
isomers proved to be inseparable, so the completion of
the synthesis was performed with the mixture of dienes.
Lactam 3 was converted to the desired enone 2 using
the previously developed protocol (Scheme 4).9 Reduction
a
Conditions: (a) LDA, THF, -78 °C; (b) ethereal formaldehyde,
-78 °C.
of the lactam with the “ate” complex derived from
DiBAL-H and n-BuLi afforded enamine 10, which was
subsequently treated with p-toluenesulfonic acid in a
THF/water mixture. Hydrolysis of the enamine to keto
aldehyde 11 was followed by intramolecular condensation
to give enone 2 in 72% yield over the three-step sequence.
The synthesis of 1 was completed by hydroxymethylation
of enone 2 with formaldehyde14 in 57% yield (Scheme 5).
Interestingly, epi-penienone (12) was also formed in 32%
yield. Attempts with a number of variations in the
reaction conditions failed to significantly improve this 2:1
ratio. We noted that the undesired diastereomer 12 of
the hydroxyenone can be epimerized using sodium or
potassium carbonate in THF/water or methanol. In either
case, epimerization afforded no better than a 1:1 mixture
of the two compounds, along with some deformylated
product, reaffirming the lack of induced stereocontrol in
the hydroxymethylation reaction. The 9.5:1 E,E to E,Z
diene mixture formed earlier upon sulfoxide elimination
(Scheme 3), was readily purified at this point by simple
crystallization, giving pure (-)-penienone (1). The com-
pound thus obtained showed spectroscopic data identical
to that reported by Kimura11 for the original isolated
compound.
In conclusion, the total asymmetric synthesis of peni-
enone (1) has been achieved in 24% yield from a previ-
(10) (a) Dwyer, M. P.; Lamar, J . E.; Meyers, A. I. Tetrahedron Lett.
1999, 40, 8965. (b) Schwarz, J . B. Meyers, A. I. J . Org. Chem. 1998,
63, 1732. (c) Schwarz, J . B. Meyers, A. I. J . Org. Chem. 1998, 63, 1619.
(11) Kimura, Y.; Mizuno, T.; Shimada, A. Tetrahedron Lett. 1997,
38, 469.
(12) The bicyclic 5,6-lactam is available from Aldrich and Ultrafine,
U.K.
(13) Comins, D.; Meyers, A. I. Synthesis 1978, 19, 403.
(14) The formaldehyde solution was generated by predrying paraform-
aldehyde and cracking according to the method of Stork: Stork, G.;
d’Angelo, J . J . Am. Chem. Soc. 1974, 96, 7114.

7242 J . Org. Chem., Vol. 65, No. 21, 2000
Notes
solvent was removed under reduced pressure. The residue was
subjected to silica gel chromatography to give 1.60 g (75%) of
lactam 8 as a 1.4:1 mixture of diasteromers.
ously reported bicyclic lactam-derived starting material.
The synthesis uses a cyanoenamine 4 derived from a
chiral, nonracemic bicyclic lactam as a diastereoselective
homoenolate equivalent to construct the cyclohexenone
core of the molecule and to install the hydrocarbon side
chain. In addition, a heretofore unobserved bicyclic
lactam rearrangement was discovered, leading to the
formation of a chiral, substituted lactone 7.
High-Rf diastereomer (8a ): 0.93 g (44%) as a colorless oil;
[R]23 +26.8 (c 1.01, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.95
D
(t, 3H, J ) 7.0 Hz), 1.28-1.42 (m, 5H), 1.66 (s, 3H), 2.07-2.22
(m, 5H), 2.54 (t, 2H, J ) 11.7 Hz), 3.42 (s, 3H), 3.65 (dd, 1H, J
) 10.2 and 3.0 Hz), 3.85 (dd, 1H, J ) 10.2 and 4.8 Hz), 3.95 (t,
1H, J ) 6.6 Hz), 4.10 (ddd, 1H, J ) 9.9, 5.1, and 3.3 Hz), 5.30
(d, 1H, J ) 8.1 Hz), 5.49 (ddt, 1H, J ) 15.3, 7.5, and 1.5 Hz),
5.57 (dt, 1H, J ) 15.3 and 6.6 Hz), and 7.34-7.44 (m, 5H); 13C
NMR (75 MHz, CDCl3) δ 14.0, 22.3, 24.4, 31.2, 32.0, 34.0, 35.7,
38.1, 59.3, 63.2, 70.4, 76.0, 78.3, 91.7, 99.9, 126.6, 128.3, 128.5,
129.7, 134.8, 139.01, 160.9, and 168.9; IR (neat) 3400, 2922,
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, all starting
materials were obtained from commercial suppliers and were
used without further purification. Solvents were dried according
to established procedures by distillation from an appropriate
drying agent under an inert atmosphere. Tetrahydrofuran was
distilled from sodium/benzophenone ketyl under argon im-
mediately prior to use. Reactions involving air- or moisture-
sensitive reagents or intermediates were performed under an
inert atmosphere of argon in glassware that had been flame-
dried. Flash chromatography was performed using Merck silica
gel 60 (230-400 mesh ASTM).
1627, 1455, 1394, and 1122 cm -1; HRMS (m/ e) calcd for C23H34
-
NO4 (M + H+) 388.2488, found 388.2485.
Low-Rf diastereomer (8b): 0.66 g (31%) as a colorless oil:
[R]23 +27.6 (c 1.04, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.95
D
(t, 3H, J ) 7.0 Hz), 1.28-1.44 (m, 5H), 1.65 (s, 3H), 1.69 (brs,
1H), 2.10 (q, 2H, J ) 7.0 Hz), 2.17-2.29 (m, 2H), 2.35 (t, 1H, J
) 10.5 Hz), 2.71 (dd, 1H, J ) 17.4 and 5.7 Hz), 3.42 (s, 3H),
3.64 (dd, 1H, J ) 10.2 and 3.0 Hz), 3.85 (dd, 1H, J ) 10.2 and
5.1 Hz), 4.02 (t, 1H, J ) 6.6 Hz), 4.10 (ddd, 1H, J ) 7.2, 4.8, and
3.0 Hz), 5.30 (d, 1H, J ) 7.8 Hz), 5.50 (ddt, 1H, J ) 14.4, 7.8,
and 1.5 Hz), 5.76 (dt, 1H, J ) 15.6 and 6.6 Hz), and 7.34-7.45
(m, 5H); 13C NMR (75 MHz, CDCl3) δ 13.9, 22.3, 24.4, 31.2, 32.0,
33.5, 35.7, 38.3, 59.3, 63.2, 70.4, 76.1, 78.2, 93.6, 99.9, 126.3,
128.3, 128.5, 129.6, 135.1, 138.9, 166.9, and 169.1; IR (neat) 3406,
2927, 1629, 1458, 1399, and 1117 cm -1; HRMS (m/ e) calcd for
C23H34NO4 (M + H+) 388.2488, found 388.2477.
4-Aceton yltetr a h yd r ofu r a n -2-on e (7). To a solution con-
taining 0.09 mL (0.528 mmol) of 2,2,6,6-tetramethylpiperidine
(TMP) and 4 mL of THF at -78 °C was added 0.28 mL (0.528
mmol) of 1.86 M n-BuLi in hexanes and then 0.09 mL (0.528
mmol) of HMPA. The reaction mixture was allowed to stir for
15 min at -78 °C and then raised to 0 °C for 5 min. At the end
of this time, the bright yellow solution was cooled to -78 °C and
a solution containing 100 mg (0.352 mmol) of cyanoenamine 49
and 1 mL of THF was added dropwise. The dark orange solution
was stirred at -78 °C for 20 min, and an excess of ethereal
formaldehyde14 was added. The reaction mixture was allowed
to stir at -78 °C for 2.0 h and was quenched by the addition of
aqueous NaHCO3. The mixture was extracted with CH2Cl2, and
the combined organic extracts were dried over MgSO4. The
solvent was removed under reduced pressure, and the residue
was taken up in 5 mL of THF. To this solution was added 5 mL
of 1 M aqueous HCl, and the mixture was heated at reflux for
12 h. The THF was removed under reduced pressure, and the
mixture was partitioned between CH2Cl2 and water. The phases
were separated and the aqueous phase was further extracted
with CH2Cl2. The combined organic extracts were dried over
MgSO4, and the solvent was removed under reduced pressure.
The residue was subjected to silica gel chromatography to give
Su lfoxid e 9. To a solution containing 1.40 g (3.61 mmol) of
lactam 8 and 30 mL of THF was added 0.75 mL (5.42 mmol) of
triethylamine. The solution was allowed to stir at room tem-
perature for 15 min, and 0.57 g (3.97 mmol) of freshly prepared
benzene sulfenyl chloride was added dropwise. The reaction
mixture was allowed to stir at room temperature for 1.5 h and
then poured into brine and extracted with EtOAc. The combined
organic extracts were dried over MgSO4, and the solvent was
removed under reduced pressure. The residue was subjected to
silica gel chromatography to give 1.45 g (81%) of sulfoxide 9 as
a 1.4:1 mixture of inseparable diastereomers: 1H NMR (300
MHz, CDCl3) δ 0.88-0.93 (m, 6H), 1.23-1.46 (m, 10H), 1.56 (s,
3H major), 1.60 (s, 3H minor), 1.75-1.80 (m, 2H), 1.88-2.15 (m,
6H), 2.33-2.70 (m, 4H), 2.98 (ddd, 1H major, J ) 8.7, 8.7, and
5.8 Hz), 3.22 (ddd, 1H minor, J ) 10.4, 10.4, and 3.8 Hz), 3.34
(s, 3H major); 3.35 (s, 3H minor), 3.55-3.60 (m, 2H), 3.75-3.81
(m, 2H), 3.95-4.06 (m, 2H), 5.00-5.13 (m, 2H), 5.21-5.37 (m,
2H), 7.30-7.35 (m, 10H), and 7.45-7.54 (m, 10H); 13C NMR (75
MHz, CDCl3) δ 13.9, 14.0, 21.0, 22.4, 24.4, 24.5, 27.7, 27.8, 28.6,
28.7, 29.0, 29.1, 32.8, 32.9, 32.95, 33.0, 36.9, 37.0, 37.1, 37.2,
41.4, 41.6, 41.7, 41.8, 59.2, 63.2, 63.3, 67.8, 69.1, 69.4, 70.4, 78.1,
93.0, 93.1, 122.1, 122.2, 122.6, 122.7, 124.5, 125.5, 125.6, 128.3,
128.5, 128.6, 128.7, 130.7, 131.3, 131.4, 138.8, 138.9, 139.0, 139.1,
140.0, 141.2, 141.8, 141.9, 167.9, and 168.0; IR (neat) 2929, 1649,
1443, 1396, and 1043 cm -1; HRMS (m/ e) calcd for C29H38NSO4
(M + H+) 496.2522, found 496.2523.
44 mg (44%) of lactone 7 as a colorless oil: [R]23 -30.8 (c 1.12,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 2.21 (dd, 1H, J ) 17.7
and 7.8 Hz), 2.22 (s, 3H), 2.65-2.82 (m, 3H), 2.97-3.05 (m, 1H),
3.95 (dd, 1H, J ) 9.3 and 6.6 Hz), and 4.58 (dd, 1H, J ) 9.3 and
7.2 Hz); 13C NMR (75 MHZ, CDCl3) δ 30.2, 30.8, 34.1, 46.6, 73.0,
176.6, and 206.0; IR (neat) 2917, 1774, 1711, 1173, and 1017
cm -1; HRMS (m/ e) calcd for C7H11O3 (M + H+) 143.1640, found
143.1635.
La cta m 8. To a solution containing 1.39 mL (8.23 mmol) of
2,2,6,6-tetramethylpiperidine (TMP) and 40 mL of THF at -78
°C was added 3.40 mL (8.23 mmol) of 2.40 M n-BuLi in hexanes
and then 1.43 mL (8.23 mmol) of HMPA. The reaction mixture
was allowed to stir for 15 min at -78 °C and then raised to 0 °C
for 5 min. At the end of this time, the bright yellow solution
was cooled to -78 °C and a solution containing 1.56 g (0.352
mmol) of cyanoenamine 49 and 10 mL of THF was added
dropwise. The dark orange solution was stirred at -78 °C for
20 min, and a solution containing 0.94 mL (7.15 mmol) of trans-
2-heptenal and 5 mL of THF was added slowly. The reaction
mixture was allowed to stir at -78 °C for 2.5 h and was
quenched by the addition of aqueous NaHCO3. The mixture was
extracted with CH2Cl2, and the combined organic extracts were
dried over MgSO4. The solvent was removed under reduced
pressure, and the residue was taken up in 20 mL of THF. To
this solution was added 20 mL of 1 M aqueous HCl, and the
mixture was allowed to stir at room temperature for 13 h. The
THF was removed under reduced pressure, and the mixture was
partitioned between EtOAc and water. The phases were sepa-
rated, and the aqueous phase was further extracted with EtOAc.
The combined organic extracts were dried over MgSO4, and the
Dien e 3. A solution containing 1.45 g (2.93 mmol) of sulfoxide
9 and 75 mL of THF was heated at reflux for 24 h. The reaction
mixture was cooled, poured into brine, and extracted with
EtOAc. The combined organic extracts were washed with 10%
aqueous KOH, washed with brine, and dried over MgSO4. The
solvent was removed under reduced pressure, and the residue
was subjected to silica gel chromatography to give 1.00 g (93%)
as a colorless oil as a 9.5:1 E:E to E:Z diene mixture: [R]23D +51.7
1
(c 0.99, CHCl3); H NMR (300 MHz, CDCl3) δ 0.96 (t, 3H, J )
7.2 Hz), 1.44 (app. sextet, 2H, J ) 7.2 Hz), 1.67 (s, 3H), 1.68-
1.80 (m, 1H), 2.11 (app. q, 2H, J ) 7.2 Hz), 2.23-2.32 (m, 2H),
2.68-2.84 (m, 2H), 3.42 (s, 3H), 3.66 (dd, 1H, J ) 10.2 and 3.0
Hz), 3.86 (dd, 1H, J ) 10.2 and 5.1 Hz), 4.12 (ddd, 1H, J ) 8.1,
5.1, and 3.0 Hz), 5.30 (d, 1H, J ) 8.4 Hz), 5.53 (dd, 1H, 14.7 and
6.6 Hz), 5.72 (dt, 1H, J ) 13.8 and 7.5 Hz), 6.02-6.15 (m, 2H),
and 7.34-7.45 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.0, 22.7,
24.8, 33.2, 34.9, 37.8, 42.2, 59.5, 63.5, 70.7, 78.4, 93.6, 126.8,
128.5, 128.7, 129.8, 130.5, 132.8, 134.8, 139.2, and 168.8; IR
(neat) 2928, 1651, 1396, 1124, and 989 cm -1; HRMS (m/ e) calcd
for C23H32NSO3 (M + H+) 370.2382, found 370.2378.

Notes
En on e 2. To a solution containing 1.35 mL (2.03 mmol) of
J . Org. Chem., Vol. 65, No. 21, 2000 7243
MgSO4, and the solvent was removed under reduced pressure.
The residue was subjected to silica gel chromatography using a
pentane/Et2O mixture as the eluent to give 10 mg (57%) of
penienone (1) as a white solid, along with 5.6 mg (32%) of epi-
penienone (12) as a colorless oil.
1.5 M DiBAL-H in toluene and 10 mL of THF at 0 °C was added
0.86 mL (2.03 mmol) of 2.35 M n-BuLi in hexanes. The solution
was stirred at this temperature for 30 min, and a solution
containing 75 mg (0.203 mmol) of lactam 3 and 1 mL of THF
was added. The reaction mixture was allowed to warm to room
temperature, stirred for 13 h, and quenched by the dropwise
addition of MeOH. The solvent was removed under reduced
pressure, and the residue was taken up in 1:1 hexanes-Et2O,
washed with 10% aqueous KOH, washed with brine, and dried
over MgSO4. The solvent was removed under reduced pressure
to give crude enamine 10, which was used in the next step
without further purification.
To a solution containing crude enamine 10, 3.4 mL of THF,
and 3.4 mL of water was added 0.19 g (1.02 mmol) of p-
toluenesulfonic acid. The reaction mixture was heated at reflux
for 36 h and cooled, and the THF was removed under reduced
pressure. The residue was taken up in Et2O, washed with
saturated aqueous NaHCO3, washed with brine, and dried over
MgSO4. The solvent was removed under reduced pressure, and
the residue was subjected to silica gel chromatography, using a
pentane/Et2O mixture as the eluent to give 28 mg (72%) of enone
2 as a slightly volatile oil: [R]D23 -10.8 (c 0.26, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 0.89 (t, 3H, J ) 7.5 Hz), 1.42 (tq, 2H, J )
7.5 and 7.5 Hz), 2.04 (dt, 2H, J ) 7.5 and 7.5 Hz), 2.12-2.36
(m, 2H), 2.42-2.58 (m, 2H), 2.74-2.87 (m, 1H), 5.53 (dd, 1H, J
) 13.8 and 6.3 Hz), 5.65 (dt, 1H, J ) 13.8 and 7.5 Hz), 5.94-
6.09 (m, 3H), and 6.95 (ddd, 1H, J ) 8.2, 5.3, and 2.3 Hz); 13C
NMR (75 MHz, CDCl3) δ 13.9, 22.6, 32.3, 34.9, 38.2, 44.2, 129.8,
129.9, 130.4, 132.9, 134.7, 149.9, and 199.1; IR (neat) 2958, 1682,
1386, 1248, and 984 cm-1; HRMS (m/ e) calcd for C13H19O (M +
H+) 191.1436, found 191.1432.
Penienone (1): mp: 60-62 °C (lit.11 mp: 61-63 °C); [R]23
D
-42 (c 0.30, EtOH); 1H NMR (300 MHz, CDCl3) δ 0.95 (t, 3H, J
) 7.5 Hz), 1.45 (tq, 2H, J ) 7.5 and 7.5 Hz), 2.09 (dt, 2H, J )
7.5 and 7.5 Hz), 2.37-2.49 (m, 2H), 2.66-2.78 (m, 1H), 2.94 (dd,
1H, J ) 8.4 and 4.5 Hz), 3.77 (ddd, 1H, J ) 11.7, 5.5, and 5.1
Hz), 3.95 (ddd, 1H, J ) 11.7, 8.7, and 3.6 Hz), 5.49 (dd, 1H, J )
14.4 and 8.7 Hz), 5.71 (dt, 1H, J ) 13.5 and 7.5 Hz), 6.00-6.19
(m, 3H), and 7.03 (ddd, 1H, J ) 8.0, 5.0, and 1.9 Hz); 13C NMR
(75 MHz, CDCl3) δ 13.8, 22.7, 33.3, 35.0, 40.4, 53.0, 61.0, 129.5,
129.7, 131.9, 132.8, 135.3, 150.1, and 202.4; IR (neat) 3463, 2958,
1672, 1391, and 990 cm-1; HRMS (m/ e) calcd for C14H21O2 (M
+ H+) 221.1542, found 221.1551.
epi-Penienone (12): [R]23 -84 (c 0.40, EtOH); 1H NMR (300
D
MHz, CDCl3) δ 0.94 (t, 3H, J ) 7.4 Hz), 1.43 (tq, 2H, J ) 7.4
and 7.4 Hz), 2.07 (dt, 2H, J ) 7.4 and 7.4 Hz), 2.39-2.49 (m,
1H), 2.69 (dd, 9.5 and 2.8 Hz), 2.76-2.86 (m, 2H), 2.96-3.02
(m, 1H), 3.54 (ddd, 1H, J ) 11.3, 9.6, and 5.4 Hz), 4.01 (ddd,
1H, J ) 11.3, 8.1, and 2.0 Hz), 5.55 (dd, 1H, J ) 14.6 and 8.8
Hz), 5.67 (dt, 1H, J ) 14.6 and 6.4 Hz), 5.92-6.13 (m, 3H), and
6.97 (ddd, 1H, J ) 9.3, 6.4, and 3.0 Hz); 13C NMR (75 MHz,
CDCl3) δ 13.9, 22.6, 32.9, 34.9, 40.8, 52.6, 62.5, 128.4, 129.7,
129.8, 133.2, 135.2, 148.6, and 202.3; IR (neat) 3436, 2944, 1669,
1388 and 992 cm-1; HRMS (m/ e) calcd for C14H21O2 (M + H+)
221.1542, found 221.1551.
Ack n ow led gm en t. The authors are grateful to the
National Institute of Health for financial support. This
paper is dedicated to Professor Victor Sniekus on the
occasion of his 64th birthday and his many excellent
contributions to synthetic chemistry.
P en ien on e (1). To a solution containing 20 µL (0.13 mmol)
of diisopropylamine and 2 mL of THF at -78 °C was added 58
µL (0.13 mmol) of 2.35 M n-BuLi in hexanes. After the solution
was stirred at this temperature for 30 min, a solution containing
15 mg (0.079 mmol) of enone 2 and 0.5 mL of THF was added
slowly. The reaction mixture was allowed to stir at -78 °C for
45 min, and an excess of ethereal formaldehyde was added. After
being stirred for 1 h, the reaction was quenched by the addition
of saturated aqueous NH4Cl. The THF was removed under
reduced pressure, and the residue was extracted with Et2O. The
combined organic layers were washed with brine and dried over
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H or 13C
NMR spectra for all new compounds described in the Experi-
mental Section. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O000860Y