Biomimetic cyclization of enamide-containing polyenes as a new route to azapolycycles

Article abstract of DOI:10.1021/jo960924y

Enamide 4 was studied for its effectiveness as a polyene precursor in biomimetic cyclizations. While most conventional Lewis acids were poor cyclization promoters, FeCl₃·6H₂O initiated the conversion of 4 into tricycles 6 and 7 in excellent yield. The two isomeric products result from the cyclization of intermediate aldehyde 5 by either a chair or boat B-ring transition state. These results suggest that enamides may be incorporated into polyene precursors for the construction of larger azapolycycles such as azasteroids.

Full text of DOI:10.1021/jo960924y

6646
J . Org. Chem. 1996, 61, 6646-6650
Biom im etic Cycliza tion of En a m id e-Con ta in in g P olyen es a s a New
Rou te to Aza p olycycles†
Stephanie E. Sen* and Steven L. Roach
Department of Chemistry, Indiana University-Purdue University at Indianapolis (IUPUI),
402 North Blackford Street, Indianapolis, Indiana 46202
Received May 20, 1996X
Enamide 4 was studied for its effectiveness as a polyene precursor in biomimetic cyclizations. While
most conventional Lewis acids were poor cyclization promoters, FeCl3‚6H2O initiated the conversion
of 4 into tricycles 6 and 7 in excellent yield. The two isomeric products result from the cyclization
of intermediate aldehyde 5 by either a chair or boat B-ring transition state. These results suggest
that enamides may be incorporated into polyene precursors for the construction of larger
azapolycycles such as azasteroids.
In tr od u ction
A general approach to the construction of nitrogen-
containing polycycles by biomimetic polyene cyclization
methodology is depicted in Scheme 1. Incorporating an
appropriately positioned enamide functionality into a
polyene chain was expected to provide a dual electronic
benefit during the cyclization process. First, we antici-
pated that initial cyclization would be enhanced by the
increased nucleophilicity of the â-carbon center. Next,
once partial cyclization had proceeded, we envisioned that
the resulting N-acyliminium ion would function as a
stabilized cation/initiation site for further cyclization
processes. Because monocyclizations of transient imin-
ium and N-acyliminium ions are well-known,7 it seemed
likely that the reaction, once initiated, would proceed as
planned. To determine the possible utility of the enamide
moiety as a CS auxiliary in biomimetic polyene cycliza-
tions, the tricyclization of enamide 4 was examined.
Biomimetic polyene cyclizations provide an elegant and
efficient means of preparing polycycles with stereochem-
ical control at several ring fusion centers.1 Carbocation-
stabilizing (CS) auxiliaries, such as the isobutenyl2 and
fluoride3 moieties, have recently been shown to enhance
both the yield and rate of polyene cyclizations. These
functionalities apparently mimic a putative function of
cyclase enzymes by lowering the energy of the cationic
transition state(s) and/or intermediate(s) in the process.4
We now report an extension of this methodology to the
efficient synthesis of the ABC ring nucleus of a 7-aza-
steroid by inclusion of an enamide within the polyene
chain as the CS auxiliary. Since azasteroids have been
shown to be both potent enzyme inhibitors5 and difficult
compounds to synthesize,6 new routes for their construc-
tion are expected to be of great utility in the development
of new chemotherapeutic agents.
Resu lts a n d Discu ssion
† This paper is dedicated to the memory of William Summer
J ohnson.
Enamide 4 was constructed in nine steps from geraniol
in a 33% overall yield, as outlined in Scheme 2. The
acetal initiator was introduced by conversion of the ∆-6,7
olefin into the corresponding trisnoraldehyde 1 by m-
CPBA epoxidation of TBDPS-protected geraniol, followed
by periodic acid cleavage.8 Subsequent Wittig homolo-
gation and reaction of the resulting enol ether with
ethylene glycol/TsOH gave, after silyl deprotection, al-
cohol 2 (67% overall yield, three steps). The allylic
alcohol was converted to amine 3 under mild conditions
via conversion to the allylic phthalimide and subsequent
phthalimide removal with methylamine.9 Enamide 4
was prepared by a one-pot procedure involving condensa-
tion of allylic amine 3 with cyclohexanone (benzene,
K2CO3, reflux for 12 h), followed by reaction of the
resulting unisolated imine with acetyl chloride and
pyridine.10
X Abstract published in Advance ACS Abstracts, August 15, 1996.
(1) For a review on biomimetic polyene cyclizations, see: J ohnson,
W. S. Tetrahedron 1991, 47, xi.
(2) (a) J ohnson, W. S.; Telfer, S. J .; Cheng, S.; Schubert, U. J . Am.
Chem. Soc. 1987, 109, 2517. (b) J ohnson, W. S.; Lindell, S. D.; Steele,
J . J . Am. Chem. Soc. 1987, 109, 5852. (c) Guay, D.; J ohnson, W. S.;
Schubert, U. J . Org. Chem. 1989, 54, 4731.
(3) (a) J ohnson, W. S.; Chenera, B.; Tham, F. S.; Kullnig, R. K. J .
Am. Chem. Soc. 1993, 115, 493. (b) J ohnson, W. S.; Fletcher, V. R.;
Chenera, B.; Bartlett, W. R.; Tham, F. S.; Kullnig, R. K. J . Am. Chem.
Soc. 1993, 115, 497. (c) J ohnson, W. S.; Buchanan, R. A.; Bartlett, W.
R.; Tham, F. S.; Kullnig, R. K. J . Am. Chem. Soc. 1993, 115, 504. (d)
J ohnson, W. S.; Plummer, M. S.; Reddy, S. P.; Bartlett, W. R. J . Am.
Chem. Soc. 1993, 115, 515. (e) Fish P. V.; J ohnson, W. S. Tetrahedron
Lett. 1994, 35, 1469.
(4) (a) Abe, I.; Rohmer, M.; Prestwich, G. D. Chem. Rev. 1993, 93,
2189. (b) Corey, E. J .; Virgil, S. C.; Sarshar, S. J . Am. Chem. Soc. 1991,
113, 8171. (c) Corey, E. J .; Virgil, S. C.; Cheng, H.; Baker, C. H.;
Matsuda, S. P. T.; Singh, V.; Sarshar, S. J . Am. Chem. Soc. 1995, 117,
11819.
(5) Examples of biologically active azasteroids include: (a) Li, X.;
Singh, S. M.; Labrie, F. J . Med. Chem. 1995, 38, 1158. (b) Frye, S. V.;
Haffner, C. D.; Maloney, P. R.; Mook, R. A., J r.; Dorsey, G. F., J r.;
Hiner, R. N.; Cribbs, C. M.; Wheeler, T. N.; Ray, J . A.; Andrews, R. C.;
Batchelor, K. W.; Bramson, H. N.; Stuart, J . D.; Schweiker, S. L.; van
Arnold, J .; Croom, S.; Bickett, D. M.; Moss, M. L.; Tian, G.; Unwalla,
R. J .; Lee, F. W.; Tippin, T. K.; J ames, M. K.; Grizzle, M. K.; Long, J .
E.; Schuster, S. V. J . Med. Chem. 1994, 37, 2352. (c) Bakshi, R. K.;
Patel, G. F.; Rasmusson, G. H.; Baginsky, W. F.; Cimis, G.; Ellsworth,
K.; Chang, B.; Bull, H.; Tolman, R. L.; Harris, G. S. J . Med. Chem.
1994, 37, 3871. (d) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N.
G.; Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.;
Brooks, J . R.; Berman, C. J . Med. Chem. 1986, 29, 2298. (e) Dolle, R.
E.; Allaudeen, H. S.; Kruse, L. I. J . Med. Chem. 1990, 33, 877. (f)
Sampson, W. J .; Houghton, J . D.; Bowers, P.; Suffolk, R. A.; Botham,
K. M.; Suckling, C. J .; Suckling, K. E. Biochim. Biophys. Acta 1988,
960, 268.
(6) (a) Huisman, H. O. Angew. Chem., Int. Ed. Engl. 1971, 10, 450.
(b) Morzycki, J . W. Pol. J . Chem. 1995, 69, 321.
(7) For reviews on iminium and N-acyl iminium ion cyclizations,
see: (a) Blumenkopf, T. A.; Overman, L. E. Chem. Rev. 1986, 86, 857.
(b) Thebtaranonth, C.; Thebtaranonth, Y. Cyclization Reactions; CRC
Press: Boca Raton, FL, 1994; Chapter 1. (c) Speckamp, W. N.;
Hiemstra, H. Tetrahedron 1985, 41, 4367. (d) Overman, L. E. Aldrich-
chimica Acta 1995, 28, 107.
(8) Davisson, V. J .; Neal, T. R.; Poulter, C. D. J . Am. Chem. Soc.
1993, 115, 1235.
(9) Sen, S. E.; Roach, S. L. Synthesis 1995, 756.
(10) For a review on the construction of enamides, see: Campbell,
A. L.; Lenz, G. R. Synthesis 1987, 421.
S0022-3263(96)00924-3 CCC: $12.00 © 1996 American Chemical Society

Biomimetic Cyclization of Azapolyenes
J . Org. Chem., Vol. 61, No. 19, 1996 6647
Sch em e 1
Sch em e 2. Syn th esis of En a m id e 4a
Ta ble 1. Cycliza tion Stu d y of En a m id e 4, Usin g Sever a l
Differ en t Lew is Acid s
Lewis acida
equiv
temp (°C)
resultb
SnCl4
SnCl4
SnCl4
5
5
5
-40
0
23
no reaction
<7% cyclizationc
decompositiond
TiCl4
TiCl4
TiCl4
6
6
6
-78
0
23
no reaction
no reaction
decompositiond
EtAlCl2
5
-78
decompositione
Me2AlCl
Me2AlCl
Me2AlCl
5
5
5
-78
0
23
no reaction
no reaction
no reaction
a
BF3‚Et2O
BF3‚Et2O
5
5
-78
no reaction
(a) m-CPBA, NaHCO3; (b) H5IO6, THF/H2O; (c) MeOCHdPPh3;
23
<20% cyclizationf
(d) ethylene glycol, TsOH; (e) TBAF; (f) DIAD, PPh3, phthalimide;
(g) MeNH2, EtOH, reflux; (h) cyclohexanone, benzene, reflux;
followed by AcCl, pyridine.
FeCl3‚6H2O
FeCl3‚6H2O
3.5
3.5
0
23
no reaction
84% cyclization
a
All reaction were performed under an inert atmosphere in
To determine conditions for the cyclization of enamide
4, small-scale (3-5 mg) cyclization studies were per-
formed. Reactions with standard Lewis acid promoters,
such as SnCl4, TiCl4, EtAlCl2, and Me2AlCl, at several
different temperatures resulted in either no reaction or
decomposition of the starting material (Table 1). BF3‚Et2O
was a more effective cyclization promoter, yielding a
small (18%) amount of cyclic product, with the remaining
material consisting of unreacted polyene and aldehyde
5 which results from Lewis acid promoted acetal hydroly-
sis. We attribute these results to strong coordination of
the metals to the amide functionality of 4, which in-
hibits the ability of the nitrogen to participate in the
cyclization process. In contrast, enamide 4 was ef-
fectively cyclized with the use of the iron-based Lewis
acid FeCl3‚6H2O.
A more detailed examination of the FeCl3‚6H2O-
promoted cyclization of enamide 4 showed that the
reaction is sensitive to small changes in reaction condi-
tions. Efficient cyclization is only achieved at higher
temperatures; thus, reaction of 4 with FeCl3‚6H2O at 0
°C resulted in no reaction, even with prolonged (6 h)
reaction times (Table 1). However, after the solution was
warmed to room temperature, rapid cyclization proceeded
within 1 h to yield up to 95% cyclic products. GLC
analysis of preparative-scale reaction mixtures revealed
complete consumption of starting material and the pres-
anhydrous solvent. GLC yield. c Composition: 6% 6 and 7, 6%
b
enamide 4, 11% aldehyde 5, remaining mass consists of monocyclic
d
material and unidentified decomposition products. No starting
material recovered. e 20% enamide 4 remained. f Composition:
18% 6 and 7, 60% enamide 4, 16% aldehyde 5.
ence of a 5.7:1 mixture of two new components with
retention times approximately 1 min shorter than that
of enamide 4. 1H NMR analysis (500 MHz NMR COSY)
of the purified components established that these major
products are the trans-anti and trans-syn tricycles (6 and
7, respectively, Scheme 3) resulting from either a chair
or boat transition state for B-ring formation upon attack
by the cyclohexene enamide terminator.
Changes in both the amount of Lewis acid present and
type of solvent used had a pronounced effect on the
outcome of the reaction (Tables 2 and 3, respectively).
Excess Lewis acid was required for efficient cyclization
to proceed; on the basis of these findings, 3.5 equiv of
FeCl3
‚6H O was used for subsequent cyclization studies.
2
As observed with other reactions involving the use of
FeCl3,11 CH2Cl2 was found to be the best solvent for the
cyclization of enamide 4 (Table 3). In contrast, coordi-
nating solvents (e.g., THF) strongly inhibited the cycliza-
tion process, resulting in almost complete recovery of
starting material. The use of benzene and acetonitrile
resulted in a complex mixture of materials that has been

6648 J . Org. Chem., Vol. 61, No. 19, 1996
Sen and Roach
Sch em e 3. P r op osed P a th w a y for
F eCl3‚6H2O-P r om oted Cycliza tion of 4
Ta ble 2. Effect of In cr ea sin g Am ou n t of F eCl3‚6H2O on
th e Cycliza tion of 4a
equiv of
FeCl3‚6H2O
tricycles
enamide
4 (%)
aldehyde
5 (%)
6 and 7 (%)b
1.0
2.0
3.5
7.0
4
20
83
67
89
1
0
7
61c
5c
F igu r e 1. Effect of water content (v/v) on the cyclization of
enamide 4: 9, enamide 4; b, tricycles 6 and 7; 2, aldehyde 5.
Reaction conditions: 2-3 mg of 4 in CH2Cl2 (3 mM), rt for 2
h.
2
7c
a
Reaction conditions: 2-3 mg of 4 in CH2Cl2 (3 mM), rt for 2
h. GLC yield. c Remaining mass consists of unidentified cyclic
b
the reaction of 4 with FeCl3 containing 0.1% (v/v) water
provided azapolycycles 6 and 7, with negligible amounts
of starting material and aldehyde remaining. Con-
versely, under anhydrous conditions a complex mixture
of unidentified cyclic and decomposition products was
obtained, whereas addition of more water (1-5%) led to
an accumulation of aldehyde and a decrease in cyclization
products. The latter is most likely due to competitive
complexation of FeCl3 by water, resulting in a less active
cyclization promoter. Thus, formation of the C-4 hydroxy
tricycles is the result of a two-step sequence, acetal
deprotection followed by Lewis acid activation of the
corresponding aldehyde derivative of 4 (Scheme 3). This
conclusion was supported by the observed efficient cy-
clization of aldehyde 5 (obtained by deprotection with
pyridinium p-toluenesulfonate) to azapolycycles 6 and 7
by reaction with FeCl3‚6H2O in CH2Cl2 at room temper-
ature. The ratio of the products formed was identical to
that obtained in the reaction of 4 with FeCl3‚6H2O,
supporting the likelihood that 5 is a true intermediate
in this process.
material and decomposition products.
Ta ble 3. Effect of Differ en t Solven ts on th e
F eCl3‚6H2O-P r om oted Cycliza tion of 4a
tricycles
enamide
4 (%)
aldehyde
5 (%)
solvent
benzene
6 and 7 (%)b
12
7
7
4
96
72
0
25c
28c
3
24
5
acetonitrile
tetrahydrofuran
methanol
1
0
methylene chloride
83
a
Reaction conditions: 2-3 mg of 4 (3 mM), 3.5 equiv of
FeCl3‚6H2O, rt for 2 h. GLC yield. c Remaining mass consists of
unidentified cyclic material and decomposition products.
b
tentatively assigned as monocyclic and polymeric prod-
ucts (determined by 1H NMR analysis of the crude
reaction mixture).
Analysis of several crude reaction mixtures showed the
presence of aldehyde 5 resulting from hydrolysis of the
acetal functionality of enamide 4. This result, in addition
to the observed exclusive recovery of C-4 hydroxy (steroid
numbering) azapolycycles, prompted us to establish that
formation of 5 is a prerequisite for cyclization (Scheme
3). If aldehyde 5 is a true intermediate in the reaction,
one would expect that FeCl3-promoted cyclization of this
material would also yield polycycles 6 and 7 and that the
presence of water is essential for the initial acetal
hydrolysis.
An examination of the effect of water on the cyclization
process showed that an optimum water content was
necessary for efficient cyclization (Figure 1).12 In sharp
contrast to conventional Lewis acid promoted transfor-
mations which require the rigorous exclusion of moisture,
Con clu sion
The preparation of azapolycycles by biomimetic polyene
cyclization methodology has been demonstrated with the
efficient cyclization of 4 by FeCl3‚6H2O. The reaction is
selective, yielding a mixture of 4-hydroxy-7-aza (steroid
numbering) tricycles 6 and 7 that results from initial
hydrolysis of the acetal functionality followed by cycliza-
tion of the corresponding aldehyde. These results suggest
that other azapolycycles, such as azasteroids, may be
prepared by similar methodology with appropriate posi-
tioning of the enamide functionality within a polyene
precursor chain. The application of this chemistry to
higher-order cyclizations is currently under investigation.
(11) (a) Sisko, J .; Henry, J . R.; Weinreb, S. M. J . Org. Chem. 1993,
58, 4945. (b) Tietze, L. F.; Bratz, M. Chem. Ber. 1989, 122, 997. (c)
Tietze, L. F.; Beifuss, U. Synthesis 1988, 359. (d) Albaugh-Robertson,
P.; Katzenellenbogen, J . A. J . Org. Chem. 1983, 48, 5288. (e) Denmark,
S. E.; J ones, T. K. J . Am. Chem. Soc. 1982, 104, 2642.
Exp er im en ta l Section
(12) A similar phenomenon has been seen in the FeCl3-promoted
Nazarov reaction of â-substituted divinyl ketones, see: J ones, T. K.;
Denmark, S. E. Helv. Chim. Acta 1983, 2397.
(13) Barta, N. S.; Paulvannan, K.; Schwartz, J . B.; Stille, J . R. Synth.
Commun. 1994, 24, 583.
Gen er a l Meth od s. Unless otherwise stated, all chemicals
obtained from commercial sources were used without further
purification. THF was distilled from benzophenone sodium
ketyl, Et3N and C5H5N were distilled from KOH, and AcCl was

Biomimetic Cyclization of Azapolyenes
J . Org. Chem., Vol. 61, No. 19, 1996 6649
distilled from PCl5. CH3OCH2PPh3Cl was recrystallized from
CH2Cl2/hexane and dried in vacuo overnight prior to use.
Routine 1H and 13C NMR spectra were recorded at 300 and
75 MHz, respectively, using CDCl3 as solvent. Proton δ and
J assignments of cyclic products 6 and 7 were based on 500
MHz COSY studies using a standard pulse experiment. Flash
chromatography was performed using silica gel 60 (230-400
mesh, EM Science). Gas-liquid chromatography was per-
formed using a DB5-HT 30 m capillary column (J & W
Scientific), and retention times (tR) are given in minutes.
Elemental analyses were performed by Desert Analytics
Laboratory, Tucson, AZ.
1-P h th a lim id o-3-m eth yl-7,7-(eth ylen ed ioxy)-2(E)-h ep -
ten e. Triphenylphosphine (742 mg, 2.8 mmol) and phthal-
imide (410 mg, 2.8 mmol) were added to a stirred solution of
alcohol 2 (400 mg, 2.2 mmol) in 15 mL of THF. Diisopropyl
azodicarboxylate (550 µL, 2.8 mmol) was added dropwise to
the solution in the dark over 10 min. The reaction was stirred
at rt for 6 h and quenched by the addition of 15 mL of water.
The aqueous layer was extracted three times with 15 mL of
hexanes, and the combined organics were washed with brine,
dried over MgSO4, and concentrated in vacuo. The crude oil
was purified by flash chromatography using MeOH/CH2Cl2 (5:
95) to yield 588 mg of allylic phthalimide (1.8 mmol, 86%) as
a white solid: IR (KBr) cm-1 2947, 2876, 1720, 1706, 1549,
1381; 1H NMR δ 1.56 (m, 4 H), 1.80 (s, 3 H), 2.05 (t, 2 H, J )
7 Hz), 3.78-3.94 (m, 4 H), 4.24 (d, 2 H, J ) 7 Hz), 4.80 (t, 1 H,
J ) 4 Hz), 5.25 (t, 1 H, J ) 6 Hz), 7.70 (m, 2 H), 7.79 (m, 2 H);
13C NMR δ 16.16, 21.91, 33.30, 35.72, 39.19, 64.76, 104.35,
118.21, 123.08, 132.25, 133.73, 140.32, 168.06.
1-Am in o-3-m eth yl-7,7-(eth ylen edioxy)-2(E)-h epten e (3).
To a solution of 1-phthalimido-3-methyl-7,7-(ethylenedioxy)-
2(E)-heptene (320 mg, 1.0 mmol) in 10 mL of ethanol was
added 700 µL of methylamine (7.9 mmol, 40% by wt solution).
The reaction was refluxed for 7 h and quenched by the addition
of 20 mL of ice-cold H2O. The aqueous layer was basified (pH
> 10) with solid KOH and extracted three times with 20 mL
of Et2O. The combined ether layers were washed with brine,
dried over MgSO4, and concentrated in vacuo. Flash chroma-
tography using MeOH/CH2Cl2 (20:80) provided 170 mg of
amine 3 (0.9 mmol, 91%): IR (neat) cm-1 3289, 2949, 2873,
1558, 1457, 1136; 1H NMR δ 1.44-1.54 (m, 4 H), 1.56 (s, 3H),
1.97 (t, 2 H, J ) 7 Hz), 3.20 (d, 2 H, J ) 6 Hz), 3.76-3.93 (m,
4 H), 4.79 (t, 1 H, J ) 5 Hz), 5.20 (t, 1 H, J ) 7 Hz); 13C NMR
δ 15.84, 22.05, 33.32, 39.28, 39.52, 64.81, 104.46, 126.10,
136.04. Anal. Calcd for C10H19NO2‚1/4 H2O: C, 64.05; H, 10.21;
N, 7.47. Found: C, 64.05; H, 10.30; N, 7.77.
1-((ter t-Bu t yld ip h en ylsilyl)oxy)-3-m et h yl-7-m et h oxy-
2(E),6(E/Z)-h ep ta d ien e. To a stirred solution of (methoxy-
methyl)triphenylphosphonium chloride (3.9 g, 11.4 mmol) in
50 mL of THF at -78 °C was added 7.2 mL of n-BuLi (1.6 M
in hexanes, 11.5 mmol). After 15 min of stirring, the temper-
ature was raised to 0 °C and the reaction mixture was stirred
for 1 h, after which time a red solution was obtained. The
reaction was cooled to -78 °C, and trisnoraldehyde 1 (2.8 g,
7.7 mmol, prepared as previously described)8 dissolved in 10
mL of THF was added dropwise. The solution was stirred an
additional 1 h and quenched with 60 mL of H2O. The aqueous
layer was extracted three times with 60 mL of hexanes, and
the combined organics were washed with brine, dried over
MgSO4, and concentrated in vacuo. Cold hexane (20 mL) was
added to precipitate triphenylphosphine oxide, which was
removed by filtration. The filtrate was concentrated in vacuo,
and the resulting oil was chromatographed using EtOAc/
hexanes (5:95) as the eluent to yield 2.6 g of the enol ether
(6.6 mmol, 86%, 6(Z):6(E) ) 53:47): MS m/ z (rel intensity)
394.2 (0.34), 337.1 (20.9), 213.2 (16.3), 199.2 (100), 183.2 (10.4),
81.0 (9.4), 153.1 (11.4), 107.1 (10.5), 71.2 (24.5); IR (neat) cm-1
1
3112, 2960, 1658, 1432, 1110, 1054; H NMR δ 1.06 (s, 9 H),
1.45 (s, 3 H), 2.01-2.12 (m, 4 H), 3.49 (s, OMe(E)), 3.57 (s,
OMe(Z)), 4.24 (d, 2 H, J ) 6 Hz), 4.32 (m, 6(Z)), 4.72 (m, 6(E)),
5.39 (t, 1 H, J ) 7 Hz), 5.86 (d, 7(Z), J ) 6 Hz), 6.30 (d, 7(E),
J ) 12 Hz), 7.40 (m, 6 H), 7.68 (m, 4 H); 13C NMR δ 16.25,
19.18, 26.88, 39.40, 40.69, 55.85, 61.14, 104.57, 124.23, 124.51,
127.51, 129.56, 134.29, 136.61, 146.11, 147.20.
1-(N-1-Cycloh exen yla cet a m id o)-3-m et h yl-7,7-(et h yl-
en ed ioxy)-2(E)-h ep ten e (4). To a stirred solution of amine
3 (30 mg, 0.16 mmol) in 10 mL of dry benzene were added
138 mg of K2CO3 (1.0 mmol) and 33 µL of cyclohexanone (0.32
mmol). The flask was equipped with a Dean-Stark apparatus
whose side arm was filled with activated 4 Å molecular sieves
and refluxed for 15 h.13 The reaction was cooled to rt, and 13
µL of acetyl chloride (0.18 mmol) and 17 µL of pyridine (0.20
mmol) were added. After 20 min the reaction was quenched
by the addition of 15 mL of H2O. The aqueous layer was
extracted three times with 15 mL of Et2O, and the combined
ether extracts were washed (saturated aqueous NaHCO3,
brine), dried over MgSO4, and concentrated in vacuo. Flash
chromatography using MeOH/CH2Cl2 (1:99) provided 40 mg
of enamide 4 (0.13 mmol, 81%) as a colorless oil: GLC (220
°C for 1 min, 10 °C/min to 325 °C) 7.98 min; MS m/ z (rel
intensity) 307.2 (3.6), 206.0 (12.6), 164.05 (100), 139.0 (30.6),
122.0 (29.2), 107.0 (13.6), 98.9 (16.4), 97.0 (50.5), 96.0 (19.2),
80.9 (58.5), 78.9 (34.8), 72.9 (51.4), 68.9 (15.5), 66.9 (19.5), 54.9
(24.5), 52.9 (15.6); IR (neat) cm-1 2933, 2881, 1651, 1404, 1144,
1-((ter t-Bu t yld ip h en ylsilyl)oxy)-3-m et h yl-7,7-(et h yl-
en ed ioxy)-2(E)-h ep t en e. To a solution of 1-((tert-butyldi-
phenylsilyl)oxy)-3-methyl-7-methoxy-2(E),6(E/ Z)-heptadiene
(1.3 g, 3.3 mmol) in 150 mL of dry benzene were added 3.7
mL of ethylene glycol (66.0 mmol) and a catalytic amount of
TsOH. The reaction was stirred vigorously and refluxed for 5
h. After the addition of 100 mL of H2O, the aqueous layer
was extracted two times with 100 mL of Et2O. The combined
ether layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. Chromatography of the crude oil using
EtOAc/hexanes (4:96) provided 1.1 g of the acetal (2.7 mmol,
82%) as a clear oil: IR (neat) cm-1 3075, 2950, 1450, 1110,
1
1070; H NMR δ 1.05 (s, 9 H), 1.43 (s, 3 H), 1.51-1.65 (m, 4
H), 2.01 (t, 2 H, J ) 7 Hz), 3.84-3.96 (m, 4 H), 4.22 (d, 2 H, J
) 6 Hz), 4.85 (t, 1 H, J ) 5 Hz), 5.40 (t, 1 H, J ) 6 Hz), 7.40
(m, 6 H), 7.71 (m, 4 H); 13C NMR δ 16.04, 19.14, 22.01, 26.85,
33.47, 39.19, 61.10, 64.79, 104.57, 124.44, 127.47, 127.63,
129.38, 134.24, 135.58, 136.71. Anal. Calcd for C26H36O3Si:
C, 73.54; H, 8.54. Found: C, 73.50; H, 8.37.
1
1035; H NMR δ 1.49-1.70 (m, 8 H), 1.61 (s, 3 H), 1.96-2.09
(m, 6 H), 1.98 (s, 3 H), 3.80-3.97 (m, 4 H), 4.01 (d, 2 H, J ) 7
Hz), 4.82 (t, 1 H, J ) 5 Hz), 5.17 (t, 1 H, J ) 6 Hz), 5.56 (br s,
1 H); 13C NMR δ 17.52, 23.11, 23.19, 23.65, 24.45, 26.38, 29.79,
34.99, 40.90, 44.89, 66.43, 106.10, 122.12, 128.95, 139.93,
140.77, 171.03. Anal. Calcd for C18H29NO3: C, 70.32; H, 9.51;
N, 4.56. Found: C, 70.20; H, 9.22; N, 4.67.
3-Meth yl-7,7-(eth ylen ed ioxy)-2(E)-h ep ten -1-ol (2). To
a stirred solution of 1-((tert-butyldiphenylsilyl)oxy)-3-methyl-
7,7-(ethylenedioxy)-2(E)-heptene (3.7 g, 9.1 mmol) in 30 mL
of THF at 0 °C was added tetrabutylammonium fluoride (1.0
M in THF, 27 mmol). The reaction was allowed to warm to rt
over 3 h and quenched by the addition of 20 mL of H2O. The
aqueous layer was extracted three times with 20 mL of Et2O,
and the combined ether layers were washed (saturated aque-
ous NaHCO3, brine), dried over MgSO4, and concentrated in
vacuo. Flash chromatography using Et2O/hexanes (60:40)
yielded 1.6 g of 2 (8.6 mmol, 95%): IR (neat) cm-1 3417, 2947,
1-(N-1-Cycloh exen yla ceta m id o)-3-m eth yl-2(E)-h ep ten -
7-a l (5). To a solution of polyene 4 (8 mg, 0.03 mmol),
dissolved in 7 mL of a 95:5 mixture of acetone:water, was
added pyridinium p-toluenesulfonate (1 equiv, 7 mg). The
reaction was refluxed for 7 h and then quenched by the
addition of water. The aqueous layer was extracted three
times with 10 mL of Et2O, and the combined ether layers were
washed (saturated aqueous NaHCO3, brine), dried over Mg-
SO4, and concentrated in vacuo. GLC analysis of the reaction
mixture revealed a 55:45 mixture of aldehyde 5 and starting
material. Chromatography using i-PrOH/hexane (5:95) pro-
vided 3 mg of aldehyde 5 (0.01 mmol, 38%) as a colorless oil:
GLC (220 °C for 1 min, 10 °C/min to 325 °C) 5.97 min; IR (neat)
1
2876, 1669, 1408, 1134; H NMR δ 1.51-1.63 (m, 4 H), 1.65
(s, 3H), 2.05 (t, 2 H, J ) 7 Hz), 3.80-4.14 (m, 4 H), 4.10 (d, 2
H, J ) 7 Hz), 4.80 (t, 1 H, J ) 5 Hz), 5.30 (t, 1 H, J ) 7 Hz);
13C NMR δ 16.01, 21.96, 33.39, 39.24, 59.32, 64.83, 104.49,
123.86, 139.28.
1
cm-1 2938, 2719, 1721, 1646, 1392; H NMR δ 1.64 (s, 3 H),

6650 J . Org. Chem., Vol. 61, No. 19, 1996
Sen and Roach
1.66-1.78 (m, 6 H), 2.01 (s, 3 H), 2.03-2.12 (m, 6 H), 2.39 (t,
2 H, J ) 7 Hz), 4.02 (d, 2 H, J ) 7 Hz), 5.19 (t, 1 H, J ) 6 Hz),
5.57 (br s, 1 H), 9.76 (br s, 1H).
J ) 13.7 Hz, J ) 3.2 Hz), 3.79 (ddd, H4, 1 H, J ) 3.5 Hz, J )
3.1 Hz, J ) 6.2 Hz), 4.19 (dd, H6ax, 1 H, J ) 13.7 Hz, J ) 12.1
Hz), 4.63 (dd, OH, 1 H, J ) 3.5 Hz, J ) 1.6 Hz), 5.5 (dd, 1 H,
J ) 2.2 Hz, J ) 2.6 Hz); 13C NMR δ 19.21, 21.50, 22.70, 23.90,
24.73, 27.27, 29.72, 31.87, 41.85, 43.67, 48.97, 65.18, 72.04,
127.91, 138.66, 172.15. Tricycle 7: 1H NMR δ 1.12, (s, C10-
Me, 3H), 1.21-1.80 (m, 6 H), 1.90-2.29 (m, 8 H), 2.08 (s, 3
H), 3.07 (dd, H6eq, 1 H, J ) 14.3 Hz, J ) 4.2 Hz), 3.81 (br m,
H4, 1 H), 4.40 (dd, H6ax, 1 H, J ) 13.9 Hz, J ) 12.5 Hz), 4.74
(br s, H2O), 5.34 (br m, OH, 1 H), 5.51 (br m, 1 H).
Tr icycles 6 a n d 7. To a solution of enamide 4 (20 mg, 0.06
mmol) in 3 mL of CH2Cl2 at rt was added FeCl3‚6H2O (61 mg,
3.5 equiv). The mixture was stirred at rt for 2 h, and then
washed with saturated aqueous NaHCO3, dried over MgSO4,
and concentrated in vacuo. The crude residue (15 mg, 88%
mass recovery) was purified by flash chromatography using
i-PrOH/hexane (5:95) to give a mixture of tricycles 6 and 7
(11 mg, 65%, 6:7 ) 85:15): GLC (220 °C for 1 min, 1 °C/min
to 250 °C) 10.26 min (6), 10.10 min (7). Anal. Calcd for
C16H27NO2‚4/3H2O: C, 66.87; H, 9.70; N, 4.88. Found: C, 66.74;
H, 9.86; N, 4.69.
Ack n ow led gm en t. This work was supported by the
American Heart Association, Indiana Affiliate, Inc. S.R.
is the recipient of an American Heart Association
predoctoral fellowship. 500 Mz NMR spectra were
obtained with the help of Dr. Bruce Ray. We also thank
J oe Magrath for his scientific contributions to this work
and for help in manuscript preparation.
The tricycles were separated by MPLC (10% i-PrOH/hex)
and further purified by recrystallization from hexane/CH2Cl2
to give fine needles. Tricycle 6: IR (KBr) cm-1 3402, 2936,
1
2867, 2363, 2332, 1652, 1620, 1558; H NMR δ 1.36 (s, C10-
Me, 3 H), 1.42-1.68 (m, 4 H), 1.75 (m, 4 H), 1.95 (m, 3 H),
2.09 (s, 3 H), 2.15 (m, 2 H), 2.26 (m, 1 H), 3.21 (dd, H6eq, 1 H,
J O960924Y