An asymmetric approach to spirocylic systems: A formal synthesis of zizaene

Article abstract of DOI:10.1021/jo010439p

A general route to enantiopure spirocarbocycles is described. The use of various chiral bicyclic lactams 1 that have been doubly alkylated with olefinic halides gives good yields of α,α-disubstituted chiral lactams 2 which were cyclized to spiro-olefins using ring closure metathesis methodology (Grubbs' catalyst). These spirolactams 3, formed in generally excellent yields, were shown to be smoothly transformed into spirocyclopentenone 6, spirocyclohexenone, 7, and spirolactams 8. Further demonstration of this spirocyclization methodology was featured in a formal synthesis of zizaene, by preparing in enantiomeric form the Coates' intermediate 21. This synthetic effort provided additional examples of the synthetic versatility of chiral bicyclic lactams 2a,b.

Full text of DOI:10.1021/jo010439p

J . Org. Chem. 2001, 66, 5545-5551
5545
An Asym m etr ic Ap p r oa ch to Sp ir ocylic System s: A F or m a l
Syn th esis of Ziza en e†
Robert C. Hughes, Curt A. Dvorak, and A. I. Meyers*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
aimeyers@lamar.colostate.edu
Received April 25, 2001
A general route to enantiopure spirocarbocycles is described. The use of various chiral bicyclic
lactams 1 that have been doubly alkylated with olefinic halides gives good yields of R,R-disubstituted
chiral lactams 2 which were cyclized to spiro-olefins using ring closure metathesis methodology
(Grubbs’ catalyst). These spirolactams 3, formed in generally excellent yields, were shown to be
smoothly transformed into spirocyclopentenone 6, spirocyclohexenone, 7, and spirolactams 8. Further
demonstration of this spirocyclization methodology was featured in a formal synthesis of zizaene,
by preparing in enantiomeric form the Coates’ intermediate 21. This synthetic effort provided
additional examples of the synthetic versatility of chiral bicyclic lactams 2a ,b.
Sch em e 1
The creation of quaternary centers, especially those
representing stereogenic centers, continues to be a chal-
lenging task for the synthetic organic chemist. One
solution to this problem has been developed in these
laboratories through the ongoing successful evaluation
of the bicyclic lactam 1 as a chiral template in the
synthesis of a variety of molecules of quaternary stereo-
centers (Scheme 1).1 An even more difficult problem is
the assemblage of chiral spirocyclic centers, a structural
array found in many natural products. At the center of
the chiral spirocycle center resides a quaternary carbon
(e.g., 3), which can be readily accessed utilizing the above-
mentioned lactam template. We describe herein the use
of chiral bicyclic lactams, doubly substituted with olefinic
appendages 2 followed by ring-closing metathesis2,3 to
furnish 3. The chiral nonracemic spirocyclic compounds
3 resulting from this sequence can serve as useful
intermediates in a variety of synthetic endeavors.
lactams failed,1b presumably due to the interaction of the
sulfur atom with the ruthenium catalyst.
Various bicyclic lactams 1 were doubly alkylated
following previously described conditions4 (LDA or s-
BuLi, THF, -78 °C), thus providing the dialkyl deriva-
tives 2a -h listed in Table 1. The alkylations leading to
the quaternary center in 2 were all highly diastereo-
selective (>95% de) in the second alkylation step except
for entries 1 and 6 (2a and 2f). In both of these cases,
the two diastereomers proved to be inseparable by flash
chromatography and the mixtures were thus utilized as
such for the ring-closing metathesis that followed. In all
other entries, the crude dialkylated diastereomers 2b-
e,g,h (>98% de) were subjected to the ring-closing
metathesis (RCM) conditions.2 With monosubstituted
terminal olefins, the cyclization proceeded smoothly using
5 mol % of Cl2(PCy3)2RuCHPh catalyst at room temper-
ature, producing the corresponding spirocyclic lactams
3 in excellent yields with various appended ring sizes.
However, if a geminally substituted olefin was present
in the starting material (entries 1, 4, and 5), the metath-
esis appeared to be considerably slower using the semi-
stable commercially available ruthenium benzylidene
catalyst. However, it was later found that significantly
improved yields were obtained when the reaction mixture
was heated along with slow addition of the catalyst
(method C, Table 1).
We have previously reported that a wide variety of
bicyclic lactams 1 can be dialkylated at the R-carbon with
very high diastereoselectivity.1,4 Therefore, it was envi-
sioned that alkylation with two different unsaturated
electrophiles would provide suitable precursors for ring-
closing metathesis remote from the newly formed chiral
center to furnish 2. This could be followed by cyclization
using the ruthenium catalyst2 resulting in the creation
of a new spiroappended ring adjacent to the lactam
carbonyl (3). The spiro systems are then poised to be
transformed into a variety of useful intermediates,
including cyclic enones and substituted piperidines (vide
supra). It should be noted that early attempts to effect
the ring-closing methathesis on the corresponding thio-
† This paper is dedicated to the memory of Professor Arthur G.
Schultz.
(1) For reviews on this subject, see: (a) Romo, D.; Meyers, A. I.
Tetrahedron 1991, 47, 9503. (b) Groaning, M. H.; Meyers, A. I.
Tetrahedron 2000, 56, 9843. (c) Meyers, A. I.; Brengel, G. P. J . Chem.
Soc., Chem. Commun. 1997, 1.
(2) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(3) Fu, G.; Nguyen, S. T.; Grubbs, R. H. J . Am. Chem. Soc. 1993,
115, 9856.
(4) (a) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A. J . Org. Chem. 1996,
61, 5712. (b) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J . F.;
Williard, P. G. J . Am. Chem. Soc. 1998, 120, 7429.
10.1021/jo010439p CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/18/2001

5546 J . Org. Chem., Vol. 66, No. 16, 2001
Hughes et al.
Ta ble 1
a
The substituent from the first alkylation is present on the exo face (except for 2d where the allyl group was introduced first). The
endo substituent was introduced in the second alkylation step (except for 2d ). The yields for the purified double alkylation products, 2,
b
are given in the Experimental. Conditions: (A) substrate was stirred in dichloromethane (0.007 M) at ambient temperature with 5 mol
% of Cl2(PCy3)2RuCHPh for 18-24 h; (B) substrate was stirred in dichloromethane (0.007 M) heated at reflux with 15 mol % of
Cl2(PCy3)2RuCHPh (added in three equal portions every 4-6 h) for 18-24 h; (C) substrate was heated in toluene (100 °C) and
Cl2(PCy3)2RuCHPh (5 mol %) added via syringe pump over 3 h.
Sch em e 2a
The nature of the substituents on bicyclic lactams 1
appeared to have little effect on the outcome of the spiro
cyclization leading to 3. Furthermore, lactam 2d (entry
4) was chosen for further study due to the earlier
observation that [3.3.0] bicyclic lactams bearing an
angular hydrogen (i.e. 1, n ) 1, R3 ) H, Scheme 1)
generally gave poor selectivity during the second alky-
lation step. The presence of the endo phenyl group in 2d
(Table 1) resulted in exclusive alkylation on the exo-face
of the lactam. This is in contrast to the generally observed
alkylation pathway, which almost invariably gave endo
alkylation.4a In the absence of any substituent on the
endo face (1, R2 ) H), the alkylation of bicyclic lactam
enolate almost exclusively furnished the endo alkylation
product. As Table 1 illustrates, both [3.3.0] and [4.3.0]
bicyclic lactams (2f, 2g, 2h ) with various substitution
patterns can be utilized in conjunction with the meta-
thesis cyclization to create a wide variety of useful
synthetic intermediates.
a
Conditions: (a) Red-Al, THF, 0 °C; (b) EtOH, 1 M Bu4NH2PO4,
rt; (c) EtOH, KOH, rt; (d) DIBAL-H, THF -78 °C to room
temperature.
With the metathesis products 3 in hand, an effort was
made to determine whether the remote chirality of the
quaternary center, as well as lactam carbonyl, could
affect the stereochemistry of reduction of the double bond
present in 3. In other words, a new stereogenic center
could potentially be set in place via the selective hydro-
genation. In this regard, spiro lactam 3d was exposed to
the iridium catalyst5 under an atmosphere of hydrogen,
(5) Crabtree, R. H.; Felkin, H.; Fellebeen-Kahn, T.; Morris, G. E. J .
Organomet. Chem. 1979, 168, 183.

Formal Synthesis of Zizaene
J . Org. Chem., Vol. 66, No. 16, 2001 5547
Sch em e 3a
a
Conditions: (a) LDA, THF -78 °C, 72%; (b) LDA, THF -78 °C, allyl bromide, 98%, (c) Cl2(PCy3)2RudCHPh (method C) 95%; (d)
[PCy3Ir(COD)Py]Pf6 (1%) H2, CH2Cl2, 85%; (e) i. Red-Al, THF, 0 °C, ii. EtOH, 1 M Bu4NH2PO4, rt; iii. EtOH, KOH, rt 85%; (f) LiCuMe2(CN),
THF -78 °C, 97%.
Sch em e 4a
which afforded 4 as a single diastereomer in excellent
yield. The stereochemistry was initially assigned on the
a
Conditions: (a) TBAF, 83%; (b) Swern oxidation, 99%; (c)
basis of the assumption that the lactam carbonyl should
facilitate the delivery of hydrogen on the same face of
H, 62%; (f) MCPBA, 48%; (g) Im2CS, DMAP, 84%; (h) Bu3SnH,
EtOH, TsOH(cat.); (d) TsOH(cat.), toluene reflux, 63%; (e) Dibal-
the molecule due to the oxygen lone pairs coordinating
with the catalyst metal center. This latter effect has been
previously observed by the late professor Schultz.6It was
therefore necessary to unambiguously confirm the ster-
eochemistry of the reduction, and this was accomplished
by removing the silicon protecting groups in 4, which
afforded the crystalline diol 5. Single-crystal X-ray
analysis (Supporting Information) revealed that the
assignment of the newly formed stereogenic center in 5
was as predicted. Thus, the notion of the lactam carbonyl
acting as a remote director of stereochemical reduction
appeared to be verified.
To afford more generally useful products, the amino
alcohol portions of lactams 3c, 3f, and 3g were removed
by utilizing methods previously described1 to furnish
various spirocyclic enones 6 and 7 as well as piperidine
8 shown in Scheme 2.
To demonstrate the further synthetic utility of this
method, a sequence leading to the key intermediate 21
in the synthesis of zizaene7 was investigated. Com-
mercially available lactam 1 (Scheme 3) was alkylated
with the allylic iodide ICH2C(CH2)CH2CH2OTBS (readily
available from dimethyl itaconate, see Experimental).
This was followed directly by a second alkylation with
allyl bromide to furnish the 2,2-disubstituted lactam 2e
as an initial 6:1 mixture of diastereomers. After separa-
tion (to >97:3) by flash column chromatography, the ring-
closing metathesis generated the expected spirocyclopen-
AIBN, 64%; (i) PDC, 67%; (j) Pd-C, H2, 99%.
tene 3e (Table 1) in 95% yield. The resulting olefin in 3e
was reduced with Crabtree’s iridium catalyst5 to 9 in
greater than >97% de, thus setting the remote stereo-
genic center needed in the tricyclic framework of the
zizaene family of natural products. Removal of the chiral
auxiliary was accomplished by treatment of 9 with Red-
Al to reduce the lactam carbonyl to the carbonolamine,
which was then hydrolyzed using a 1 M Bu4NH2PO4
buffer. The resulting keto-aldehyde was treated with
KOH to effect the aldol cyclization affording spiroenone
10 in good overall yield. The addition of the requisite
methyl group was accomplished by conjugate addition of
the higher order cuprate (Me2Cu(CN)Li)8 to enone 10 to
produce the corresponding cyclopentanone 11. As ex-
pected, the addition of the methyl group was highly
1
stereoselective as judged by H NMR.
Scheme 4 describes the final sequence wherein 11 was
transformed into the known advanced zizaene intermedi-
ate 21. With the final methyl group in place, the TBS
protecting group in 11 was removed using TBAF followed
by Swern oxidation of the resulting alcohol 12 which
afforded the pivotal aldehyde 13. An intramolecular aldol
reaction on aldehyde 13 was now required to form the
desired tricyclic system 15 found in zizaene. Basic
catalysis (KOH, EtOH) failed to produce the desired
(8) (a) Lipshutz, B. H.; Sengupta, S. Org. React. (b) Posner, G. H.
An Introduction to Synthesis Using Organocopper Reagents; Wiley:
New York, 1980.
(6) Schultz, A. G.; McCloskey, P. J . J . Org. Chem. 1985, 50, 5905.
(7) Coates, R. M.; Sowerby, R. L. J . Am. Chem. Soc. 1972, 94, 5386.

5548 J . Org. Chem., Vol. 66, No. 16, 2001
Hughes et al.
1) afforded 283 mg (65% after both alkylations) of 2b as a
colorless oil: IR (NaCl) ν 2962, 1710, 1322 cm-1; 1H NMR (300
MHz, CDCl3) δ 0.96 (s, 9H), 1.51 (s, 3H), 1.65-1.72 (m, 2H),
1.98 and 2.30 (Abq, J gem ) 14.1 Hz, 2H), 2.08 (m, 2H), 2.29 (m,
2H), 3.69 (dd, J ) 7.8, 9 Hz, 1H), 3.84 (dd, J ) 9, 9.3 Hz, 1H),
4.10 (dd, J ) 8.1, 9 Hz, 1H), 4.94-5.11 (m, 4H), 5.11 (m, 1H),
5.66 (m, 1H), 5.80 (ddt, J ) 17.1, 10.1, 6.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 26.2, 27.2, 28.8, 32.8, 37.6, 40.9, 44.3, 50.8,
65.8, 67.1, 97.2, 114.8, 118.6, 133.8, 137.9, 184.6; mass
spectrum (FAB), m/z (rel intensity) 292 (M + 1, 100), 290 (13),
276 (7), 234 (10); HRMS, calcd for C18H29NO2 + 1 292.2198,
found 292.2281.
La cta m 2c from 5-iodo-1-pentene, followed by allylbromide.
Flash chromatography (silica gel, hexanes/ethyl acetate, 25:
1) afforded 503 mg (66% after both alkylations) of 2c as a
colorless oil: IR (NaCl) ν 2964, 1712, 1319 cm-1; 1H NMR (300
MHz, CDCl3) δ 0.95 (s, 9H), 1.40-1.48 (m, 2H), 1.50 (s, 3H),
1.57-1.63 (m, 2H), 1.95 and 2.28 (Abq, J gem ) 14.1 Hz, 2H),
2.08 (m, 2H), 2.27 (m, 2H), 3.69 (dd, J ) 8.2, 9.3 Hz, 1H), 3.83
(dd, J ) 9, 9.3 Hz, 1H), 4.10 (dd, J ) 8.3, 9.2 Hz, 1H), 4.94-
5.07 (m, 3H), 5.09 (m, 1H), 5.65 (m, 1H), 5.78 (ddt, J ) 17.1,
10.2, 6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.7, 26.2, 27.2,
32.9, 33.8, 37.8, 40.9, 44.3, 51.0, 65.7, 67.1, 97.3, 114.9, 118.4,
137.9134.0, 138.3, 184.9; mass spectrum (FAB), m/z (rel
intensity) 306 (M + 1, 100), 290 (7.5), 248 (10); HRMS, calcd
for C19H31NO2 + 1 306.2355, found 306.2420.
La cta m 2d from allyl bromide, followed by tert-butylsiloxy-
ethalyl iodide. Flash chromatography (silica gel, hexanes/ethyl
acetate, 15:1) afforded 671 mg (68% after both alkylations) of
2d as a pale yellow oil: IR (NaCl) ν 1710, 1110 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.02 (s, 3H), 0.03 (s, 3H), 0.88 (s, 9H),
1.08 (s, 9H), 2.20-2.32 (m, 5H), 2.41-2.53 (m, 3H), 3.68 (m,
2H), 3.76 (m, 1H), 3.94 (m, 2H), 4.93 (m, 1H), 4.99 (m, 1H),
5.15 (m, 3H), 5.31 (dd, J ) 6.3, 2.4 Hz, 1H), 5.78 (m, 1H), 7.17
(m, 2H), 7.28 (m, 3H), 7.24 (m, 6H), 7.66 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ -5.3, -5.3, 15.3, 18.3, 19.3, 25.9, 26.9, 33.8,
40.2, 43.0, 44.2, 51.5, 62.3, 63.2, 63.7, 65.8, 82.3, 90.5, 116.2,
119.2, 127.8, 128.2, 128.5, 129.8, 129.9, 132.8, 133.0, 133.9,
tricycle, leading only to unidentifiable products with
complete consumption of starting material. However, it
was observed that acid catalysis on 13 (TsOH, toluene
reflux) did produce the desired tricycle in modest yields
with recovered starting material. In addition, the corre-
sponding diethyl acetal 14 also underwent an acid-
catalyzed intramolecular aldol reaction with reduced
reaction times and greater conversion to the aldol tricyclic
product 15.
To complete the synthesis of the Coates’ intermediate7
21, a 1,3-carbonyl transposition was carried out as
follows: Dibal reduction of the aldol enone 15 gave a
diastereomeric mixture of allylic alcohols 16. Epoxidation
of the alcohol mixture with MCPBA to epoxide 17 was
followed by conversion to the xanthate esters 18 using
thiocarbonyldiimidazole (TCDI). Exposure of the xan-
thate mixture to standard radical conditions (Barton
deoxygenation9) resulted in the epoxycarbinyl radical
rearrangement, which cleaved the epoxide, thus furnish-
ing the two diastereomerically transposed allylic alcohols
19 in excellent yield. Oxidation of the mixture of alcohols
to the ketone followed by hydrogenation of the remaining
double bond gave tricycle 21 which was identical in all
respects to the key intermediate reported by Coates in
his synthesis of zizaene.7
In conclusion, we have demonstrated that [3.3.0]- and
[4.3.0]bicyclic lactams with various substitution patterns
can be utilized in conjunction with the RCM to create a
wide variety of useful spirocyclic synthetic intermediates
which can be used in the synthesis of complex natural
products.
Exp er im en ta l Section
Gen er a l Exp er im en ta l for Alk yla tion s of La cta m s 1.
(A) Gen er a l F ir st Alk yla tion Step . To a stirred solution of
diisopropylamine (1.1 equiv) in THF (0.71 M) was added
n-BuLi (1.1 equiv) at 0 °C. The resulting solution was stirred
for 5 min at 0 °C and transferred via cannula to a precooled
(-78 °C) solution of the lactam 1 (1.0 equiv) in THF (0.28 M).
The resulting solution was stirred 1 h at -78 °C, at which
time a solution of the olefinic halide (1.2 equiv) in THF (1.5
M) was added dropwise. The reaction mixture was stirred for
2 h at -78 °C and warmed to room temperature, and saturated
NH4Cl was added. The mixture was extracted with diethyl
ether (4 × 25 mL), and the combined organic layers were
washed with brine (25 mL) and dried over anhydrous magne-
sium sulfate. Flash chromatography (silica gel, hexanes/
EtOAc) provided the monoalkylated lactam that was used
immediately in the second alkylation step.
135.6, 135.6, 139.1, 143.1, 181.3. Anal. Calcd for C43H59
NSi2O4: C, 72.73; H, 8.37; N, 1.97. Found: C, 72.83; H, 8.46;
N, 1.85.
-
La cta m 2e from tert-butylsiloxyethalyl iodide, followed by
allyl bromide. Flash chromatography (silica gel, hexanes/ethyl
acetate, 20:1) afforded 1.28 g (83% after both alkylations) of
2e as a colorless oil: [R]D +20° (c, 1.39, CHCl3); IR (NaCl) ν
1
2930, 1713, 1640 cm-1; H NMR (300 MHz, CDCl3) δ 0.03 (s,
6H), 0.86 (s, 9H), 1.03 (d, J ) 6.6 Hz, 3H), 1.41 (s, 3H), 1.62
(m, 1H), 2.07-2.26 (m, 6H), 2.33 (dd, J ) 8.8, 13.2 Hz, 1H),
2.44 (d, J ) 13.2 Hz, 1H), 3.56 (m, 1H), 3.59 (dd, J ) 6.6, 10.2
Hz, 1H), 3.68 (m, 3H), 4.12 (t, J ) 8.0 Hz, 1H), 4.85 (s, 1H),
4.96 (s, 1H), 5.06 (m, 2H), 5.64 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ -5.3, 18.3, 19.1, 20.9, 25.1, 25.9, 34.4, 39.7, 40.3, 43.4,
50.9, 62.1, 62.6, 70.1, 96.9, 116.1, 118.7, 133.7, 143.2, 183.5.
La cta m 2f from allyl bromide, followed by 5-iodo-1-pentene.
Flash chromatography (silica gel, hexanes/ethyl acetate, 15:
1) afforded 118 mg (50% after both alkylations) of a diaster-
eomeric mixture (2:1) of 2f as a colorless oil: (major diaste-
reomer) 1H NMR (300 MHz, CDCl3) δ 0.84 (d, J ) 7.1 Hz, 3H),
1.39-1.48 (m, 3H), 1.59 (s, 3H), 1.66-2.07 (m, 8H), 2.47 (ddt,
J ) 5.7, 13.2, 1.2 Hz, 1H), 4.77 (m, 1H), 4.87-5.09 (m, 5H),
5.58-5.82 (m, 2H), 7.21-7.34 (m, 5H).
(B) Secon d Alk yla tion Step . The previous procedure was
used except that a different olefinic halide was employed.
La cta m 2a from methallyl chloride, followed by allyl
bromide. Flash chromatography (silica gel, hexanes/ethyl
acetate, 20:1) afforded 229 mg (51% after both alkylations) of
a diastereomeric mixture (6:1) of 2a as a colorless oil. Major
diastereomer: IR (NaCl) ν 2958, 1711, 1317 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 0.94 (s, 9H), 1.45 (s, 3H), 1.76 (m, 3H),
2.09 and 2.25 (Abq, J gem ) 14.1 Hz, 2H), 2.15-2.41 (m, 4H),
3.69 (dd, J ) 4.5, 9.3 Hz, 1H), 3.81 (dd, J ) 9.9, 3 Hz, 1H),
4.07 (dd, J ) 8.1, 9 Hz, 1H), 4.76 (m, 1H), 4.91 (m, 1H), 5.02-
5.10 (m, 2H), 5.57-5.71 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
23.5, 25.7, 27.3, 33.0, 42.1, 42.8, 46.5, 50.8, 66.2, 66.9, 97.3,
115.8, 118.8, 133.9, 142.2, 185.2; mass spectrum (FAB), m/z
(rel intensity) 292 (M + 1, 100), 291 (M+, 14), 276 (6), 234 (11);
HRMS, calcd for C18H29NO2 + 1 292.2198, found 292.2268.
La cta m 2b from 4-iodo-1-butene, followed by allyl bromide.
Flash chromatography (silica gel, hexanes/ethyl acetate, 25:
La cta m s 2g and 2h from 5-iodopentene, followed by allyl
bromide. Flash chromatography (silica gel, hexanes/ethyl
acetate, 25:1) afforded 177 mg (38% after both alkylations) of
2g and 73 mg (15%) of 2h as colorless oils. 2g: [R]D ) +95° (c,
1.10); IR (NaCl) ν 2939, 1644, 1380 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.41-1.45 (m, 1H), 1.49 (s, 3H), 1.69-1.89 (m, 3H),
1.99-2.11 (m, 3H), 2.30 (dd, J ) 7.3, 13.9 Hz, 1H), 2.51 (dd, J
) 7.3, 13.9 Hz, 1H) 3.90 (t, J ) 8.8 Hz, 1H), 4.49 (t, J ) 8.8
Hz, 1H), 4.95-5.12 (m, 4H), 5.35 (t, J ) 8.8 Hz, 1H) 5.72-
5.88 (m, 2H), 7.17-7.34 (m, 5H), 13C NMR (75 MHz, CDCl3) δ
23.6, 26.2, 32.9, 33.9, 39.1, 43.6, 45.2, 59.2, 69.9, 93.9, 114.6,
118.1, 125.3, 127.1, 128.6, 134.5, 138.4, 140.1, 174.1; mass
spectrum (EI), m/z (rel intensity) 339 (M+, 9.7), 324 (26.9), 298
(48.8), 271 (100); HRMS, calcd for C22H29NO2 339.2198, found
(9) Barton, P. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans.
1 1975, 1574.

Formal Synthesis of Zizaene
J . Org. Chem., Vol. 66, No. 16, 2001 5549
339.2186. 2h : IR (NaCl) ν 2941, 1645, 1388 cm-1
;
1H NMR
dd, J ) 2.2, 16.1 Hz, 1H), 3.05 (m, 1H), 3.66 (m, 1H), 3.68 (t,
J ) 6.8 Hz, 2H), 4.12 (t, J ) 8 Hz, 1H), 3.81 (dd, J ) 6.6, 8.8
Hz, 1H), 4.20 (dd, J ) 7.3, 8.8 Hz, 1H), 5.31 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ -5.2, 18.3, 19.0, 20.6, 25.9, 34.1, 43.7, 46.4,
49.5, 51.2, 61.3, 61.9, 70.9, 96.8, 116.1, 123.4, 138.0, 182.9.
Sp ir o La cta m 3f. Lactam 2f (112 mg, 0.317 mmol) was
treated with Cl2(PCy3)2RhCHPh (13.1 mg, 0.0159 mmol) in 1,2-
dichlororethane (45 mL) according to method A. Flash chro-
matography (silica gel, hexanes/ethyl acetate, 20:1) furnished
85 mg (82%) of 3f as a colorless solid: mp ) 139.5-141 °C
(300 MHz, CDCl3) δ 1.30-1.42 (m, 1H), 1.46 (s, 3H), 1.51-
1.63 (m, 2H), 1.72-1.86 (m, 3H), 1.94-2.15 (m, 5H), 2.53 (dd,
J ) 5.8, 13.2 Hz, 1H), 3.90 (t, J ) 8.8 Hz, 1H), 4.48 (t, J ) 8.8
Hz, 1H), 4.93-5.21 (m, 4H), 5.31 (t, J ) 8.1 Hz, 1H) 5.71-
5.86 (m, 2H), 7.18-7.34 (m, 5H); mass spectrum (EI), m/z (rel
intensity) 339 (M+, 10.7), 324 (34.0), 298 (34.3), 271 (100);
HRMS, calcd for C22H29NO2 339.2198, found 339.2192.
Sp ir o La cta m 3a . Lactam 2a (96 mg, 0.33 mmol) was
treated with Cl2(PCy3)2RhCHPh (14 mg, 0.017 mmol) in 1,2-
dichloroethane (47 mL) according to method B. Flash chro-
matography (silica gel, hexanes/ethyl acetate, 20:1) furnished
79 mg (91%) of 3a as a colorless oil: IR (NaCl) ν 2953, 1714,
1338 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.96 (s, 9H), 1.53 (s,
1
(hexanes); H NMR (300 MHz, CDCl3) δ 0.85 (d, J ) 7.3 Hz,
3H), 1.34-1.48 (m, 2H), 1.63 (s, 3H), 1.65-2.27 (m, 7H), 2.82
(m, 1H), 4.72 (dd, J ) 5.7, 7.5 Hz, 1H), 5.02 (dd, J ) 6.9, 6.3
Hz, 1H), 5.57 (m, 1H), 5.87 (m, 1H), 7.21-7.33 (m, 5H). Anal.
Calcd for C21H27NO2: C, 77.50; H, 8.36; N, 4.30. Found: C,
77.66; H, 8.30; N, 4.29.
3H), 1.69 (m, 3H), 2.16 (m, 1H), 2.18 and 2.34 (Abq, J gem
)
12.9 Hz, 2H), 2.44 (m, 1H), 2.71 (m, 1H), 3.05 (m, 1H), 3.70
(dd, J ) 8.1, 9.3 Hz, 1H), 3.92 (dd, J ) 9, 9.3 Hz, 1H), 4.17
(dd, J ) 8.1, 9.3 Hz, 1H), 5.27 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 16.2, 25.8, 27.1, 33.0, 43.2, 50.6, 51.7, 53.6, 64.7, 68.0,
97.2, 123.1, 118.8, 136.3,184.4; mass spectrum (FAB), m/z (rel
intensity) 264 (M + 1, 100), 248 (4.7), 206 (5); HRMS, calcd
for C16H25NO2 + 1 264.1885, found 264.1968.
Sp ir o La cta m 3g. Lactam 2g (51.5 mg, 0.158 mmol) was
treated with Cl2(PCy3)2RhCHPh (8.9 mg, 0.0108 mmol) ac-
cording to method A. Flash chromatography (silica gel, hex-
anes/ethyl acetate, 9:1) furnished 44.5 mg (95%) of 3g as a
colorless oil: [R]D +154° (c, 1.11, CHCl3); IR (NaCl) ν 2928,
1
1641, 1386 cm-1; H NMR (300 MHz, CDCl3) δ 1.43 (s, 3H),
Sp ir o La cta m 3b. Lactam 2b (112 mg, 0.384 mmol) was
treated with Cl2(PCy3)2RhCHPh (15.8 mg, 0.0192 mmol) in 1,2-
dichloroethane (55 m) according to method A. Flash chroma-
tography (silica gel, hexanes/ethyl acetate, 25:1) furnished 98
mg (97%) of 3b as a colorless solid: mp ) 79.5-80 °C
(hexanes); [R]D +117 (c, 0.54, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 0.96 (s, 9H), 1.52 (s, 3H), 1.69-1.93 (m, 3H), 2.01
and 2.25 (Abq, J gem ) 13.8 Hz, 2H), 2.17 (m, 2H), 2.56 (m, 1H),
3.71 (dd, J ) 8.1, 9.3 Hz, 1H), 3.88 (dd, J ) 9, 9.3 Hz, 1H),
4.14 (dd, J ) 8.1, 9 Hz, 1H), 5.67 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 22.1, 26.2, 27.1, 30.4, 32.8, 34.3, 46.2, 46.3, 65.3, 67.4,
97.0, 124.8, 125.5, 185.3. Anal. Calcd for C16H25NO2: C, 72.97;
H, 9.57; N, 5.32. Found: C, 72.90; H, 9.58; N, 5.36.
Sp ir o La cta m 3c. Lactam 2c (119 mg, 0.390 mmol) was
treated with Cl2(PCy3)2RhCHPh (16.0 mg, 0.0194 mmol) in 1,2-
dichloroethane (56 mL) according to method A. Flash chro-
matography (silica gel, hexanes/ethyl acetate, 20:1) furnished
97 mg (90%) of 3c as a colorless solid: mp ) 100-101 °C
(hexanes); [R]D +195 (c, 1.12, CHCl3); IR (NaCl) ν 2929, 1710,
1322 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.95 (s, 9H), 1.47 (s,
3H), 1.43 (m, 1H), 1.47 (s, 3H), 1.72 (m, 1H), 1.95-2.05 (m,
4H), 2.13-2.23 (m, 3H), 2.56 (m, 1H), 3.69 (dd, J ) 8.1, 9.3
Hz, 1H), 3.86 (dd, J ) 9, 9.3 Hz, 1H), 4.26 (dd, J ) 8.1, 9.3
Hz, 1H), 5.63 (m, 1H), 5.88 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 21.6, 26.2, 27.2, 28.3, 32.9, 35.9, 40.2, 44.6, 49.0, 65.6, 67.5,
97.4, 127.6, 133.8, 186.3. Anal. Calcd for C17H27NO2: C, 73.60;
H, 9.81; N, 5.05. Found: C, 73.51; H, 9.81; N, 5.06.
1.51-1.89 (m, 4H), 2.05 (m, 1H), 2.12-2.35 (m, 6H), 2.74 (d(br),
J ) 15.4 Hz, 1H), 3.94 (dd, J ) 8.1, 8.8 Hz, 1H), 4.52 (t, J )
8.8 Hz, 1H), 5.36 (t, J ) 8.1 Hz, 1H), 5.60 (m, 1H), 5.94 (m,
1H), 7.12-7.36 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 20.6,
23.2, 26.5, 28.9, 32.1, 34.1, 42.9, 58.4, 69.7, 93.7, 125.1, 126.9,
127.7, 128.5, 133.8, 140.2, 176.2; mass spectrum (EI), m/z (rel
intensity) 311 (M+, 83), 244 (100), 231 (21), 91 (52); HRMS,
calcd for C20H25NO2 311.1885, found 311.1876.
Sp ir o La cta m 3h . Lactam 2h (44.9 mg, 0.132 mmol) was
treated with Cl2(PCy3)2RhCHPh (6.9 mg, 0.0083 mmol) ac-
cording to method A. Flash chromatography (silica gel, hex-
anes/ethyl acetate,9:1) furnished 39.0 mg (93%) of 3h as a
colorless oil: [R]D +27 (c, 1.47, CHCl3); IR (NaCl) ν 2928, 1641,
1
1386 cm-1; H NMR (300 MHz, CDCl3) δ 1.45 (s, 3H), 1.52-
1.78 (m, 4H), 1.89 (m, 1H), 2.01-2.28 (m, 6H), 2.90 (d(br), J
) 13.9 Hz, 1H), 3.95 (dd, J ) 8.1, 8.8 Hz, 1H), 4.52 (t, J ) 8.8
Hz, 1H), 5.36 (t, J ) 8.1 Hz, 1H), 5.66 (m, 1H), 5.92 (m, 1H),
7.12-7.36 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 20.8, 23.3,
26.0, 28.5, 32.3, 36.9, 42.6, 58.3, 69.7, 93.7, 125.3, 126.9, 128.5,
128.6, 133.9, 140.3, 176.2; mass spectrum (EI), m/z (rel
intensity) 311 (M+, 40), 244 (100), 231 (32), 120 (27); HRMS,
calcd for C20H25NO2 311.1885, found 311.1881.
Sp ir o La cta m 4. To a stirred solution of 3d (573 mg, 0.840
mmol) in CH2Cl2 (4.7 mL) was added [Cy3PIr(COD)Py]PF6
(34.0 mg, 0.042 mmol). A balloon of hydrogen with a needle
inlet was inserted through the rubber septum. Hydrogen was
bubbled through the solution for ∼5 min, and the reaction
mixture was stirred under a positive pressure of hydrogen for
16 h. The solvent was removed in vacuo, and the residue was
subjected to flash chromatography (silica gel, hexanes/ethyl
acetate, 6:1), affording 544 mg (95%) of 4 as a pale yellow oil:
Sp ir o La cta m 3d . Lactam 2d (671 mg, 0.945 mmol) was
treated with Cl2(PCy3)2RhCHPh (39.0 mg, 0.0473 mmol) in 1,2-
dichloroethane (100 mL) according to method B. Flash chro-
matography (silica gel, hexanes/ethyl acetate, 20:1) furnished
573 mg (89%) of 3d as a pale yellow oil: [R]D +31.3 (c, 1.95,
1
[R]D +22.2 (c, 0.86, CHCl3); IR (NaCl) ν 1714, 1113 cm-1; H
CHCl3); IR (NaCl) ν 1713, 1107 cm-1
;
1H NMR (300 MHz,
NMR (300 MHz, CDCl3) δ 0.06 (s, 6H), 0.91 (s, 9H), 1.09 (s,
9H), 1.27-1.42 (m, 2H), 1.62 (m, 2H), 1.72 (m, 1H), 2.00-2.40
(m, 6H), 3.64 (m, 2H), 3.81 (dd, J ) 12.3, 5.1 Hz, 1H), 3.98 (m,
2H), 5.20 (d, J ) 5.7 Hz, 1H), 5.36 (dd, J ) 5.7, 2.7 Hz, 1H),
7.22-7.46 (m, 11H), 7.66 (m, 4H); 13C NMR (75 MHz, CDCl3)
δ -5.3, 18.3, 19.3, 26.0, 26.9, 32.8, 36.5, 38.1, 39.4, 41.8, 46.2,
52.8, 62.5, 63.5, 64.0, 126.4, 127.7, 127.8, 128.3, 128.6, 129.8,
CDCl3) δ 0.07 (s, 6H), 0.91 (s, 9H), 1.10 (s, 9H), 2.23 (dd, J )
14.1, 3 Hz, 1H), 2.31-2.42 (m, 4H), 2.50 (dd, J ) 13.8, 5.7 Hz,
1H), 2.86 (m, 1H), 3.08 (m, 1H), 3.74 (m, 2H), 3.82 (m, 1H),
4.00 (m, 2H), 5.24 (d, J ) 6.3 Hz, 2H), 5.36 (m, 1H), 5.41 (dd,
J ) 5.7, 2.7 Hz, 1H), 7.23-7.46 (m, 11H); 13C NMR (75 MHz,
CDCl3) δ -5.3, 18.3, 19.2, 25.9, 26.9, 34.3, 43.2, 45.0, 49.1, 52.6,
61.9, 63.3, 63.8, 82.9, 90.5, 123.1, 126.4, 127.8, 127.8, 128.3,
128.6, 129.8, 133.0, 133.1, 135.6, 138.6, 139.1, 182.8; mass
spectrum (FAB), m/z (rel intensity) 682 (M + 1, 24), 624 (100),
604 (75); HRMS, calcd for C41H55Si2NO4 + 1 682.3670, found
682.3765.
129.9, 135.6, 135.6, 139.2, 176.2; HRMS, calcd for C41H57
NSi2O4 684.3826, found 684.3911.
-
Diol 5. To a stirred solution of 4 (695 mg, 1.02 mmol) in
THF (5 mL) at 0 °C was added a 1.0 M solution of tetrabuty-
lammonium fluoride in THF (2.55 mmol). The reaction mixture
was slowly warmed to room temperature and stirred for 3 h.
Water was added, and the mixture was extracted with EtOAc
(3 × 25 mL). The combined organic layers were washed with
brine and dried over anhydrous magnesium sulfate. Flash
chromatography (silica gel, ethyl acetate) afforded 294 mg
(87%) of 5 as a colorless solid: mp ) 106.5-108 °C (hexanes,
ethyl acetate); [R]D +51.6 (c, 0.73, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.36 (m, 2H), 1.67 (m, 3H), 2.00-2.44 (m, 6H), 2.56
(bs, 2H), 3.64 (t, J ) 6.6 Hz, 2H), 3.70 (m, 1H), 3.84 (dd, J )
Sp ir o La cta m 3e. Lactam 2e (244 mg, 1.57 mmol) was
treated with Cl2(PCy3)2RhCHPh (51.2 mg, 0.0622 mmol) in
toluene (100 mL) according to method C. Flash chromatogra-
phy (silica gel, hexanes/ethyl acetate, 20:1) furnished 223 mg
(94%) of 3e as a colorless oil: [R]D +65 (c, 1.67, CHCl3); IR
(NaCl) ν 2929, 1714, 1359 cm-1; 1H NMR (300 MHz, CDCl3) δ
0.05 (s, 3H), 0.89 (s, 9H), 1.04 (d, J ) 6.6 Hz, 3H), 1.50 (s,
3H), 1.66 (m, 1H), 2.13-2.32 (m, 4H), 2.15 (d, J ) 13.2, 1H),
2.29 (d, J ) 13.2, 1H), 2.46 (br d, J ) 16.1 Hz, 1H), 2.76 (br

5550 J . Org. Chem., Vol. 66, No. 16, 2001
Hughes et al.
4.8, 15 Hz, 2H), 4.92 (d, J ) 6.9 Hz, 1H), 5.32 (m, 1H), 7.33
(m, 5H); 13C NMR (75 MHz, CDCl3) δ 32.7, 36.5, 37.6, 38.8,
42.0, 46.0, 53.2, 62.0, 62.3, 65.0, 83.2, 83.2, 90.0, 126.4, 128.6,
128.7, 138.1, 185.0. Anal. Calcd for C19H25NO4: C, 68.86; H,
7.60; N, 4.23. Found: C, 68.83; H, 7.62; N, 4.21. This sample
was submitted for single-crystal X-ray determination. Data
may be found in the Supporting Information.
13C NMR (75 MHz, CDCl3) δ 21.1, 21.5, 28.7, 31.9, 33.3, 34.1,
34.5, 45.3, 54.1, 54.9, 59.2, 60.7, 127.5, 128.0, 128.5, 128.9,
133.5.
2-(ter t-Bu tylsiloxyeth yl)a llyl Iod id e. To a solution of
methyl itaconate (4.24 g, 26.8 mmol) in THF (250 mL) cooled
to -78 °C was added neat DIBAL-H (21.0 mL, 117 mmol)
dropwise over 15 min. The mixture was stirred for 30 min at
-78 °C and then warmed to room temperature. After 1 h the
reaction mixture was cooled to 0 °C and water (15 mL) was
added (caution!) slowly over 30 min. The reaction mixture
slowly gelled. Aqueous NaOH (15 mL, 2.0 M) was added over
30 min followed by an additional 30 mL of water. After 3 h,
solid Na2SO4 was added (∼40 g) and the mixture was stirred
for 12 h. The solids were filtered away and the filter cake
washed with THF (300 mL). The solvent was removed to afford
a yellow oil that was subjected to flash chromatography
(hexanes/ethyl acetate, 4:1) to furnish 2.50 g (91%) of 2-me-
thylenebutane-1,4-diol as a yellow oil that was used in the next
step without further purification. Dimethyl sulfide was added
(3.0 mL, 40.7 mmol) to a white suspension of N-chlorosuccin-
imide (5.03 g, 37.7 mmol) in dichloromethane (100 mL) and
cooled to 0 °C. The resulting milky suspension was stirred for
10 min, and a solution of 2-methylenebutane-1,4-diol (2.50 g,
24.5 mmol) in dichloromethane (10 mL) was added. After 30
min the mixture turned homogeneous, and then the mixture
was stirred for 12 h and tert-butyldimethylsilyl chloride (4.60
g, 30.5 mmol) and imidazole (3.23 g, 47.4 mmol) were added.
The mixture was stirred for an additional 12 h, and the
reaction was quenched with aqueous bicarbonate (50 mL). The
layers were separated, and the dichloromethane layer was
washed with water (3 × 20 mL). The combined aqueous
washings were extracted with dichloromethane (2 × 15 mL),
and the organic layer was dried over anhydrous magnesium
sulfate. The solvent was removed in vacuo, and the crude
material was subjected to flash chromatography (hexanes) to
afford 4.42 g (77%) of a clear oil that was added to a suspension
of K2CO3 (5.24 g, 37.9 mmol) and NaI (5.18 g, 34.5 mmol) in
acetone (25 mL). This mixture was stirred in the dark for 24
h at ambient temperature. The mixture was then diluted with
water (900 mL) and the product extracted with hexanes (3 ×
200 mL). The combined organic layers were washed with brine
(150 mL) and dried over anhydrous magnesium sulfate. The
solvent was removed to furnish 2.47 g (97%) of a light yellow
unstable oil that was immediately used without further
purification: 1H NMR (300 MHz, CDCl3) δ 0.06 (s, 6H), 0.89
(s, 9H), 2.44 (t, J ) 6.6 Hz, 2H), 3.76 (t, J ) 6. Hz, 2H), 3.97
(s, 2H), 4.94 (d, J ) 1.1 Hz, 1H), 5.27 (s, 1H).
Sp ir o La cta m 9. To a solution of spirocyclo lactam 3e (1.09
g, 2.74 mmol) in dichloromethane (25 mL) was added [PCy3-
Ir(COD)Py]PF6 (18.4 mg). The solution was then placed under
an atmosphere of hydrogen (balloon) and stirred at ambient
temperature. After stirring at room temperature for 36 h, the
solvent was removed, and flash chromatography (silica gel,
hexanes/ethyl acetate, 4:1) afforded 1.04 g (96%) of spirocyclo
lactam 9 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.03
(s, 6H), 0.87 (d, J ) 6.6, 3H), 0.88 (s, 9H), 1.02 (d, J ) 6.6,
3H), 1.21 (m, 1H), 1.37 (dd, J ) 8.8, 12.5, 1H), 1.47 (s, 3H),
1.50-1.71 (m, 4H),1.96 (m, 1H), 2.13-2.32 (m, 5H), 3.51-3.63
(m, 3H), 3.80 (dd, J ) 7.3, 8.8, 1H), 4.16 (dd, J ) 8.0, 8.8, 1H);
13C NMR (75 MHz, CDCl3) δ -5.2, 19.1, 20.7, 25.5, 26.0, 32.7,
33.9, 36.3, 37.1, 39.1, 46.8, 50.5, 53.9, 61.4, 62.6, 70.8, 96.8,
183.8; IR (neat) 2930, 1714, 1471, 1352, 1254, 1101, 1030, 899,
836, 775, 662 cm-1; [R]D +44 (c, 1.41, CHCl3).
Sp ir ocyclop en ten on e 10. A solution of lactam 9 (239 mg,
0.60 mmol) in THF (6 mL) was cooled to 0 °C, and Red-Al was
added (0.3 mL, 1.0 mmol). The resulting mixture was stirred
for 1 h at 0 °C and then quenched with MeOH (0.8 mL). The
reaction mixture was concentrated in vacuo, the residue was
dissolved in EtOH (4 mL), and Bu4NH2PO4 (3 mmol) and water
(3 mL) were added. The mixture was stirred at room temper-
ature for 17 h and then heated at a gentle reflux for 5 h. The
mixture was diluted with water and extracted with ethyl ether.
The solvents were removed in vacuo, and the residue was
dissolved in EtOH (3 mL) and treated with 1 M NaOH (10
drops). The resulting solution was stirred at room temperature
Sp ir ocyclop en ten on e 6. To a stirred solution of spiro
lactam 3c (41.3 mg, 0.0148 mmol) in THF (1.0 mL) at 0 °C
was added Red-Al (0.4 mL, 3.3 M). After stirring for 3 h at 0
°C, the reaction was quenched with methanol (0.5 mL) and
stirred for 1 h. The resulting mixture was partitioned between
diethyl ether and water. The organic layer was concentrated
in vacuo, the residue was dissolved in ethanol (2 mL), and Bu4-
NH2PO4 (2.0 mL, 1 M) was added. After stirring at room
temperature for 24 h, the reaction mixture was diluted with
diethyl ether (75 mL) and washed with water (3 × 20 mL).
Diethyl ether was removed in vacuo, the crude keto aldehyde
was dissolved in ethanol (3.5 mL), and aqueous potassium
hydroxide (0.2 mL, 1 M) was added. The reaction mixture was
stirred at room temperature for 16 h and diluted with diethyl
ether (75 mL). The solution was washed with water (3 × 10
mL) and brine and dried over anhydrous magnesium sulfate.
Flash chromatography (silica gel, hexanes/ethyl acetate 19:1)
afforded 18.1 mg (75%) of 6 as a colorless oil: 1H NMR (300
MHz, CDCl3) δ 1.65 (m, 3H), 1.96 (m, 1H), 2.12-2.26 (m, 6H),
5.69 (m, 1H), 5.78 (m, 1H), 6.08 (d, J ) 5.1 Hz, 1H), 5.57 (d, J
) 5.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.1, 32.1, 36.1,
43.7, 47.7, 124.7, 126.9, 132.0, 149.7, 171.8; mass spectrum
(EI), m/z (rel intensity) 148 (M+, 49), 94 (53), 66 (100).
Sp ir ocycloh exen on e 7. To a stirred solution of 3f (35.0
mg, 0.108 mmol) at 0 °C was added Red-Al (0.216 mmol, 3.4
M). The reaction mixture was warmed to room temperature
and stirred for 15 h, at which time it was quenched by cautious
addition of methanol (0.5 mL). The mixture was diluted with
water (10 mL) and extracted with diethyl ether (3 × 25 mL).
The ethereal solution was dried over anhydrous magnesium
sulfate. After removing diethyl ether in vacuo, the residue was
dissolved in ethanol (2.2 mL) and 1.0 M Bu4NH2PO4 (2.2 mL)
and the mixture was heated at reflux with stirring for 16 h.
The contents were cooled to room temperature, and diethyl
ether was added until a biphasic mixture was observed. The
biphasic mixture was stirred vigorously for 1 h, and the layers
were separated. The aqueous layer was extracted with diethyl
ether (3 × 20 mL), and the combined organic layers were
washed with brine and dried over anhydrous magnesium
sulfate. Flash chromatography (silica gel, hexanes/ethyl ac-
etate, 10:1) furnished 15.3 mg (81%) of 7 as a colorless oil: IR
(NaCl) ν 2921, 1680, 1445 cm-1; 1H NMR (300 MHz, CDCl3) δ
1.53-1.63 (m, 2H), 1.80 (dd, J ) 5.1, 6.6 Hz, 2H), 1.89 (dd, J
) 6.6, 13.9 Hz, 2H), 2.14-2.34 (m, 4H), 2.40 (t, J ) 6.6 Hz,
2H), 5.62 (m, 1H), 5.86 (d, J ) 10.2 Hz, 1H), 5.94 (m, 1H),
6.83 (d, J ) 10.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.2,
28.6, 34.7, 34.3, 36.8, 37.2, 42.3, 126.6, 126.8, 134.2, 158.5,
200.4; mass spectrum (EI), m/z (rel intensity) 176 (M+, 68),
109 (71), 91 (77), 79 (100); HRMS, calcd for C12H16O 176.1201,
found 176.1203.
Sp ir o P ip er id in e 8. To a cooled (-78 °C) solution of 3g
(18.3 mg, 0.062 mmol) in THF (4 mL) was added DIBAL-H
(0.5 mL, 1.5 M/toluene). The resulting solution was stirred at
-78 °C for 1 h and then warmed to room temperature and
stirred for an additional 2 h. The reaction mixture was
quenched with aqueous NaOH (1.5 mL, 2 M) and stirred for 3
h. Water was added (40 mL), and the mixture was extracted
with diethyl ether (3 × 20 mL). The combined organic layers
were concentrated in vacuo and dried over anhydrous mag-
nesium sulfate. Flash chromatography (silica gel, hexanes/
ethyl acetate 4:1) furnished 16.0 mg (87%) of 8 as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 0.81 (m, 1H), 1.30 (d, J )
6.6 Hz, 3H), 1.35-1.51 (m, 5H), 1.60 (m, 1H), 2.10 (m, 2H),
2.27 (t, J ) 6.6 Hz, 2H), 2.36 (m, 1H), 2.69 (dd, J ) 2.2, 11.7
Hz, 1H), 3.32 (d, J ) 10.2 Hz, 1H), 3.53 (dt, J ) 5.1, 10.2 Hz,
1H), 3.69 (t, J ) 10.2 Hz, 1H), 4.30 (dd, J ) 5.1, 10.2 Hz, 1H),
5.72 (m, 1H), 5.92 (m, 1H), 7.14 (m, 2H), 7.28-7.37 (m, 3H);

Formal Synthesis of Zizaene
J . Org. Chem., Vol. 66, No. 16, 2001 5551
for 24 h. The solvent was removed in vacuo, and the crude
material was partitioned between ethyl ether and water. The
aqueous layer was extracted with ethyl ether, and the com-
bined organics were washed with brine and dried over anhy-
drous magnesium sulfate. Flash chromatography furnished
147 mg (83%) of 10 as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.39 (m, 2H), 1.6 (dd, J )
6.6, 13.9, 2H), 1.70 (m, 2H), 2.01 (m, 2H), 2.21 (m, 1H), 2.34
(d, J ) 1.5, 2H), 3.61 (t, J ) 6.6, 2H), 5.99 (d, J ) 5.9, 1H),
7.49 (d, J ) 5.9, 1H); 13C NMR (75 MHz, CDCl3) δ -5.2, 18.4,
26.0, 32.6, 39.8, 39.3, 39,7, 45.0, 50.2, 62.2, 130.9, 171.9, 209.9;
IR (neat) 3420, 2926, 2739, 1713, 1681, 1586, 1471, 1446, 1407,
filtered though SiO2. The crude diethyl acetal was then taken
up in toluene (10 mL), and TsOH was added (19.2 mg). The
resulting solution was heated at reflux for 1.5 h. The solvent
was removed in vacuo and the residue purified on SiO2 to
afford 25.1 mg (61%) of the tricycle as a mixture of diastere-
omers that were used without further purification. Enone 15
(19 mg) was dissolved in THF (2 mL) at -78 °C, and DIBAL-H
(0.1 mL, 1.5 M) was added to the solution. The mixture was
stirred for 1 h at -78 °C and quenched by the addition of
methanol (0.5 mL). The mixture was warmed to room tem-
perature and the solvent removed in vacuo. The residue was
partitioned between ethyl ether and 1 M NaOH and purified
on SiO2 to furnish 11.9 mg (62%) of a colorless oil as a mixture
of diastereomers that were immediately dissolved in CH2Cl2
(2 mL). MCPBA (40.2 mg) was added to the solution and
stirred at room temperature for 24 h. The reaction was
quenched by adding sodium thiosulfate (3 mL, 5%) and diluted
with water (20 mL). The aqueous solution was extracted with
ethyl ether, and the combined organic layers were washed with
1 M NaOH and brine and dried over anhydrous magnesium
sulfate. The crude diastereomeric epoxides were dissolved in
CH2Cl2 (1 mL), and thiocarbonyl diimidazole (10.2 mg), fol-
lowed by 4,4-dimethylamino pyridine (3.0 mg), was added.
After 24 h the reaction mixture was filtered through SiO2 and
purified to afford 8.0 mg (84%) of the diastereomeric xanthate
esters: 1H NMR (300 MHz, CDCl3) δ 1.11 (d, J ) 7.3 Hz), 1.14
(d, J ) 7.3 Hz), 1.22-2.2 (m), 2.4 (m), 2.7 (m), 3.26 (m), 3.30
(m), 5.87 (t, J ) 5.8), 6.09 (dd, J ) 3.6, 8.8), 7.02 (s), 7.61 (m),
8.34 (m).
Tr icycle 21. A mixture of xanthate ester 18 (8.0 mg), Bu3-
SnH (25 µL), and AIBN (1 mg) in benzene (3 mL) was heated
to reflux for 4 h. The mixture was cooled, and 3 M NH4OH (5
mL) was added. The resulting mixture was stirred at room
temperature for 3 h, extracted with ethyl ether, washed with
brine, and dried over anhydrous magnesium sulfate. The
solution was filtered through a plug of SiO2 to afford 3 mg
(64%) of 19 as a colorless solid. The alcohol was taken up in
CH2Cl2, and a mixture of PDC (30 mg) and Celite (30 mg) was
added. The resulting mixture was stirred for 14 h, filtered
through SiO2, and purified to afford 1.5 mg (67%) of enone 20
that was dissolved in EtOH (1.5 mL), and Pd-C (5.2 mg, 10%)
was added. The mixture was placed under an atmosphere of
hydrogen (balloon). After 12 h, the reaction mixture was
filtered through Celite to afford, after solvent evaporation, 1
mg (66%) of the tricyclic ketone 21: 1H NMR (300 MHz, CDCl3)
δ 1.03 (d, J ) 7.3 Hz), 1.07-1.72 (m), 1.81 (m), 1.96 (m), 2.38
(d, J ) 8.1 Hz), 2.45 (d, J ) 8.1) which agreed with the
spectrum of previously prepared material; GC-MS 178 (M+),
136 (100).
1387, 1360, 1254, 1177, 1101, 1005, 939, 835, 775, 662 cm-1
;
[R]D +34 (c, 1.11, CHCl3).
Meth yl Sp ir ocyclop en ten e 11. A slurry of CuCN (290 g,
3.3 mmol) in THF (2 mL) was cooled to -78 °C, and MeLi was
added (4.5 mL, 1.4 M). This mixture was warmed to 0 °C for
15 min and then cooled back to -78 °C and stirred for 20 min.
Spirocyclopentenone 10 was then added, and the mixture was
stirred at -78 °C for 6 h and then warmed to room temper-
ature and stirred for 12 h. The reaction mixture was quenched
with NH4Cl and diluted with water. The aqueous solution was
extracted with ethyl ether, and the combined organic layers
were concentrated in vacuo. Flash chromatography afforded
184 mg (94%) of 11 as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.02 (d, J ) 7.4, 3H), 1.13-
1.38 (m, 2H), 1.50-1.70 (m, 4H), 1.80-2.20 (m, 6H), 2.24-
2.41 (m, 2H), 3.61 (t, J ) 6.6, 2H); 13C NMR (75 MHz, CDCl3)
δ -5.2, 15.0, 18.4, 26.0, 31.9, 32.5, 38.2, 39.2, 39.6, 39.9, 44.3,
218.7 IR (neat) 2928, 2857, 2738, 1746, 1471, 1405, 1386, 1360,
1255, 1160, 1098, 1006, 939, 836, 775, 662 cm-1; [R]D -2 (c,
1.13, CHCl3).
Hyd r oxy Sp ir ocyclop en ten e 12. To a solution of silyl
ether 11 (184 mg) was added tetrabutylammonium fluoride
(0.7 mmol) in THF (4.5 mL). After stirring at room tempera-
ture for 2 h, the solvent was removed in vacuo and the residue
purified on SiO2 to furnish 96.2 mg (83%): 1H NMR (300 MHz,
CDCl3) δ 0.99 (d, J ) 7.4, 3H), 1.13-1.38 (m, 2H), 1.50-1.70
(m, 4H), 1.80-2.20 (m, 6H), 2.24-2.41 (m, 2H), 3.60 (t, J )
6.6, 2H); 13C NMR (75 MHz, CDCl3) δ 14.9, 15.0, 31.9, 32.3,
36.0, 36.4, 38.1, 39.1, 39.4, 39.6, 44.2, 46.0, 49.7, 53.1, 61.2,
218.9, 219.0; IR (neat) 3417 (br), 2931, 2862, 1745, 1462, 1453,
1404, 1380, 1240, 1203, 1162, 1050 cm-1
.
Ald eh yd e 13. To a cooled (-78 °C) solution of DMSO (0.1
mL) in dichloromethane (5 mL) was added a solution of oxalyl
chloride (0.4 mL, 0.8 mmol). This mixture was stirred for 5
min, and alcohol 12 (0.1034 g) was added. After 20 min,
triethylamine (0.7 mL) was added and the resulting mixture
was stirred for 5 min at -78 °C and then warmed to ambient
temperature. The reaction mixture was diluted with ether (100
mL), washed with water (3 × 20 mL) and brine (20 mL), and
dried over anhyudrous magnesium sulfate. Flash chromatog-
raphy (silica gel, hexanes/ethyl acetate, 3:1) furnished 102.6
mg (99%) of aldehyde 13: 1H NMR (300 MHz, CDCl3) δ 1.03
(d, J ) 7.4, 3H), 1.17-1.43 (m, 3H), 1.57-1.75 (m, 2H), 1.83-
2.54 (m, 9H), 9.74 (t, J ) 1.5, 1H); 13C NMR (75 MHz, CDCl3)
δ 14.9, 15.1, 31.8, 32.2, 33.4, 33.8, 37.9, 39.1, 39.5, 43.8, 45.9,
50.5, 52.9, 53.4, 201.6, 218.2.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health. We are grateful to Profes-
sor R. M. Coates for supplying spectral data of inter-
mediate 21 in the described synthesis.
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
compounds including X-ray for diol 5. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Ep oxy Xa n th a te 18. A solution of aldehyde 13 (45 mg) and
TsOH (12.6 mg) in absolute ethanol (10 mL) was stirred for
24 h. The solvent was removed in vacuo, and the residue was
J O010439P