Stereoselective synthesis of carbocyclic ring systems by pinacol-terminated Prins cyclizations

Article abstract of DOI:10.1016/S0040-4020(02)00658-0

Studies that expand the scope of the Prins-pinacol synthesis of carbocyclic ring systems are described. The construction of cyclopentacyclooctanones by ring-enlarging cyclopentane annulations of cycloheptanone precursors is broadly examined as is the synthesis of related bicyclic ketones containing larger rings. Prins-pinacol reactions of acyclic alkenyl acetals were examined to gain insight into intrinsic stereochemical control elements in ring-enlarging cyclopentane annulations. The outcome of the carbocyclic constructions described in this report are rationalized by the mechanistic analysis we developed recently to describe Prins-pinacol constructions of tetrahydrofurans.

Full text of DOI:10.1016/S0040-4020(02)00658-0

Tetrahedron 58 (2002) 6473–6483
Stereoselective synthesis of carbocyclic ring systems
by pinacol-terminated Prins cyclizations
†
Timothy C. Gahman and Larry E. Overman
*
Department of Chemistry, 516 Rowland Hall, University of California, Irvine, CA 92697-2025, USA
Received 11 April 2002; accepted 2 May 2002
We are delighted to dedicate this paper to Yoshi Kishi on the occasion of his receipt of the 2002 Tetrahedron Prize
Abstract—Studies that expand the scope of the Prins-pinacol synthesis of carbocyclic ring systems are described. The construction of
cyclopentacyclooctanones by ring-enlarging cyclopentane annulations of cycloheptanone precursors is broadly examined as is the synthesis
of related bicyclic ketones containing larger rings. Prins-pinacol reactions of acyclic alkenyl acetals were examined to gain insight into
intrinsic stereochemical control elements in ring-enlarging cyclopentane annulations. The outcome of the carbocyclic constructions
described in this report are rationalized by the mechanistic analysis we developed recently to describe Prins-pinacol constructions of
tetrahydrofurans. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
selective syntheses of oxygen2,3 and sulfur4 heterocycles
and several carbocyclic ring systems have been reported.
The efficient construction of natural products and increas-
ingly complex pharmaceutical agents requires that new
methods for stereocontrolled construction of complex ring
systems be developed. Within this context, we have
described a suite of ring-forming processes that employ
pinacol rearrangements to terminate cationic cyclization
reactions.1 The general strategy is outlined in Scheme 1
wherein the two new C–C bonds formed in the process are
emboldened. Using this reaction design paradigm, stereo-
In the carbocyclic area, the most extensively developed
reaction is an unusual annulation in which a starting ketone
is ring-expanded by one carbon as it is fused in cis fashion to
a new 5- or 6-membered carbocyclic ring: 4!5!6 (Scheme
2).5a,c,d This method is particularly useful for assembling
angularly-fused ring systems, as in the stereoselective
transformation of 7!8, which was the central strategic
step in our inaugural total syntheses of Lycopodium
alkaloids of the magellanine family (Scheme 3).5d
We describe herein recent studies aimed at expanding the
scope of the Prins-pinacol synthesis of carbocyclic ring
systems. The construction of cyclopentacyclooctanones
from cycloheptanone precursors is broadly examined, as is
the synthesis of related bicyclic ketones containing larger
rings (9- and 13-membered). We show for the first time that
depending upon the size of the starting ring and the relative
Scheme 1.
Scheme 2.
Keywords: cyclization; Prins-pinacol reaction; dione; stereoelectronic effect.
*
Corresponding author. Tel.: þ1-949-824-7156; fax: þ1-949-824-3866; e-mail: leoverma@uci.edu
†
Present address: Trega Biosciences, Inc., 9880 Campus Point Dr., San Diego, CA 92121, USA.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00658-0

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T. C. Gahman, L. E. Overman / Tetrahedron 58 (2002) 6473–6483
Scheme 3.
configuration of the alkene and acetal side chains, pinacol-
terminated Prins cyclization reactions can give trans-
fused and inside–outside bicyclic carbocycles, as well as
cis-fused products of the type illustrated in Scheme 2.
add to 2-alkylcycloheptanones with high selectivity from
the face opposite the side chain,11 precedent that formed the
basis of the configuration assignment for 12 and other
cycloheptane alkenyl acetals. The related synthesis of the
other siloxy alkenyl acetals employed in this investigation is
summarized in Table 1.
2. Results
Ring-enlarging cyclopentane annulations of alkenyl acetals
were best accomplished by adding 1.1 equiv. of SnCl4 to
CH2Cl2 solutions of the alkenyl acetals at 2788C, followed
by allowing reactions to warm to ca. 2238C (typically over
10–15 min) prior to aqueous quenching. Results obtained
from reactions of a representative set of cycloheptane
alkenyl acetals under these conditions are summarized in
Scheme 5. Consistent with our previous experience,5
annulated products were produced as mixtures of methoxy
epimers. To simplify product isolation, these keto ethers
were not separated but directly oxidized with RuO412 to give
dione products. As was observed earlier with analogous
cyclopentane and cyclohexane precursors,5a,d the cis-fused
product of ring-enlarging cyclopentane annulation was
formed with high selectivity.13 Only in the reaction of 17
was .1% of a volatile byproduct (3% in this case) seen by
capillary GLC analysis of crude reaction products. When
the alkene was a weakly nucleophilic terminal vinyl group,
it was necessary to protect the tertiary alcohol with a robust
silyl substituent to prevent capture of the oxocarbenium ion
2.1. Ring-enlarging cyclopentane annulations
A representative series of 1-alkenyl-2-(2,2-dimethoxy-
ethyl)cycloalkanol silyl ethers was prepared from cyclo-
heptanone, cyclooctanone and cyclododecanone by the
general sequence illustrated in Scheme 4 for the synthesis of
cycloheptane derivative 12. Following prescriptions of
Stork,6 and Corey and Enders,7 dimethylhydrazone 108
was deprotonated with LDA at low temperature and
alkylated with bromoacetal 13 to provide cycloheptanone
acetal 11 after cleavage9 of the hydrazone. As a result of the
poor reactivity of 13, direct reaction of the lithium enolate
of cycloheptanone with this electrophile was inefficient.
Condensation of 11 with 1-lithiocyclohexene10 at 2788C in
THF proceeded with high diastereoselection to give a 15:1
mixture of epimeric alcohols. After silyl protection and
removal of the minor stereoisomer by flash chroma-
tography, alkenyl acetal 12 was isolated in 70% yield. We
had shown earlier that alkenyl organometallic nucleophiles
Scheme 4.
Table 1. Synthesis of alkenyl acetal cyclization precursors by the general sequence exemplified in Scheme 4
Starting ketone
a-(2,2-Dimethoxyethyl) derivative yield (%)a
Alkenyl organometallic addition
Reagent
dsb
Yield (%)c
Major productc
Cycloheptanone
11, 71
Cyclopentenyllithium
2-propenyllithium
(E)-2-Butenyllithium and CeCl3
Vinylmagnesium bromide
18:1
.20:1
20:1
15:1
15:1
20:1
73
74
64
71
61
67
14
17
18
21
22
25
Cyclooctanone
Cyclododecanone
3-Pentanone
52
65
67
2-Propenyllithium
See Scheme 7
2-Propenyllithium
5:3
28
47
35
38
a
Overall yield.
By capillary GLC analysis.
After silylation; overall yield for the two steps.
b
c

T. C. Gahman, L. E. Overman / Tetrahedron 58 (2002) 6473–6483
6475
Scheme 5.
by the proximal siloxy group to produce oxabicyclodecane
acetal 23. If the hydroxyl protecting group was TBDMS,
bicyclo[6.3.0]undecandione 24 was formed in 58% overall
yield from 22. The constitution and relative configuration of
24 was secured by single-crystal X-ray analysis, whereas
stereochemical assignments for the other bicyclo[6.3.0]-
undecandiones were made on the basis of 1H nOe studies.14
silylated to give 31. Consistent with ring-enlarging annula-
tions of smaller ring congeners having similar stereo-
chemistry (Schemes 5 and 6), Prins-pinacol reaction of 30
gave cis-bicyclo[11.3.0]hexadecandione 32 as the major
product (55% yield). In this case, a second crystalline
product, the unusual inside–outside bicyclic dione 33 was
also isolated in 13% yield. Identical treatment of epimeric
alkenyl acetal 31 produced neither 32 nor 33, but rather
trans-bicyclo[11.3.0]hexadecandione 34 (61% yield). These
results contrast markedly with the outcome of Prins-pinacol
reactions in the cyclohexane series5a where both propenyl
dimethyl acetal stereoisomers gave the same cis-fused
product of ring-enlarging cyclopentane annulation. Single
crystal X-ray analysis confirmed the structures of 32–34.
Bicyclo[7.3.0]dodecanediones can be prepared in similar
fashion. Thus, cyclooctane alkenyl acetal 25 was converted
under identical conditions to cis-bicyclo[7.3.0]dodecane-
dione 26 in 62% overall yield (Scheme 6). The cis
configuration of this dione product was confirmed by single
crystal X-ray diffraction analysis.
The capacity of this chemistry to prepare diones containing
large rings was explored in the cyclododecane series
(Scheme 7). Condensation of cyclododecanone acetal 27
with 2-propenyllithium at 2788C gave largely (dr¼20:1)
one crystalline alcohol 28, whose configuration was
established by single-crystal X-ray analysis. Silylation of
this product provided 30. Epimeric siloxy alkenyl acetal 31
could be obtained by carrying out this condensation reaction
at 08C. The minor alcohol product 29 of this less selective
process was separated by flash chromatography and
2.2. Conversion of acyclic 5-alkenyl acetals to
cyclopentanyl ketones
In order to gain insight into intrinsic stereochemical control
elements in ring-enlarging cyclopentane annulations, we
examined related Prins-pinacol reactions of acyclic alkenyl
acetals (Scheme 8). Using chemistry identical to that
described in Scheme 4, 3-pentanone was elaborated to the
5-hexenyl acetal stereoisomers 35 and 38, which could be
separated by preparative HPLC. To allow their relative
1
configurations to be established by H NMR nOe experi-
ments, these epimers were converted to lactones 36 and 40
by the routine sequences summarized in Scheme 8. Lactone
1
36 showed diagnostic reciprocal H NMR nOe enhance-
ments between the C3-Me and the i-Pr methine hydrogen
and between the C3-H and methylene hydrogens of the
Et substituent, whereas lactone 40 showed diagnostic
Scheme 6.

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T. C. Gahman, L. E. Overman / Tetrahedron 58 (2002) 6473–6483
Scheme 7.
1
reciprocal H nOe enhancements between the C3-Me and
methylene hydrogens of the Et substituent. When exposed
to 1.1 equiv. of SnCl4 (278!2238C, CH2Cl2) followed by
oxidative cleavage of the resulting mixture of methyl ethers,
35 and 38 were converted respectively to the stereoisomeric
propanoyl cyclopentanones 37 and 39. Crossover in these
reactions was less than 1% as determined by capillary GLC
analysis. The relative configuration of these epimeric
diketone products was secured as follows. Reduction of
dione 39 with 1 equiv. of K[(sec-Bu)3BH] provided a 3:1
mixture of alcohol products, which could be resolved by
preparative HPLC to provide the major isomer in 49% yield.
Condensation of this alcohol epimer with phenyl isocyanate
provided X-ray quality crystals of carbamate 41.
this report can be rationalized by the mechanistic analysis
we developed recently to describe Prins-pinacol construc-
tions of tetrahydrofurans.2g As the alkene substituents of the
cyclization substrates reported here, with but one exception,
contained electron-releasing alkyl substituents on their
internal vinylic carbons, the Prins cyclization step is
expected to occur by an early transition state.2g,15 Thus, in
the absence of overriding steric effects, Prins cyclization
should take place preferentially by way of conformers in
which hyperconjugative interactions between ppCvC and the
allylic sC–R are maximized and interactions between the
allylic spC–O and the alkene pCvC are minimized.2g,16 This
analysis predicts that acyclic 5-alkenyl acetal 35 would
preferentially cyclize by the A!C pathway, whereas the
E!G pathway would be favored for epimeric substrate 38
(Fig. 1). Our previous experience strongly suggests that
pinacol rearrangement of C and G would take place more
rapidly than conformational inversion of these cyclohexanyl
carbenium ions.5e,f Thus, the stereoelectronic analysis
3. Discussion
The outcome of the carbocyclic constructions described in
Scheme 8.

T. C. Gahman, L. E. Overman / Tetrahedron 58 (2002) 6473–6483
6477
Figure 1. Stereoelectronic rationale for stereoselection in the Prins-pinacol synthesis of cyclopentanoids.
developed in Fig. 1 rationalizes the preferential formation of
acylcyclopentanes 43 and 42 from 38 and 39, respectively.17
If steric effects alternatively were paramount, cyclization of
alkenyl acetal stereoisomer 35 would have been expected to
occur by the B!D pathway wherein the homoallylic methyl
group adopts a favored quasi-equatorial orientation. The
.99:1 stereoselection observed in the cyclization of 35 to
generate 43 and ultimately dione 37 (Scheme 8) indicates
that the stereoelectronic effects that regulate the stereo-
chemical outcome in this reaction are significant in
magnitude.18
annulations of cyclic substrates having a trans orientation of
alkene and acetal side chains should take place by the I!J
pathway to deliver cis-fused products 45 (Fig. 2). For
substrates containing rings of eight members or less,
reaction by this pathway would be enforced by the inability
of these rings to access the alternate chair cyclization
topography. The formation of small amounts of the inside–
outside bicyclic dione 33 from the cyclization of alkenyl
acetal 30 (Scheme 7) signals that the alternate cyclization
topography (K!L) is energetically accessible in the
cyclododecane series. Certainly, the 12-membered ring is
large enough to span adjacent trans-diaxial positions in this
alternate chair transition structure. Why, however, is this
stereoelectronically disfavored pathway observed in the
cyclododecane and not in the acyclic series? Although we
This stereoelectronic analysis also rationalizes the stereo-
chemical outcome of other reactions disclosed here.19 Thus,
the Prins cyclization step of ring-enlarging cyclopentane

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T. C. Gahman, L. E. Overman / Tetrahedron 58 (2002) 6473–6483
Figure 2. Stereoselection in Prins-pinacol reactions of cyclic sustrates having a trans relationship of acetal and alkene side chains.
have not examined this issue yet in sufficient depth to
provide an authoritative answer, we speculate that the anti
orientation about bond a in K is better accommodated in the
12-membered ring than the gauche orientation of this bond
found in I.20 Finally, the formation of the inside–outside
bicyclic dione 33 from 30, rather than the trans-fused
product of ring-enlarging cyclopentane annulation, indi-
cates that migration of the axial ring methylene carbon of
carbenium ion intermediate L is favored over migration of
the ring bond.
electronic factors discussed earlier. However, this result
stands in contrast to our earlier observation that in the
cyclohexane series the epimer having a cis orientation of
propenyl and acetal side chains, like its trans epimer, gives
the cis-fused product of ring-enlarging cyclopentane
annulation.5a As suggested in Fig. 3, this latter outcome
would result if Prins cyclization took place by the
stereoelectronically disfavored N!P pathway and the ring
fusion bond of P migrated preferentially.21 In the cyclo-
hexane series, the stereoelectronically favored cyclization
topography would suffer destabilizing steric interactions
between the original vinylic methyl group and two carbons
of the chair cyclohexane ring (the starred carbons of M and
O, n¼1). Apparently, this steric destabilization is sufficient
to override the stereoelectronic advantage of this cyclization
topography. In the cyclododecane series, the starting ring
should be able to adopt a low energy conformation
(illustrated schematically by Q) that avoids one of these
The situation is more complex with cyclic substrates having
a cis orientation of the alkene and acetal side chains,
because two chair cyclization topographies are possible
irrespective of the size of the starting ring (Fig. 3). The
exclusive formation in the cyclododecane series of the
trans-fused product 48 (n¼6) arising from the M!O
pathway again reflects the importance of the stereo-
Figure 3. Stereoselection in Prins-pinacol reactions of cyclic substrates having a cis relationship of acetal and alkene side chains.

T. C. Gahman, L. E. Overman / Tetrahedron 58 (2002) 6473–6483
6479
destabilizing non-bonded steric interactions. Evidently, this
difference is sufficient to favor the M!O pathway in the
case of the larger ring.
14H); 13C NMR (75 MHz) 213.7, 103.4, 53.5, 52.9, 47.4,
37.4, 33.6, 29.8, 26.1, 25.9, 24.0, 23.4, 23.1, 22.2, 22.0,
21.7; IR (CCl4), 810, 1066, 1127, 1249, 1446, 1470, 1550,
1710 cm21; MS (CI) m/z 239.2029 (239.2011 calcd for
C15H27O2, MH2MeOH). Anal. calcd for C16H30O3: C,
71.07; H, 11.18. Found: C, 70.97; H, 11.16.
In summary, this study provides additional illustrations of
the diversity of carbocyclic ring systems that can be
prepared in useful yield in 4–5 steps from ketone precursors
by pinacol-terminated Prins cyclizations. We show for the
first time that depending upon the size of a starting ring and
the relative configuration of the acetal and alkene side
chains, Prins-pinacol reactions can give either cis- or trans-
fused products of ring-enlarging cyclopentane annulation or
inside–outside bicyclic products. Stereoselection in these
reactions is determined by the interplay of steric and
stereoelectronic effects.
4.2. General procedure for adding alkenyllithium
reagents to a-(2,2-dimethoxyethyl) ketones to prepare
rearrangement substrates
4.2.1. Synthesis of (1R p,2R p)-2-(2,2-dimethoxyethyl)-1-
(2-propenyl)-1-(trimethylsiloxy)cyclododecane (30) and
(1R p,2S p)-2-(2,2-dimethoxyethyl)-1-(2-propenyl)-1-(tri-
methylsiloxy)cyclododecane (31). To a THF (30 mL)
solution of 2-bromopropene (0.8 mL, 9 mmol) at 2788C
was added t-BuLi (12 mL, 18 mmol, 1.54 M in pentane)
dropwise.10 The reaction was maintained at 2788C for 0.5 h
prior to the slow addition (over 30 min by syringe pump) of
a THF (15 mL) solution of 27 (810 mg, 3.0 mmol). The
resulting solution was maintained at 2788C for 4 h before
being quenched with saturated aqueous NH4Cl (10 mL).
The organic layer was separated and the aqueous phase was
extracted with EtOAc (2£25 mL). The combined organic
layers were washed with brine (15 mL), dried (MgSO4) and
concentrated to give 820 mg of a nearly colorless oil, which
was a 15:1 mixture of epimers by GLC analysis. This
mixture was silylated directly without purification. Diag-
4. Experimental22
4.1. General procedure for preparing a-(2,2-dimethoxy-
ethyl) ketones
4.1.1. Synthesis of 2-(2,2-dimethoxyethyl)cyclododeca-
none (27). Following the general procedure of Corey,7a
a
hexane solution of n-BuLi (26.7 mL, 2.9 M, 77 mmol) was
added slowly to a solution of diisopropylamine (10.8 mL,
77.0 mmol) and dry THF (50 mL) at 2788C. The reaction
was maintained at 2788C for 45 min prior to adding a THF
(30 mL) solution of cyclododecanone dimethylhydrazone
(15.7 g, 70.0 mmol) over 30 min. Care was taken not to
allow the internal temperature to exceed 2658C. After the
addition was complete, the reaction was maintained at
2788C for 1 h then warmed to 08C where it was maintained
for 1 h. The reaction was then cooled to 2788C and
bromoacetaldehyde dimethylacetal (16.5 mL, 140 mmol)
was added dropwise. The resulting solution was allowed to
warm slowly to 238C. The reaction solution was then
partitioned between EtOAc (160 mL) and water (80 mL).
The organic layer was separated and the aqueous layer was
extracted with EtOAc (2£40 mL). The organic layers were
combined and washed with brine (50 mL), dried (MgSO4)
and concentrated. The crude residue was filtered through a
60 g plug of basic, activity I, alumina, using 400 mL of
EtOAc as the eluent to give a thick oil (22.2 g), which was
dissolved in CH2Cl2 (500 mL). Following the general
procedure of Walborsky,9 this solution was cooled to
2608C, m-chloroperbenzoic acid (74%, 18 g, 77 mmol) was
added slowly with vigorous stirring, and the reaction was
maintained at 2608C for 25 min. The mixture was then
poured into cold aqueous saturated NaHCO3 (50 mL), the
organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (2£100 mL). The combined organic
layers were washed successively with cold aqueous
saturated NaHSO3 (100 mL), cold aqueous saturated
NaHCO3 (100 mL) and brine (100 mL), and then dried
(MgSO4) and concentrated. Purification of the residue by
flash chromatography (10% EtOAc in hexanes) gave 13.6 g
(72%) of ketone 27 as a thick colorless oil, which was a
single spot by TLC analysis and showed no volatile
impurities by GLC analysis: 1H NMR (300 MHz) 4.27
(app t, J¼5.8 Hz, 1H), 3.28 (s, 3H), 3.26 (s, 3H), 2.78–2.67
(m, 2H), 2.31 (ddd, J¼17.3, 7.7, 3.5 Hz, 1H), 2.10–1.83 (m,
1H), 1.82–1.76 (m, 1H), 1.67–1.50 (m, 4H), 1.42–1.00 (m,
1
1
nostic H NMR data for the major epimer 28: H NMR
(500 MHz) 4.90 (d, J¼1 Hz, 1H), 4.89 (app s, 1H), 4.47
(app t, J¼6.0 Hz, 1H), 3.31 (s, 3H), 3.29 (s, 3H), 2.36 (broad
s), 1.74 (s, 3H), 1.1–1.9 (m, 23H).
Imidazole (820 mg, 12 mmol) and TMSCl (0.76 mL,
6.0 mmol) were added sequentially to a solution of this
crude epimer mixture and DMF (15 mL) at 08C.23 The
resulting solution was allowed to warm slowly to 238C
where it was maintained for 12 h before being partitioned
between Et2O (20 mL) and water (10 mL). The separated
organic layer was washed with water (2£5 mL), brine
(5 mL), dried (MgSO4) and concentrated. Purification of the
residue by flash chromatography (2% EtOAc in hexanes)
gave 829 mg of 30 as a thick oil (72% over two steps, a 20:1
mixture of epimers by GLC analysis): 1H NMR (500 MHz)
d 4.84 (app t, J¼1.4 Hz, 1H), 4.82 (app s, 1H), 4.45 (dd,
J¼7.6, 4.5 Hz, 1H), 3.29 (s, 3H), 3.27 (s, 3H), 1.8–1.9 (m,
2H), 1.72 (s, 3H), 1.2–1.6 (m, 21H), 0.14 (s, 9H); 13C NMR
(125 MHz) 145.0, 110.6, 104.4, 85.7, 53.0, 52.4, 37.9, 37.8,
35.5, 27.7, 27.5, 27.0, 26.4, 26.3, 25.1, 23.4, 23.0, 22.0,
21.2, 3.1; IR (film) 2936, 2864, 1470, 1447, 1386, 1371,
1250, 1082, 898 cm21; MS (CI) m/z 385.3115 (385.3138
calcd for C22H45O3Si, MH), 353.2859 (353.2876 calcd for
C21H41O2Si, MH2MeOH).
Separation of a 6.8 g sample of the 4:1 mixture of epimeric
alcohols generated from the reaction of 27 with 2-lithio-
propene at 08C by MPLC (Lobar size C column packed with
63–125 mm Lichroprep Si 60 using 5% EtOAc–hexanes as
eluent) provided a 330 mg sample of 29, which was
silylated to give 31: 1H NMR (500 MHz) 4.92 (d, J¼
0.9 Hz, 1H), 4.88 (app t, J¼1.4 Hz, 1H), 4.59 (dd, J¼6.9,
5.3 Hz 1H), 3.36 (s, 3H), 3.31 (s, 3H), 2.17 (app tt, J¼14.2,
5.7 Hz, 1H), 0.8–2.0 (m, 25H), 1.76 (s, 3H), 0.10 (s, 9H);

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T. C. Gahman, L. E. Overman / Tetrahedron 58 (2002) 6473–6483
1
13C NMR (125 MHz) 149.4, 112.9, 105.6, 82.7, 54.1, 51.6,
36.5, 34.5, 33.7, 28.3, 26.5, 24.9, 23.0, 22.8, 22.5, 22.4,
22.2, 19.5, 2.4; IR (film) 2936, 2884, 1470, 1457,
1250 cm21; MS (CI) m/z 385.3123 (385.3138 calcd for
C22H45O3Si, MH), 353.2870 (353.2876 calcd for
C21H41O2Si, MH2MeOH).
1-(trimethylsiloxy)cyclooctane (25). H NMR (300 MHz)
4.89 (br s, 1H), 4.82 (br s, 1H), 4.39 (dd, 1H, J¼8.6, 3.0 Hz),
3.31 (s, 3H), 3.30 (s, 3H), 1.94–1.24 (m, 15H), 1.74 (s, 3H),
0.14 (s, 9H); 13C NMR (75 MHz) 149.8, 110.3, 104.5, 85.4,
53.0, 38.9, 36.6, 35.7, 29.7, 28.8, 26.6, 25.6, 23.6, 21.1, 3.1;
IR (film) 838, 1076, 1122, 1250 cm21; MS (CI) m/z
297.2216 (297.2250 calculated for C17H33O2Si, MH2
MeOH).
4.2.2. (1R p,2R p)-2-(2,2-Dimethoxyethyl)-1-(1-cyclohexe-
nyl)-1-(trimethylsiloxy)cycloheptane (12). 1H NMR
(500 MHz) 5.66 (app s, 1H), 4.42 (dd, J¼8.2, 3.4 Hz, 1H),
3.32 (s, 3H), 3.21 (s, 3H), 1.2–2.1 (m, 21H), 0.09 (s, 9H,
Si(CH3)3); 13C NMR (125 MHz) 142.0, 120.7, 104.1, 83.9,
53.9, 50.4, 41.4, 41.3, 33.2, 30.4, 28.3, 27.6, 25.2, 25.1,
24.1, 23.3, 22.4, 2.8; IR (film) 2930, 2858, 1463, 1448,
1250 cm21; MS (CI) m/z 323.2349 (323.2327 calcd for
C19H34O2Si, MH2MeOH).
4.3. General procedure for Prins-pinacol reaction and
oxidation of the crude product
4.3.1. Synthesis of (1R p,13S p)-1-methylbicyclo[11.3.0]-
hexadecan-2,15-dione (32) and (1R p,12R p)-1-methyl-
bicyclo[10.3.1]hexadecan-14,16-dione (33). A solution of
allylic silyl ether 30 (397 mg, 1.03 mmol) and CH2Cl2
(5 mL) was cooled to 2788C and SnCl4 (1 M in CH2Cl2,
1.1 mL) was added dropwise. The resulting solution was
maintained at 2788C for 5 min, was warmed to 2238C over
6 min and then maintained at 2238C for 5 min. The reaction
was then quenched by the addition of saturated aqueous
NaCl (3 mL), and the aqueous phase was separated and
extracted with CH2Cl2 (2£5 mL). The combined organic
layers were dried (MgSO4) and concentrated before being
filtered through a 1 in. plug of silica gel using 25 mL of
CH2Cl2 as eluent. Concentration gave 300 mg of an
epimeric mixture of crude methoxy ketones as a colorless
oil.
4.2.3. (1R p,2R p)-2-(2,2-Dimethoxyethyl)-1-(1-cyclopen-
tenyl)-1-(trimethylsiloxy)cycloheptane (14). 1H NMR
(500 MHz) 5.53 (app s, 1H), 4.42 (dd, J¼8.5, 3.5 Hz, 1H),
3.32 (s, 3H), 3.20 (s, 3H), 2.28–2.31 (m, 4H), 2.09 (dd,
J¼14.0, 8.6 Hz, 1H), 1.3–1.9 (m, 14H), 0.09 (s, 9H); 13C
NMR (125 MHz) 150.3, 124.4, 104.1, 81.9, 53.9, 50.5, 42.1,
41.2, 33.3, 32.4, 32.0, 30.4, 28.4, 27.3, 23.9, 23.3, 2.7; IR
(film) 2948, 2863, 1463, 1446, 1250 cm21; MS (CI) m/z
341.2515 (341.2512 calcd for C19H37O3Si, MH), 309.2267
(309.2250 calcd for C18H33O2Si, MH2MeOH).
4.2.4. (1R p,2R p)-2-(2,2-Dimethoxyethyl)-1-(2-propenyl)-
1-(trimethylsiloxy)cycloheptane (17). 1H NMR (300
MHz) 4.95 (1H, d, J¼2.1 Hz), 4.80 (1H, app t, J¼1.5 Hz)
4.41 (1H, dd, J¼3.3, 8.4 Hz), 3.31 (s, 3H), 3.24 (s, 3H), 1.74
(s, 3H), 2.11–1.20 (m, 13), 0.13 (s, 9H); 13C NMR
(75 MHz) 150.8, 111.6, 104.2, 84.2, 53.5, 51.2, 41.6, 41.5,
34.0, 30.8, 29.0, 28.1, 24.2, 20.7, 2.7; IR (film) 838, 887,
1010, 1055, 1091, 1021, 1364, 1390, 1457, 1639 cm21; MS
(EI) m/z 314.2770 (314.2778 calcd for C17H34O3Si, M).
Following the general procedure of Sharpless,12 a 135 mg
sample of this crude residue was added to a mixture of CCl4
(1 mL), MeCN (1 mL) and H2O (1.5 mL) at 238C; NaIO4
(514 mg, 2.4 mmol) was then added. After stirring for
15 min, RuCl3·3H2O (1 mg) was added and the mixture was
stirred overnight at 238C. Additional NaIO4 (514 mg,
2.4 mmol) was then added and the mixture was stirred for
an additional 6 h, filtered through Celite (0.25 in. pad), dried
(MgSO4) and the eluent was concentrated. This residue was
purified by flash chromatography (1!10% EtOAc in
hexanes) to give 68 mg (55%) of the cis diketone 32 and
16 mg (13%) of the inside outside bridged bicyclic diketone
33, each as crystalline solids. Both products were single
spots by TLC analysis and showed no volatile impurities by
capillary GLC analysis. Crystals suitable for single crystal
X-ray analysis were obtained from 32 and 33 by slow
evaporation of hexane solutions.
4.2.5. (1R p,2R p)-2-(2,2-Dimethoxyethyl)-1-[(E)-2-butenyl]-
1-(trimethylsiloxy)cycloheptane (18). 1H NMR (500
MHz) 5.24 (q, J¼7.3 Hz, 1H), 4.44 (dd, J¼8.7, 3.0 Hz,
1H), 3.32 (s, 3H), 3.22 (s, 3H), 2.19 (dd, J¼14.7, 9.1 Hz,
1H), 1.77 (d, J¼7.5 Hz, 3H), 1.71 (s, 3H), 1.3–1.9 (m,
12H), 0.15 (s, 9H); 13C NMR (125 MHz) 142.1, 120.9,
104.0, 85.6, 53.6, 50.6, 43.2, 42.3, 34.3, 30.3, 28.7, 27.4,
25.0, 24.1, 16.1, 2.8; IR (film) 2955, 2947, 2925, 1457,
1260, 1120, 838 cm21; MS (CI) m/z 296.2167 (296.2171
calcd for C17H32O2Si, MH2MeOH).
(1R p,13S p)-1-Methylbicyclo[11.3.0]hexadecan-2,15-dione
(32). Mp 125–1268C; 1H NMR (500 MHz) d 2.88 (d,
J¼18.4 Hz, 1H), 2.82 (ddd, J¼18.8, 10.0, 2.4 Hz, 1H),
2.37–2.44 (m, 2H), 2.14–2.25 (m, 2H), 2.01–2.05 (m, 1H),
1.87 (d, J¼18.3 Hz, 1H), 1.40 (s, 3H), 1.0–1.5 (m, 17H);
13C NMR (125 MHz) 216.7, 212.8, 55.4, 47.1, 45.7, 41.1,
36.6, 27.9, 26.3, 25.1, 24.8, 24.33, 24.28, 23.8, 23.3, 21.2;
IR (CCl4) 2924, 2863, 1751, 1709, 1550, 1460, 1407,
1012 cm21; MS (CI) m/z 265.2151 (265.2167 calcd for
C17H29O2, MH). Anal. calcd for C17H28O2: C, 77.22; H,
10.67. Found: C, 77.19; H, 10.72.
4.2.6. (1R p,2R p)-2-(2,2-Dimethoxyethyl)-1-(1-ethenyl)-
1
1-(tert-butyldimethylsiloxy)cycloheptane (22). H NMR
(500 MHz) 5.97 (dd, J¼17.4, 11.0 Hz, 1H), 5.16 (d, J¼
17.4 Hz, 1H), 5.02 (d, J¼11.2 Hz, 1H), 4.41 (dd, J¼8.4,
3.2 Hz, 1H), 3.30 (s, 3H), 3.25 (s, 3H), 2.01 (dd, J¼14.0,
9.2 Hz, 1H), 1.2–1.9 (m, 12H), 0.88 (s, 9H), 0.86 (s, 3H),
0.47 (s, 3H); 13C NMR (125 MHz) 145.1, 111.8, 104.2,
80.7, 53.0, 51.7, 44.4, 41.2, 34.2, 30.4, 29.5, 27.7, 26.1,
26.0, 22.5, 18.7, 21.6, 22.0; IR (film) 2949, 3931, 2857,
1472, 1463, 1253, 1124, 1077 cm21; MS (EI) m/z 342.2573
(342.2590 calcd for C19H38O3Si, M), 311.2392 (311.2406
calcd for C18H35O2Si, M2OMe).
(1R p,12R p)-1-Methylbicyclo[10.3.1]hexadecan-14,16-dione
1
(33). Mp 111–1128C; H NMR (500 MHz) d 3.16–3.22
(m, 1H), 2.96 (d, J¼14.7 Hz, 1H), 2.64 (ddd, J¼17.2, 6.3,
4.2.7. (1R p,2R p)-2-(2,2-Dimethoxyethyl)-1-(2-propenyl)-
0.8 Hz, 1H), 2.38 (d, J¼14.8 Hz, 1H), 2.23 (dd, J¼17.1,

T. C. Gahman, L. E. Overman / Tetrahedron 58 (2002) 6473–6483
6481
14.4 Hz, 1H), 2.01–2.07 (m, 1H), 1.60–1.68 (m, 1H),
1.52–1.58 (m, 2H), 1.1–1.4 (m, 16H), 1.1 (s, 3H); 13C
NMR (125 MHz) 216.7, 212.8, 55.4, 47.1, 45.7, 41.1, 36.6,
27.9, 26.3, 25.1, 24.8, 24.34, 24.27, 23.8, 23.3, 21.1; IR
(CCl4) 2932, 2857, 1719, 1549, 1254, 1007, 795 cm21; MS
(CI) m/z 265.2148 (265.2167 calcd for C17H29O2, MH).
Anal. calcd for C17H28O2: C, 77.22; H, 10.67. Found: C,
77.26; H, 10.64.
1457 cm21; MS (EI) m/z 181.1231 (181.1309 calcd for
C11H17O2, MH).
4.3.7. (1R p,9S p)-1-Methylbicyclo[7.3.0]dodecan-2,15-
dione (26). Crystals suitable for single crystal X-ray
analysis were obtained by slow evaporation from hexane:
1
mp 65.5–66.08C; H NMR (300 MHz) 3.07 (ddd, J¼18.6,
11.7, 3.1 Hz, 1H), 2.88 (d, 18.6 Hz, 1H), 2.57 (dd, J¼18.4,
7.8 Hz, 1H), 2.31–2.40 (m, 2H), 2.01–2.08 (m, 1H), 1.86
(d, 18.6 Hz, 1H), 1.38 (s, 3H), 1.0–1.5 (m, 10H); 13C NMR
(75 MHz) 214.7, 217.1, 65.8, 45.3, 43.4, 35.7, 29.6, 28.0,
25.7, 23.1, 23.0, 21.7, 15.2; IR (film) 2925, 2852, 1744,
1695, 1474, 1465, 1407, 1143 cm21; MS (CI) m/z 209.1447
(209.1541 calcd for C13H21O2, MH). Anal. calcd for
C13H20O2: C, 74.76; H, 9.68. Found: C, 74.97; H, 9.66.
4.3.2. (1R p,8R p,11S p)-Tricyclo[6.3.0.41,11]pentadecan-
1
2,10-dione (15). H NMR (500 MHz) 2.91 (ddd, J¼13.5,
8.8, 5.0 Hz, 1H), 2.85 (d, J¼3.8 Hz, 1H), 2.76 (dd, J¼19.5,
8.8 Hz, 1H), 2.47 (app t, 9.0 Hz, 1H), 2.30 (ddd, J¼13.5,
8.0, 5.4 Hz, 1H), 2.20 (dd, J¼13.7 Hz, 1H), 2.09 (dd,
J¼13.3 Hz, 1H), 1.99 (dd, J¼19.5 Hz, 1H), 0.9–1.9 (m,
14H); 13C NMR (125 MHz) 218.4, 215.4, 58.7, 47.9, 46.1,
42.5, 38.1, 33.7, 32.0, 26.7, 26.3, 24.4, 22.6, 22.4, 21.2; IR
(film) 2956, 2869, 1740, 1718, 1457 cm21; MS (CI) m/z
221.1536 (221.1541 calcd for C14H21O2, MH). Anal. calcd
for C15H22O2: C, 76.88; H, 9.46. Found: C, 77.01; H, 9.49.
4.3.8. (1R p,13R p)-1-Methylbicyclo[11.3.0]hexadecan-
2,15-dione (34). Crystals suitable for single crystal X-ray
analysis were obtained by slow evaporation from hexane:
1
mp 129–1308C; H NMR (500 MHz) 3.03 (d, J¼17.9 Hz,
1H), 2.82 (ddd, J¼8.4, 18.7 Hz, 1H), 2.46 (ddd, J¼18.4, 7.0,
3.1 Hz, 1H), 2.22–2.32 (m, 1H), 2.05 (d, J¼17.8 Hz, 1H),
1.89–1.99 (m, 2H), 1.24 (s, 3H, CH3), 1.2–1.4 (m, 17H);
13C NMR (125 MHz) 216.3, 213.3, 54.7, 51.2, 43.9, 42.0,
37.3, 27.5, 26.35, 26.27, 25.12, 24.9, 24.61, 24.60, 23.2,
21.8, 16.0; IR (CCl4) 2934, 2863, 1741, 1700, 1461, 1406,
1226 cm21; MS (CI) m/z 265.2158 (265.2167 calcd for
C17H29O2, MH). Anal. calcd for C17H28O2: C, 77.22; H,
10.67. Found: C, 77.04; H, 10.69.
4.3.3. (1R p,8R p,11S p)-Tricyclo[6.3.0.31,11]tetradecan-
2,10-dione (16). 1H NMR (500 MHz) 3.12 (app d, J¼
9.4 Hz, 1H), 2.87 (m, 1H), 2.57 (m, 2H), 2.46 (dd, J¼17.7,
7.4 Hz, 1H), 2.34 (app dt, J¼13.8, 5.8 Hz, 1H), 2.18 (ddd,
J¼17.7, 5.9, 1.7 Hz, 1H) 1.4–2.1 (m, 13H); 13C NMR
(125 MHz) 220.1, 215.3, 67.6, 52.9, 46.0, 43.2, 38.7, 36.1,
32.5, 29.4, 27.6, 25.2, 23.5; IR (film) 2956, 2869, 1740,
1718, 1457 cm21; MS (CI) m/z 221.1536 (221.1541 calcd
for C14H21O2, MH). Anal. calcd for C14H20O2: C, 77.22; H,
10.67. Found: C, 77.16; H, 10.71.
4.3.9. (2R p,3S p)-1,1-(Dimethoxy)-3,5-dimethyl-4-ethyl-
4-(trimethylsiloxy)-5-hexene (35) and (2R p,3R p)-1,1-
(dimethoxy)-3,5-dimethyl-4-ethyl-4-(trimethylsiloxy)-5-
hexene (38). The mixture of hexenyl siloxy acetals was
separated by HPLC (5% EtOAc in hexanes, Supelco column
packed with Supelcosil LC-Si semiprep silica gel) to give
pure samples of both epimers as clear oils. Both compounds
were single spots by TLC analysis and showed no volatile
impurities by GLC analysis. Compound 35. 1H NMR
(500 MHz) 4.95 (d, J¼2.3 Hz, 1H), 4.89 (app t, J¼1.0 Hz,
1H), 4.39 (dd, J¼8.0, 3.6 Hz, 1H), 3.30 (s, 3H), 3.27 (s, 3H),
1.4–1.8 (m, 7H), 1.1–1.2 (m, 1H), 0.94 (d, J¼6.7 Hz, 3H),
0.77 (t, J¼7.4 Hz, 3H), 0.14 (s, 9H); 13C NMR (125 MHz)
147.3, 112.4, 104.0, 85.4, 53.1, 52.1, 36.0, 34.4, 28.7, 20.1,
4.3.4. (1R p,8R p)-1-Methylbicyclo[6.3.0]undecan-2,10-
1
dione (19). H NMR (500 MHz) 2.89 (ddd, J¼13.9, 9.1,
4.6 Hz, 1H), 2.87 (d, J¼17.9 Hz, 1H), 2.5–2.7 (m, 2H), 2.29
(ddd, J¼13.5, 7.7, 4.7 Hz, 1H), 2.04 (app d, J¼15.8 Hz,
1H), 1.95 (d, J¼18.1 Hz, 1H), 1.8–2.0 (m, 2H), 1.4–1.7 (m,
6H), 1.37 (s, 3H); 13C NMR (125 MHz) 216.7, 216.0, 55.2,
45.8, 45.4, 45.1, 37.8, 32.2, 27.2, 25.2, 24.1, 24.0; IR (film)
2931, 2863, 1744, 1705, 1694, 1457 cm21; MS (EI) m/z
195.1386 (195.1385 calcd for C12H19O2, MH). Anal. calcd
for C12H18O2: C, 74.19; H, 9.34. Found: C, 74.39; H, 9.42.
4.3.5. (1R p,8R p,11R p)-1,11-Dimethylbicyclo[6.3.0]unde-
can-2,10-dione (20). 1H NMR (500 MHz) 2.8–2.9 (m, 2H),
2.64 (dd, J¼19.0, 8.6 Hz, 1H), 2.55 (app dt, J¼16.1, 7.8 Hz,
1H), 3.31 (app dt, J¼13.6, 6.9 Hz, 1H), 2.00 (d, J¼19.0 Hz),
1.89 (app dt, J¼12.5, 6.1 Hz, 2H), 1.4–1.7 (m, 6H), 1.17 (s,
3H), 0.99 (d, J¼7.0 Hz, 3H); 13C NMR (125 MHz) 218.9,
215.2, 57.6, 46.7, 45.6, 43.3, 38.0, 33.8, 26.5, 26.1, 24.9,
19.2, 9.1; IR (film) 2934, 2863, 1741, 1700, 1461, 1406,
1222 cm21; MS (EI) m/z 209.1541 (209.1541 calcd for
C13H21O2, MH). Anal. calcd for C13H20O2: C, 74.96; H,
9.68. Found: C, 75.03; H, 9.59.
14.0, 8.7, 2.6; IR (film) 2966, 2830, 1456, 1382, 1251 cm21
;
MS (CI) m/z 289.2204 (289.2199 calcd for C15H33O3Si,
MH), 257.1935 (257.1937 calcd for C14H29O2Si, MH2
1
MeOH). Compound 38. H NMR (500 MHz) 4.91 (d, J¼
2.3 Hz, 1H), 4.87 (d, J¼1.3 Hz, 1H), 4.45 (dd, J¼8.2,
3.5 Hz, 1H), 3.33 (s, 3H), 3.31 (s, 3H), 1.9–2.0 (m, 1H),
1.60 (s, 3H), 1.1–1.8 (m, 4H), 0.76–0.81 (m, 6H), 0.14 (s,
9H); 13C NMR (125 MHz) 147.5, 112.6, 104.3, 85.3, 52.9,
52.4, 36.5, 34.1, 26.9, 20.3, 14.7, 8.7, 2.7; IR (film) 2971,
2830, 1450, 1378, 1250 cm21; MS (CI) m/z 289.2200
(289.2199 calcd for C15H33O3Si, MH), 257.1934 (257.1937
calcd for C14H29O2Si, MH2MeOH).
4.3.6. (1R p,8S p)-Bicyclo[6.3.0]undecan-2,10-dione (24).
1H NMR (500 MHz) 2.18 (ddd, J¼13.5, 8.8, 5.0 Hz, 1H),
2.85 (d, J¼3.8 Hz, 1H), 2.76 (dd, J¼19.5, 8.8 Hz, 1H), 2.47
(app t, 9.0 Hz, 1H), 2.30 (ddd, J¼13.5, 8.0, 5.4 Hz, 1H),
2.20 (dd, J¼13.7 Hz, 1H), 2.09 (dd, J¼13.3 Hz, 1H), 1.99
(dd, J¼19.5 Hz, 1H), 0.9–1.9 (m, 14H); 13C NMR
(125 MHz) 216.6, 216.5, 47.2, 44.9, 43.0, 41.7, 41.5, 29.9,
28.7, 25.1, 24.3; IR (film) 2956, 2869, 1740, 1718,
4.3.10. Preparation of (4R p,5S p)-dihydro-5-ethyl-4-
methyl-5-(2-propyl)-2(3H )-furanone (40) from 38. A
solution of allylic silyl ether 38 (18 mg, 0.062 mmol) and
EtOAc (2 mL) was stirred over palladium on carbon (5 mg,
Pd content 1%) under an atmosphere of hydrogen for 18 h.
The reaction mixture was then filtered through a 0.5 in. plug

6482
T. C. Gahman, L. E. Overman / Tetrahedron 58 (2002) 6473–6483
of silica gel using 30 mL of EtOAc as eluent. Concentration
afforded 16 mg of the crude hydrogenation product. This
sample was dissolved in acetone (3 mL) and H2O (3 mL),
250 mg of Amberlyst-15 acidic resin was added and the
mixture was heated at reflux (ca. 858C) for 1 h. After
allowing the reaction to cool to 238C, the mixture was
filtered and the filtrate was extracted with EtOAc
(3£15 mL). The combined organic layers were washed
with brine (15 mL), dried (MgSO4) and concentrated to give
11.6 mg of a mixture of lactols. Pyridinium chlorochromate
(PCC, 20 mg, 0.093 mmol) was added to a solution of these
crude lactols and CH2Cl2 (3 mL). The resulting mixture was
stirred for 1.5 h at 238C before being diluted with Et2O
(20 mL). This mixture was filtered through Celite (0.25pin.
pad) and the filtrate was concentrated. Purification of the
residue by flash chromatography (20% EtOAc in hexanes)
provided 10 mg (87%) of lactone 40 as a clear oil, which
was a single spot by TLC analysis and showed no volatile
aqueous H2O2 (0.5 mL) were added. After stirring the
resulting mixture for 15 min, the organic layer was
separated and the aqueous layer extracted with EtOAc
(3£10 mL). The combined organic layers were washed with
brine (10 mL), dried (MgSO4) and concentrated to afford
68 mg of a 3:1 mixture of alcohol epimers (by GLC
analysis). The major epimer (34 mg, 49%) was isolated by
HPLC (40% EtOAc in hexanes, Supelco column packed
with Supelcosil LC-Si semiprep silica gel).
This alcohol (18 mg, 0.11 mmol), CH2Cl2 (1 mL) and
phenylisocyanate (12 mL, 0.11 mmol) were combined and
heated at reflux for 12 h. The solution was cooled and the
crystalline product was collected by filtration. Recrystalli-
zation by slow evaporation of a CHCl3 solution resulted in
X-ray quality crystals of phenylurethane 41 (11 mg, 36%):
mp 129–1308C; 1H NMR (500 MHz) 7.0–7.5 (m, 5H,
C6H5), 6.60 (brs, 1H), 5.39 (m, 1H), 2.8 (dd, J¼14.2,
7.9 Hz, 1H), 2.4–2.6 (m, 2H), 2.1–2.2 (m, 1H), 1.9–2.0 (m,
2H), 1.55 (dd, J¼14.2, 2.9 Hz, 1H), 1.42 (s, 3H), 1.05 (t,
J¼6.9 Hz, 3H), 0.91 (d, J¼6.7 Hz, 3H); 13C NMR
(125 MHz) 215.0, 153.2, 138.0, 129.0, 123.3, 118.7, 76.5,
57.5, 44.1, 43.2, 40.5, 33.3, 24.2, 15.6, 7.6; IR (film) 3419,
2960, 2875, 1719, 1683, 1532, 1464, 1445, 1222 cm21; MS
(CI) m/z 288.1482 (288.1600 calcd for C10H19O2, MH).
1
impurities by GLC analysis: H NMR (500 MHz) 2.5–2.7
(m, 2H), 2.1–2.3 (m, 2H), 1.6–1.8 (m, 2H), 1.11 (d,
J¼6.7 Hz, 3H), 0.98 (t, J¼7.4 Hz, 3H), 0.93 (t, J¼7.1 Hz,
6H); 13C NMR (125 MHz) 176.2, 92.7, 38.0, 33.3, 32.7,
24.8, 17.4, 16.4, 16.2, 7.6; IR (film) 2971, 2926, 1771, 1283,
1239 cm21; MS (CI) m/z 171.1375 (171.1385 calcd for
C10H19O2, MH).
4.3.11. (4R p,5R p)-Dihydro-5-ethyl-4-methyl-5-(2-pro-
1
pyl)-2(3H )-furanone (36). H NMR (500 MHz) 2.68 (dd,
Acknowledgments
J¼17.6, 9.2 Hz, 1H), 2.53 (m, 1H), 2.28 (dd, J¼17.6,
9.5 Hz, 1H), 2.06 (m, 1H), 1.74 (m, 2H), 1.15 (d, J¼7.1 Hz,
3H), 1.00 (d, J¼6.8 Hz, 3H), 0.96 (d, J¼6.8 Hz, 3H), 0.92
(t, J¼7.6 Hz, 3H); 13C NMR (125 MHz) 176.6, 92.2, 38.2,
37.3, 31.2, 29.0, 18.0, 15.5, 7.9; IR (film) 2971, 2886, 1772,
1468, 1251 cm21; MS (CI) m/z 171.1374 (171.1385 calcd
for C10H19O2, MH).
This research was supported by a Javits Neuroscience
Investigator Award from NIH NINDS (NS-12389). We
would like to thank Dr J. Ziller for single crystal X-ray
analyses, Dr T. LaCour for useful suggestions and Merck,
Pfizer, Roche Biosciences and SmithKline Beecham for
additional unrestricted financial support. NMR and mass
spectra were determined at UCI using instruments acquired
with the assistance of NSF and NIH shared instrumentation
grants.
4.3.12. (3R p,4R p)-3,4-Dimethyl-3-(1-oxopropyl)cyclo-
1
pentanone (37). H NMR (500 MHz) 2.66 (d, J¼18.1 Hz,
1H), 2.53 (m, 3H), 2.43 (dd, J¼18.9, 8.2 Hz, 1H), 2.13 (d,
J¼17.8 Hz, 1H), 1.95 (ddd, J¼18.8, 9.9, 1.2 Hz, 1H), 1.20
(s, 3H), 1.05 (t, J¼7.2 Hz, 3H), 1.03 (d, J¼6.9 Hz, 3H); 13C
NMR (125 MHz) 215.8, 213.4, 54.2, 50.0, 44.1, 36.2, 31.3,
16.9, 15.2, 8.1; IR (film) 2972, 2910, 1744, 1702, 1457,
1406, 1375, 1243 cm21; MS (CI) m/z 169.1235 (169.1228
calcd for C10H17O2, MH). Anal. calcd for C10H16O2: C,
71.39; H, 9.59. Found: C, 71.23; H, 9.62.
References
1. For brief reviews see: (a) Overman, L. E. Acc. Chem. Res.
1992, 25, 352–359. (b) Overman, L. E. Aldrichim. Acta 1995,
28, 107–120. (c) Overman, L. E. In Selectivities in Lewis
Acid-Promoted Reactions. NATO ASSI Series 289, Schinzer,
D., Ed.; Kluwer Academic: Dordrecht, The Netherlands, 1989;
pp 1–20.
4.3.13. (3R p,4S p)-3,4-Dimethyl-3-(1-oxopropyl)cyclo-
1
pentanone (39). H NMR (500 MHz) 2.81 (d, J¼18.3 Hz,
1H), 2.4–2.6 (m, 3H), 2.32 (m, 1H) 2.07 (dd, J¼19.0,
6.8 Hz, 1H), 1.92 (d, J¼18.3 Hz, 1H), 1.41 (s, 3H), 1.05 (t,
J¼7.2 Hz, 3H), 0.94 (d, J¼7.1 Hz, 3H); 13C NMR
(125 MHz) 216.4, 213.9, 54.8, 47.6, 44.4, 40.7, 32.7, 23.0,
16.4, 7.4; IR (film) 2988, 1744, 1702, 1460, 1407 cm21; MS
(CI) m/z (169.1228 calcd for C10H17O2, MH). Anal. calcd
for C10H16O2: C, 71.39; H, 9.59. Found: C, 71.33; H, 9.69.
2. Representative examples include (a) Hopkins, M. H.;
Overman, L. E.; Rishton, G. M. J. Am. Chem. Soc. 1991,
113, 5354–5365. (b) Brown, M. J.; Harrison, T.; Herrinton,
P. M.; Hopkins, M. H.; Hutchinson, K. D.; Mishra, P.;
Overman, L. E. J. Am. Chem. Soc. 1991, 113, 5365–5378.
(c) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc.
1995, 117, 10391–10392. (d) Cloninger, M. J.; Overman, L. E.
J. Am. Chem. Soc. 1999, 121, 1092–1093. (e) Hanaki, N.;
Link, J. T.; MacMillan, D. W. C.; Overman, L. E.; Trankle,
W. G.; Wurster, J. A. Org. Lett. 2000, 2, 223–226.
(f) Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2,
2683–2686. (g) Cohen, F.; MacMillan, D. W. C.; Overman,
L. E.; Romero, A. Org. Lett. 2001, 3, 1225–1228.
4.3.14. Preparation of (3R p,4S p)-3,4-dimethyl-3-(1-oxo-
propyl)cyclopentanol phenylurethane (41). A solution of
dione 39 (69 mg, 0.37 mmol) and THF (2 mL) was cooled
to 2788C and KS-selectride (370 mL, 0.37 mmol) was
added. The resulting solution was allowed to warm to 238C
and after 4 h, MeOH (0.5 mL), 1N NaOH (0.5 mL) and 30%
3. For the initial description of this route to tetrahydrofurans, see:

T. C. Gahman, L. E. Overman / Tetrahedron 58 (2002) 6473–6483
6483
Martinet, P.; Mousset, G. Bull. Soc. Chim. Fr. 1970,
1071–1076.
17. A mechanism in which the Prins cyclization and pinacol
rearrangement steps occurred with some degree of concert,
thereby avoiding the formation of cyclohexanyl carbenium
ion intermediates, would also be consistent with the results
reported here. This interesting possibility is under
investigation.
4. Molina-Ponce, A.; Overman, L. E. J. Am. Chem. Soc. 2000,
122, 8672–8676.
5. (a) Hirst, G. C.; Howard, P. N.; Overman, L. E. J. Am. Chem.
Soc. 1989, 111, 1514–1515. (b) Johnson, Jr. T. O.; Overman,
L. E. Tetrahedron Lett. 1991, 32, 7361–7365. (c) Ando, S.;
Minor, K. P.; Overman, L. E. J. Org. Chem. 1997, 62,
6379–6387. (d) Hirst, G. C.; Johnson, Jr. T. O.; Overman, L. E.
J. Am. Chem. Soc. 1993, 115, 2992–2993. (e) Minor, K. P.;
Overman, L. E. Tetrahedron 1997, 53, 8927–8940.
(f) Overman, L. E.; Pennington, L. P. Can. J. Chem. 2000,
78, 732–738.
18. The steric interaction between the homoallylic methyl group
and the original vinylic methyl group in cyclization
topography A!C is much less severe than a syn-pentane
interaction, because these groups would be tilted away from
each other.
19. Our earlier description of stereoselection in ring-enlarging
cyclopentane annulations must be discarded.1c This previous
analysis focused on the stability of chair cyclohexanyl
carbenium ions generated in the Prins cyclization step (late-
transition state model) and is not consistent with results of the
reactions of the acyclic 5-hexenyl acetals reported here.
20. The lowest energy conformation of cyclododecane is the
square (D4), see: Atavin, E. G.; Mastryukov, V. S.; Allinger,
N. L.; Almenningen, A.; Seip, R. J. Mol. Struct. 1989, 212,
87–95.
6. Stork, G.; Benaim, J. J. Am. Chem. Soc. 1971, 93, 5938–5939.
7. (a) Corey, E. J.; Enders, D. Chem. Ber. 1978, 111, 1337–1361.
(b) Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 17, 3–6.
8. Goerdeler, J.; Bischoff, M. Chem. Ber. 1972, 105, 3566–3573.
9. Duraisamy, M.; Walborsky, H. M. J. Org. Chem. 1984, 49,
3410–3411.
10. Generated by reaction of 1-bromocyclohexene with 2 equiv. of
t-BuLi following the procedure of Neumann and Seebach:
Neumann, H.; Seebach, D. Chem. Ber. 1978, 111, 2785–2812.
11. Ando, K.; Condroski, K. R.; Houk, K. N.; Wu, Y.-D.; Ly, S. K.;
Overman, L. E. J. Org. Chem. 1998, 63, 3196–3203.
12. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936–3938.
21. Why the ring fusion bond migrates preferentially in P and the
axial methylene group in L is unclear at present, as these
intermediates differ only in configuration at the angular carbon
distal to the carbenium ion. To a first approximation, both
a-substituents (fusion bond and axial bond) should have
similar overlap (,608) with the vacant p-orbital in both
carbenium ion intermediates. Studies to address this issue are
underway.
13. Capillary GLC analysis of the crude dione products showed
less than 1% of volatile impurities.
14. Gahman, T. C. PhD Dissertation, University of California,
Irvine, 1994.
22. General experimental details have been described: Metais, E.;
Overman, L. E.; Rodriguez, M. I.; Stearns, B. A. J. Org. Chem.
15. Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334–338.
16. For reviews, see: (a) Houk, K. N.; Paddon-Row, M. N.;
Rondan, N. G.; Wu, Y. D.; Brown, F. K.; Spellmeyer, D. C.;
Metz, J. T.; Li, Y.; Loncharich, R. J. Science 1986, 231,
1108–1117. (b) Hoveyda, A. H.; Evans, D. A.; Fu, G. C.
Chem. Rev. 1993, 93, 1307–1370. (c) Kahn, S. D.; Pau, C. F.;
Chamberlin, A. R.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109,
650–663.
1997, 62, 9210–9216, GLC analyses employed
30 m£0.32 mm J and W DB-5 column with flame ionization
a
detection.
23. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
6190–6191.