Enhanced channeling of the squarate cascade through the dianionic oxy-cope option. Oxy substitution markedly augments syn delivery of the second alkenyllithium

Article abstract of DOI:10.1021/ja964140d

A general means for enhancing the extent to which squarate esters enter into cascade processes involving a dianionic oxy-Cope rearrangement as the key step is presented. Adoption of this sigmatropic process requires that the two alkenyllithium reagents be

Full text of DOI:10.1021/ja964140d

3038
J. Am. Chem. Soc. 1997, 119, 3038-3047
Enhanced Channeling of the Squarate Cascade through the
Dianionic Oxy-Cope Option. Oxy Substitution Markedly
Augments Syn Delivery of the Second Alkenyllithium
Leo A. Paquette,* Lung Huang Kuo, and Julien Doyon
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity,
Columbus, Ohio 43210
ReceiVed December 2, 1996X
Abstract: A general means for enhancing the extent to which squarate esters enter into cascade processes involving
a dianionic oxy-Cope rearrangement as the key step is presented. Adoption of this sigmatropic process requires that
the two alkenyllithium reagents being introduced add cis to each other, a kinetic bias which can be realized simply
by the proper incorporation of ethereal oxygen substituents in the first organometallic reagent. Structural reorganization
occurs via boat-like transition states such that stereoinduction manifests itself with high fidelity.
About five years ago, we initiated an investigation into the
attached to a carbon atom situated proximate to the four-
membered ring. This phenomenon was attributed to coordina-
tion of the methoxy oxygen to the lithium atom of the second-
stage nucleophile, thereby facilitating its syn delivery.
consequences of adding a pair of alkenyl anions to squarate
esters in anticipation of realizing a direct, single-operation
pathway to polycyclic end-products.1 As this study broadened
in scope,2 it became clearly apparent that trans addition of the
two nucleophiles to generate dialkoxides such as 1 was heavily
preferred and often exclusive. As concerns 1, conrotatory 4π
electrocyclic ring opening occurs under control of the oxido
anions to generate a cis,cis-1,3,5,7-octatetraene capable in turn
of a second conrotatory (now 8π) event, culminating ultimately
in the formation of multicyclic ring systems housing several
stereogenic centers. The stereochemical outcome of this
mechanistic tandem is not governed by the diastereoselection
associated with the initial addition step because of helical
equilibration at the tetraene stage.2g,h The scenario is rather
different when cis addition operates since concerted dianionic
oxy-Cope rearrangement ensues and transmission of stereo-
chemical information occurs with high fidelity via a boat-like
intermediate.3
Nonetheless, critical examination of the diastereomeric monoad-
ducts 5 and 6 suggested that the working hypothesis advanced
above may be too simplistic. While 5 responded to cyclopen-
tenyllithium by generating a 3.5:1 mixture of Cope and
electrocyclic products, analogous treatment of 6 proceeded only
along the latter trajectory.5 The dearth of examples of this type
of behavior has prompted an investigation having as its explicit
goal the purposeful incorporation of structural modifications
designed to scrutinize this matter explicitly.
Several examples have come to light recently where cis
addition was found to be competitive with the production of 1
(see 3-5).4,5 Without exception, an ethereal oxygen atom was
X Abstract published in AdVance ACS Abstracts, March 15, 1997.
(1) Negri, J. T.; Morwick, T.; Doyon, J.; Wilson, P. D.; Hickey, E. R.;
Paquette, L. A. J. Am. Chem. Soc. 1993, 115, 12189.
Results and Discussion
Chiral Acetals as Directing Groups. The use of â-elimi-
natable groups has proven to be highly utilitarian, bringing
complete regiocontrol to the final transannular aldolization,
thereby limiting the number of products formed and improving
yields.2c,g,h,4 For these reasons, recourse was made to this feature
throughout the present investigation. In accord with this plan,
the lithiated acetals 8 and 17 were first prepared by reaction of
2-bromo-2-cyclopenten-1-one6 and the corresponding enan-
(2) (a) Morwick, T.; Doyon, J.; Paquette, L. A. Tetrahedron Lett. 1995,
36, 2369. (b) Paquette, L. A.; Morwick, T. J. Am. Chem. Soc. 1995, 117,
1451. (c) Paquette, L. A.; Doyon, J. J. Am. Chem. Soc. 1995, 117, 6799.
(d) Wilson, P. D.; Friedrich, D.; Paquette, L. A. J. Chem. Soc., Chem.
Commun. 1995, 1351. (e) Paquette, L. A.; Morwick, T. M.; Negri, J. T.;
Rogers, R. D. Tetrahedron 1996, 52, 3075. (f) Paquette, L. A.; Morwick,
T. M. Submitted for publication. (g) Paquette, L. A.; Doyon, J.; Kuo, L.
H.; Tetrahedron Lett. 1996, 37, 3299. (h) Paquette, L. A.; Hamme, A. T.,
II; Kuo, L. H.; Doyon, J.; Kreuzholz, R. J. Am. Chem. Soc. 1997, 119,
1242.
(3) Brands, M.; Wey, H. G.; Bruckmann, J.; Kru¨ger, C.; Butenscho¨n,
H. Chem. Eur. J. 1996, 2, 182 and references cited therein.
(4) (a) Morwick, T. M.; Paquette, L. A. J. Am. Chem. Soc. 1997, 119,
1230. (b) Paquette, L. A.; Kuo, L. H.; Hamme, A. T., II; Kreuzholz, R.;
Doyon, J. J. Org. Chem. 1997, 62, in press.
(5) Paquette, L. A.; Kuo, L. H.; Doyon, J. Tetrahedron 1996, 52, 11625.
(6) (a) Johnson, C. R.; Sakaguchi, H. Synlett 1992, 813. (b) Johnson, C.
R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.; Wovkulich, P. M.;
Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917.
S0002-7863(96)04140-6 CCC: $14.00 © 1997 American Chemical Society

Enhanced Channeling of the Squarate Cascade
J. Am. Chem. Soc., Vol. 119, No. 13, 1997 3039
Scheme 1
tiopure diols,7,8 followed by halogen-metal exchange with tert-
butyllithium.9 The addition of 1 equiv of 8 to diisopropyl
squarate (7) followed by cyclopentenyllithium gave the two
diasteromeric enol ethers 9 and 10 as a 2.3:1 mixture, readily
separated by flash chromatography on silica gel (Scheme 1).
The absolute stereochemical assignments to these tet-
raquinanes were convincingly established on the following
grounds. Acidic hydrolysis of major product 9 in aqueous
acetone provided the dextrorotary ketone 11 along with its acetal
12 in good yield. Sodium borohydride reduction of 11 in
methanol at 0 °C proceeded chemo- and regioselectively to
furnish carbinol 13, which was esterified with 3â-acetoxy-
etienoyl chloride10 to implement conversion to the highly
crystalline ester 14. X-ray crystallographic analysis of 14
(Figure 1) not only defined unambiguously the six nonsteroidal
stereogenic centers but also demonstrated beyond doubt that 9
had evolved from an anionic oxy-Cope sequence. Since the
hydrolysis of 10 gave rise to a tetracyclic ketone antipodal to
11, this product had also to materialize by [3,3] sigmatropic
rearrangement of a diastereomeric cis adduct to 7.
In the spirit of our operating paradigm, 8 and 17 were added
to 7 as lead-in reagents, to be followed by 2-propenyllithium
(Scheme 2). The objective was to sharpen our insight regarding
the possible impact of the dioxolane substituents on stereocon-
trol. Perhaps not surprisingly in light of the distance involved
between the methyl or cyclohexyl groups and the carbonyl site
in the monoadducts, the two reaction systems gave closely
(7) (2R,3R)-(-)-Butane-2,3-diol was purchased from the Aldrich Chemi-
cal Company.
(8) The dicyclohexyl-substituted diol was generously provided by Prof.
Reinhard Hoffmann, University of Marburg.
(9) (a) Shih, C.; Fritzen, E. L.; Swenton, J. S. J. Org. Chem. 1980, 45,
4462. (b) Smith, A. B., III; Branca, S. J.; Pilla, N. N.; Guaciaro, M. A. J.
Org. Chem. 1982, 47, 1855. (c) Smith, A. B., III; Branca, S. J.; Guaciaro,
M. A.; Wovkulich, P. M.; Korn, A. Organic Syntheses; Wiley: New York,
1990; Collect. Vol. VII, p 271.
Figure 1. Computer-generated X-ray drawing of the final X-ray model
of 14.
(10) Djerassi, C.; Staunton, J. J. Am. Chem. Soc. 1961, 83, 736.

3040 J. Am. Chem. Soc., Vol. 119, No. 13, 1997
Paquette et al.
Scheme 2
Figure 2. Computer-generated X-ray drawing of the final X-ray model
of 22.
Scheme 4
Scheme 3
evidenced by independent TLC monitoring of the fate of 22
under the reaction conditions. With time, 23 was observed to
form at the expense of 22. Single crystal X-ray analysis of 22
(Figure 2) revealed the stereogenic centers in the triquinane
moiety to be enantiotopic to those in 11. Consequently, the
major monoadduct diastereomer, experimentally determined to
be in excess by a factor of only 1.16:1, must be transformed
more efficiently into product in one instance than in the other.
Revealed thereby is the fact that the distribution of final products
need not be related directly to the selectivities of the first
addition. As a consequence of the several diastereomerically
related steps that must be traversed, their individual efficiencies
need not be identical and very likely are not.
The cis-3,5-Dimethoxycyclopentene Substitution Plan.
Mindful of the diagnostic role capable of being played by chiral,
nonracemic cis-3,5-disubstituted cyclopentenyllithium reagents,4
we selectively deprotected the known levorotatory bromide 24
with tetra-n-butylammonium fluoride. Subsequent O-methy-
lation provided the dimethoxy bromide 26 of 85% ee (Scheme
4). Addition of the derived lithium reagent 27 to 7 in advance
of cyclopentenyllithium-generated tetraquinanes 28 and 29 in
approximately equal amounts (ratio 1:1.1). These products hold
the advantage of retaining one of the two stereogenic centers
resident in the lead-in nucleophile. Notwithstanding the fact
that the C-5 methoxyl in 27 suffers â-elimination in order to
control the direction of transannular aldolization, the C-3
methoxyl is not configurationally perturbed and can therefore
be utilized in assignment of absolute stereochemistry at the four
newly introduced stereogenic sites. This protocol was imple-
mented with 29 whose highly crystalline nature permitted
elucidation of its three-dimensional structural features by means
of X-ray crystallography (Figure 3). Comparative analysis of
the NMR spectral data for 29 and 28 formed the basis of the
structural assignment to the latter product (see Experimental
comparable product distributions (1.6-1.8:1). To confirm that
identical stereoinduction had materialized in the two major
products 15 and 18, these enol ethers were separately hydrolyzed
as before. The identical levorotatory triquinane ketone 20 was
produced in these experiments, although conversion was much
faster for 15 (12 h) than for 18 (48 h) (Scheme 3).
For the purpose of comparing the sense of stereochemical
induction in 20 relative to 11, the tricyclic ketone was reduced
to 21 and subsequently treated with (R)-O-methylmandelic acid
chloride.11 Monoesters 22 and 23 were isolated in 86% yield.
The formation of 23 occurs by intramolecular acyl transfer as
(11) Prepared from commercially available (R)-O-methylmandelic acid
by treatment with oxalyl chloride in CH2Cl2 at 0 °C.

Enhanced Channeling of the Squarate Cascade
J. Am. Chem. Soc., Vol. 119, No. 13, 1997 3041
Scheme 5
Figure 3. Computer-generated X-ray drawing of the final X-ray model
of 29.
Section). Particularly significant is the finding that the methoxy
substituents in monoadduct diastereomer A have found it
possible to accomplish “oxy-Cope engineering” by coaxing the
cyclopentenyllithium to form only the syn diadduct B. This is
Following its conversion to 31 by literature methods,12 the same
bromination--reduction-alkylation sequence as employed in
earlier examples was applied (Scheme 5). At the reduction
stage, both alcohol stereoisomers were formed, with the cis
isomer predominating (1.8:1), as determined by NOESY
techniques. Chromatographic separation was undertaken prior
to the O-methylation step, and the independent conversion of
32 and 33 to 34 and 35, respectively, was accomplished in the
predescribed manner.
These optically pure organolithium reagents were indepen-
dently added to diisopropyl squarate (7). In the first case, the
resultant pair of diastereomeric monoadducts3 36 and 37 proved
conveniently separable by chromatography. Subsequently, both
alcohols entered smoothly into reaction with excess cyclopen-
tenyllithium (Scheme 6). Each of these experiments gave rise
to two products, with that arising from cis addition and ensuing
dianionic oxy-Cope rearrangement predominating. Since such
sigmatropic rearrangements transfer chirality efficiently, 38 and
40 would need to be diastereomerically related, and this indeed
was found to be the case. The less-predominant trans-fused
polycyclic acetonide 39 arises from trans addition and rear-
rangement along the electrocyclic cascade. In light of the nature
of this process and the very specific location of the acetonide
unit in the octatetraene intermediate, full control of product
stereochemistry can be achieved by ring closure from the less
sterically congested helix. Only one mode of 8π conrotatory
ring closure appears to be operative since only 39 was isolated
from both experiments and no evidence was found for formation
of a second trans-fused diastereomer.
not the case for C, which serves as the major and perhaps
exclusive percursor to D. These findings alert us to the
possibility that the reactive conformations of the monoadducts
may be those with an exo-oriented double bond as depicted in
A and C. Under these circumstances, A features two methoxyl
oxygens amenable to coordination to the incoming alkenyl-
lithium reagent and C does not. We recognize that the latter
diastereomer could engage in syn delivery if its endo-oriented
rotamer E were populated. However, this is evidently not a
kinetically relevant geometry. Finally, when B is generated,
the pair of cyclopentenyl double bonds must now become endo
oriented in order to allow for development of the boat-like
topography demanded for conversion to 29.
The relative configuration of the triad of tertiary protons in
the southeastern sector of 38-40 was made unambiguously
apparent on the basis of NOE experiments (see Experimental
Section). Since the configuration of the oxygenated center
derives from quinic acid, the absolute stereochemistry of these
products was established simultaneously.
Cyclohexenyl Anions Based on (-)-Quinic Acid. The point
of departure for the preparation of cyclohexenyl bromides
featuring an oxygenated substituent closer to the bond-forming
site than the methoxyl leaving group was (-)-quinic acid (30).
(12) (a) Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.;
Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738. (b) Trost, B. M.; Romero,
A. G. J. Org. Chem. 1986, 51, 2332.

3042 J. Am. Chem. Soc., Vol. 119, No. 13, 1997
Paquette et al.
Scheme 6
treatment with a pair of alkenyllithiums. Properly positioned
basic oxygen substituents resident in the initially formed
monoadduct do indeed have the capability of overriding the
customary sterically-driven kinetic tendency for trans entry of
the second alkenyl anion. This can be explained by complex-
ation of the lithium atom from this reagent to the pendant oxygen
atom in the monoadduct such that intramolecular cis delivery
can become kinetically competitive. It is important to note that
the acetal groups in 8 and 17 give evidence of directing
exclusive syn attack in the diastereomeric pairs of monoadducts
derived from them. Despite the higher level of oxidation
resident in 34 and 35, this particular substitution pattern is not
superior to the others. This is not a simple case of matched
and mismatched arrangements since neither diastereomer exerts
exceptional control. More subtle effects of a type previously
discussed5 may be operative here.
Our investigation into the control of facial selectivity of 2-fold
nucleophilic addition to squarate esters makes evident a range
of other options associated with the rapid synthetic elaboration
of extensively functionalized polycyclic compounds. In this
context, it is of utmost importance to keep in mind that
stereoinductive transmission operates superbly well in the oxy-
Cope rearrangement channel. However, when the electrocyclic
cascade is followed, a chaperone substituent must reside in
sufficient proximity to one of the termini of the octatetraene
helix to guide the directionality of its conrotatory closure and
achieve equally high levels of chirality transfer.
Scheme 7
Experimental Section
The general experimental protocols followed in this study parallel
those described earlier in refs 2f,g.
(2R,3R)-6-Bromo-2,3-dimethyl-1,4-dioxaspiro[4.4]non-6-ene. 2-Bro-
mocyclopenten-1-one (3.0 g, 18.6 mmol), (2R,4R)-2,4-butanediol (1.68
g, 18.6 mmol), and a crystal of p-toluenesulfonic acid were dissolved
in 30 mL of benzene and placed in a 50 mL flask equipped with a
Dean-Stark trap. The reaction mixture was refluxed for 2 d, cooled,
and treated with solid K2CO3 (300 mg). Evaporation of the solvent
and chromatography of the residue on silica gel (elution with 30% ethyl
acetate in hexanes) gave 3.0 g (69%) of the ketal and 0.70 g (23%) of
recovered starting ketone. For the ketal: IR (neat, cm-1) 1621, 1377,
1
1314, 1158; H NMR (300 MHz, C6D6) δ 5.77 (t, J ) 2.4 Hz, 1 H),
3.98-3.88 (m, 1 H), 3.40 (m, 1 H), 2.09-2.01 (m, 2 H), 1.99-1.87
(m, 2 H), 1.10 (d, J ) 6.0 Hz, 3 H), 0.99 (d, J ) 6.0 Hz, 3 H); 13C
NMR (75 MHz, C6D6) ppm 135.8, 125.9, 117.1, 79.8, 79.1, 35.9, 28.8,
16.8, 16.3; MS m/z (M+) calcd 232.0099, obsd 232.0104; [R]21D +10.1°
(c 1.10, CHCl3).
When 35 was added to 7, carbinols 41 and 42 were found to
co-elute (as is often observed). In this instance, however, the
tert-butyldimethylsilyl derivatives 43 and 44 proved amenable
to chromatographic separation (Scheme 7). Once accomplished,
deprotection was effected with fluoride ion to return isomerically
pure samples of the individual alcohols. These intermediates
were subjected in turn to the action of cyclopentenyllithium as
before. Careful spectroscopic analysis and chromatography of
the product mixtures revealed that 39 was the more dominant
ketone in both of these examples. These results demonstrate
that the stereogenicity of the methoxyl-substituted carbon plays
no controlling role in the electrocyclic cascade, which is totally
regulated by the acetonide unit. On the other hand, since 41 is
the precursor of 38, and 42 leads uniquely to 40, the oxy-Cope
pathway proceeds with telltale residual evidence of the specific
monoadduct stereoisomer from which the sigmatropic rear-
rangement is initiated.
(2R,3R)-6-Bromo-2,3-dicyclohexyl-1,4-dioxaspiro[4.4]non-6-
ene. The title compound was prepared in the predescribed manner
(7-d reflux) in 88% yield; IR (neat, cm-1) 1622, 1450, 1317, 1214,
1
1170; H NMR (300 MHz, CDCl3) δ 6.17 (t, J ) 2.7 Hz, 1 H), 3.83
(t, J ) 6.5 Hz, 1 H), 3.63 (t, J ) 6.5 Hz, 1 H), 2.38-2.32 (m, 2 H),
2.13 (m, 2 H), 2.00-1.50 (series of m, 10 H), 1.40-1.43 (m, 1 H),
1.40-1.00 (series of m, 10 H), 0.95-0.80 (t, J ) 3.5 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) ppm 136.6, 125.1, 117.1, 84.3, 83.2, 40.8 (2
C), 35.6, 30.3, 30.2, 28.8, 28.0, 26.4 (2 C), 26.3 (2 C), 26.0 (2 C); MS
m/z (M+) calcd 368.1349, obsd 368.1350; [R]21D +28° (c 0.80, CHCl3).
(3aR,6aS,6bR,9bR)-4,5,6,6a,6b,7,7,9b-Octahydro-9b-hydroxy-9-
[(1R,2R)-2-hydroxy-1-methylpropoxy]-1,2-diisoproxy-3H-dicyclopenta-
[a,b]pentalen-3-one (9) and (3aS,6aR,6bS,9bS)-4,5,6,6a,6b,7,7,9b-
Octahydro9b-hydroxy-9-[(1R,2R)-2-hydroxy-1-methylpropoxy]-1,2-
diisoproxy-3H-dicyclopenta[a,b]pentalen-3-one (10). The lithium
reagent 8 was prepared by treating a solution of the bromo acetal (0.42
g, 1.80 mmol) in dry THF (9 mL) with tert-butyllithium (2.3 mL of
1.7 M in pentane, 3.91 mmol) dropwise at -78 °C. The mixture was
stirred at this temperature for 1 h before 7 (0.36 g, 1.81 mmol) dissolved
in THF (9 mL) was introduced. After an additional 2.5 h of stirring at
-78 °C, a solution of cyclopentenyllithium [from 0.70 g (3.60 mmol)
of the iodide in THF (18 mL) and tert-butyllithium (4.7 mL of 1.7 M
in pentane, 7.99 mmol)] was transferred in via cannula. Afer the
Conclusions
In light of the predescribed results, we now can interpret more
sharply the options available to squarate esters during their

Enhanced Channeling of the Squarate Cascade
J. Am. Chem. Soc., Vol. 119, No. 13, 1997 3043
mixture had stirred at 22 °C for 20 h, the reaction mixture was quenched
with deoxygenated, saturated NH4Cl solution (10 mL) and extracted
with ether (2 × 20 mL). The combined organic layers were washed
with water (20 mL) and brine (20 mL), dried, and concentrated. Flash
chromatography of the residue on silica gel (elution with 3:1 hexanes/
ethyl acetate) gave 76 mg (10%) of 10 and 170 mg (23%) of 9.
(3aR,6aS,6bR,9R,9aS,9bR)-4,5,6,6a,6b,7,8,9,9a,9b-Decahydro-9,-
9b-dihydroxy-1,2-diisopropoxy-3H-dicyclopenta[a,b]pentalen-3-
one (13). A cold (0 °C), magnetically stirred solution of 11 (66 mg,
0.18 mmol) in methanol (3 mL) was treated with sodium borohydride
(7.0 mg, 0.18 mmol), stirred at 22 °C for 2 h, and quenched with water
(3 mL). The mixture was extracted with ether (2 × 10 mL), and the
combined organic layers were washed with water (10 mL) and brine
(10 mL), dried, and concentrated. Purification of the residue by flash
chromatography on silica gel (elution with 6:1 hexanes/ethyl acetate)
gave 13 (51 mg, 77%) as a white solid: mp 134-136 °C; IR (neat,
For 9: yellowish oil; IR (neat, cm-1) 3400, 1691, 1613, 1379, 1101;
1H NMR (300 MHz, C6D6) δ 5.55 (heptet, J ) 6.0 Hz, 1 H), 5.24
(heptet, J ) 6.0 Hz, 1 H), 4.92-4.88 (br, 1 H), 4.67-4.42 (br, 1 H),
3.69 (quint, J ) 6.3 Hz, 1 H), 3.56 (quint, J ) 6.3 Hz, 1 H), 2.98-
2.91 (m, 1 H), 2.57-2.49 (m, 1 H), 2.43-2.37 (m, 1 H), 2.34-2.27
(m, 1 H), 2.20-2.11 (m, 1 H), 1.92-1.74 (m, 2 H), 1.71-1.59 (m, 2
H), 1.57-1.49 (m, 1 H), 1.47-1.32 (m, 1 H), 1.28 (d, J ) 6.0 Hz, 3
H), 1.26 (d, J ) 6.0 Hz, 3 H), 1.23 (d, J ) 6.0 Hz, 3 H), 1.21 (d, J )
1
cm-1) 3550, 1691, 1612, 1306, 1101; H NMR (300 MHz, CDCl3) δ
5.36 (heptet, J ) 6.1 Hz, 1 H), 4.93 (heptet, J ) 6.1 Hz, 1 H), 4.45-
4.43 (m, 1 H), 4.32-4.07 (br, 1 H), 3.05-2.71 (br, 1 H), 2.69-2.66
(m, 1 H), 2.64-2.53 (m, 2 H), 1.98-1.70 (m, 7 H), 1.68-1.54 (m, 3
H), 1.34 (d, J ) 6.1 Hz, 1 H), 1.32 (d, J ) 6.1 Hz, 3 H), 1.20 (d, J )
6.1 Hz, 3 H), 1.18 (d, J ) 6.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 205.0, 167.2, 130.5, 83.2, 75.1, 73.9, 71.9, 69.7, 57.8, 51.1, 43.3,
36.6, 31.2, 29.1, 28.8, 25.8, 22.8 (2 C), 22.7, 22.5; MS m/z (M+) calcd
6.0 Hz, 3 H), 1.08 (d, J ) 6.3 Hz, 3 H), 1.00 (d, J ) 6.3 Hz, 3 H); 13
C
NMR (75 MHz, C6D6) ppm 202.4, 166.3, 151.6, 133.3, 120.4, 80.4,
78.1, 73.2, 71.4, 71.3, 70.6, 51.4, 44.6, 33.8, 30.3, 28.0, 27.3, 22.7,
22.6, 22.5, 22.4, 22.3, 18.6, 17.2; MS m/z (M+) calcd 420.2518, obsd
350.2097, obsd 350.2095; [R]22 -9.5° (c 0.37, CHCl3).
420.2515; [R]22 -200° (c 0.32, C6H6).
D
D
Anal. Calcd. for C20H30O5: C, 68.53; H, 8.63. Found: C, 68.44;
H, 8.63.
For 10: yellowish oil; IR (neat, cm-1) 3407, 1692, 1614, 1379, 1103;
1H NMR (300 MHz, C6D6) δ 5.43 (heptet, J ) 6.5 Hz, 1 H), 5.40
(heptet, J ) 6.5 Hz, 1 H), 4.49-4.37 (br, 1H), 3.84 (quint, J ) 6.3
Hz, 1 H), 3.63 (quint, J ) 6.3 Hz, 1 H), 3.38-3.16 (br, 1 H), 3.04-
2.96 (m, 1 H), 2.64-2.52 (m, 2 H), 2.49-2.42 (m, 1 H), 2.39-2.29
(m, 1 H), 2.24-2.05 (m, 1 H), 1.91-1.81 (m, 2 H), 1.70-1.64 (m, 2
H), 1.62-1.45 (m, 1 H), 1.42-1.30 (m, 1 H), 1.29 (d, J ) 6.5 Hz, 3
H), 1.27 (d, J ) 6.5 Hz, 3 H), 1.20 (d, J ) 6.5 Hz, 3 H), 1.18 (d, J )
3â-Acetoxyandrost-5-ene-17â-carboxylic Acid, 9-Ester with (3aR,-
6aS,6bR,9R,9aS,9bR)-4,5,6,6a,6b,7,8,9,9a,9b-decahydro-9,9b-dihy-
droxy-1,2-diisopropoxy-3H-dicyclopenta[a,b]pentalen-3-one (14). A
solution of 13 (82 mg, 0.23 mmol) in CH2Cl2 (5 mL) cooled to 0 °C
was treated with 3â-acetoxyetienoyl chloride (0.13 g, 0.34 mmol) and
triethylamine (0.10 mL, 0.71 mmol), and the mixture was stirred at
room temperature for 5 h. Water (5 mL) was added, and the product
was extracted into CH2Cl2 (2 × 10 mL). The combined organic layers
were washed with water (10 mL) and brine (10 mL), dried, and
concentrated. Purification of the product by flash chromatography on
silica gel (elution with 8:1 hexanes/ethyl acetate) gave 14 (0.15 g, 91%)
as a white solid: mp 139-141 °C; IR (neat, cm-1) 3561, 1731, 1697,
1622, 1247; 1H NMR (300 MHz, CDCl3) δ 5.51-5.44 (m, 1 H), 5.36-
5.26 (m, 2 H), 4.84 (heptet, J ) 6.1 Hz, 2 H), 4.57-4.52 (m, 1 H),
3.45 (br, 1 H), 2.66-2.53 (m, 3 H), 2.38-1.99 (m, 6 H), 1.98 (s, 3 H),
1.95-1.62 (m, 10 H), 1.61-1.40 (m, 8 H), 1.35-1.03 (series of m, 18
H), 0.97 (s, 3 H), 0.65 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 204.2,
172.7, 170.4, 168.3, 139.6, 128.8, 122.2, 82.1, 75.6, 73.7, 73.6, 71.8,
70.4, 57.1, 56.5, 55.4, 49.8, 48.6, 46.7, 44.2, 38.6, 38.0, 36.9, 36.5,
33.3, 32.0, 31.9, 31.7, 29.2 (2 C), 27.7, 24.9, 24.5, 23.6, 22.8 (3 C),
22.3, 21.4, 21.0, 19.3, 13.5; MS m/z (M+) calcd 692.4242, obsd
6.5 Hz, 3 H), 1.12 (d, J ) 6.3 Hz, 3 H), 0.99 (d, J ) 6.3 Hz, 3 H); 13
C
NMR (75 MHz, C6D6) ppm 202.7, 165.3, 152.3, 132.8, 118.1, 80.7,
77.5, 73.6, 71.8, 71.2, 71.0, 51.2, 45.9, 35.9, 30.3, 28.0, 27.1, 23.1,
22.7, 22.6, 22.5, 22.3, 18.5, 17.3; MS m/z (M+) calcd 420.2518, obsd
420.2524; [R]22 +213° (c 0.46, C6H6).
D
(3aR,6aS,6bR,9aR,9bR)-5,6,6b,7,8,9a,9b-Octahydro-9b-hydroxy-
1,2-diisopropoxy-3H-dicyclopenta[a,b]pentalene-3,9(4H)-dione (11)
and (3aR,4′R,5′R,6aR,6bR,9aR,9bS)-2,3,6a,6b,8,9,9a,9b-Octahydro-
6a-hydroxy-5,6-diisopropoxy-4′,5′-dimethylspiro(7H-dicyclopenta-
[a,b]-pentalene-7,2′-[1,3]dioxolan)-4(1H)-one (12). A solution of 9
(0.10 g, 0.23 mmol) in acetone (8 mL) and water (4 mL) was treated
with concentrated HCl (4 drops) and stirred at 22 °C for 24 h. The
mixture was extracted with ether (2 × 15 mL), and the combined
organic layers were washed with water (15 mL) and brine (15 mL)
prior to drying and evaporation. The residue was subjected to flash
chromatography on silica gel (elution with 6:1 hexanes/ethyl acetate)
and afforded 13 mg (13%) of 12 and 42 mg (51%) of 11.
692.4265; [R]22 -54.2° (c 0.8, CHCl3).
D
Anal. Calcd. for C42H60O8: C, 72.79; H, 8.73. Found: C, 72.69;
H, 8.70.
For 11: pale yellowish oil; IR (neat, cm-1) 3441, 1698, 1625, 1102;
1H NMR (300 MHz, CDCl3) δ 5.34 (heptet, J ) 6.1 Hz, 1 H), 5.12 (s,
1 H), 4.94 (heptet, J ) 6.1 Hz, 1 H), 2.84 (d, J ) 9.2 Hz, 1 H), 2.72
(dd, J ) 15.8, 8.5 Hz, 1 H), 2.61 (dd, J ) 17.1, 8.5 Hz, 1 H), 2.46-
2.42 (m, 1 H), 2.41 (d, J ) 9.2 Hz, 1 H), 2.38-2.06 (m, 1 H), 2.03-
1.89 (m, 2 H), 1.84-1.78 (m, 2 H), 1.76-1.62 (m, 2 H), 1.34 (d, J )
6.1 Hz, 3 H), 1.30 (d, J ) 6.1 Hz, 3 H), 1.21 (d, J ) 6.1 Hz, 3 H),
1.11 (d, J ) 6.1 Hz, 3 H), 1.16-1.10 (m, 1 H); 13C NMR (75 MHz,
CDCl3) ppm 223.3, 203.0, 166.0, 131.9, 83.4, 73.9, 72.0, 66.8, 55.2,
52.8, 39.9, 39.0, 31.0, 29.5, 28.0, 22.8, 22.7, 22.6, 22.5, 21.8; MS m/z
(3aS,6aR,6bS,9bS)-5,6,6a,6b,7,8,9a,9b-Octahydro-9b-hydroxy-
1,2-diisopropoxy-3H-dicyclopent[a,b]pentalene-3,9(4H)-dione (ent-
11). A solution of 10 (39 mg, 0.09 mmol) in aceteone (4 mL) and
water (2 mL) was treated with concentrated HCl (2 drops), and the
mixture was stirred at 22 °C for 21 h prior to extraction with ether (2
× 20 mL). The combined organic layers were washed with water (10
mL) and brine (10 mL), dried, and concentrated. The residue was
subjected to flash chromatography on silica gel (elution with 6:1
hexanes/ethyl acetate) and gave 22 mg (67%) of ent-11, [R]22D -13.0°
(c 0.28, CHCl3).
(M+) calcd 348.1940, obsd 348.1938; [R]22 +13.9° (c 0.55, CHCl3).
D
(3aS,6aS,7aS)-3a,5,6,6a,7,7a-Hexahydro-3a-hydroxy-4-[(1R,2R)-
2-hydroxy-1-methylpropoxy]-2,3-diisopropoxy-7a-methyl-1H-cyclo-
penta[a]pentalen-1-one (15) and (3aR,6aR,7aR)-3a,5,6,6a,7,7a-
Hexahydro-3a-hydroxy-4-[(1R,2R)-2-hydroxy-1-methylpropoxy]-
2,3-diisopropoxy-7a-methyl-1H-cyclopenta[a]pentalen-1-one (16).
Reaction of 8 [from 932 mg (4.0 mmol) of bromo acetal] with 7 (400
mg, 2.0 mmol) and 2-lithiopropene [from 484 mg (4.0 mmol) of
2-bromopropene] in the predescribed manner was followed by overnight
stirring at room temperature, an aqueous NH4Cl quench, and the usual
workup. The thick oil so obtained was subjected to flash chromatog-
raphy on silica gel (elution with 1:1 hexanes/ethyl acetate) to give 254
mg (32%) of 15 and 143 mg (18%) of 16.
For 15: thick colorless oil; IR (neat, cm-1) 3412, 1692, 1614, 1452,
1380, 1330; 1H NMR (300 MHz, C6D6) δ 5.41 (heptet, J ) 6.1 Hz, 1
H), 5.32 (heptet, J ) 6.1 Hz, 1 H), 3.90 (br s, 1 H), 3.57-3.46 (m, 2
H), 3.10 (br s, 1 H), 2.66-2.56 (m, 1 H), 2.51 (m, 1 H), 2.41-2.20
(m, 2 H), 1.72 (m, 1 H), 1.41 (s, 3 H), 1.40-1.20 (m, 1 H), 1.22 (d, J
Anal. Calcd. for C20H28O5: C, 68.93; H, 8.10. Found: C, 69.03;
H, 8.12.
For 12: pale yellowish oil; IR (neat, cm-1) 3485, 1698, 1625, 1102;
1H NMR (300 MHz, CDCl3) δ 5.32 (heptet, J ) 6.2 Hz, 1 H), 4.92 (s,
1 H), 4.88 (heptet, J ) 6.2 Hz, 1 H), 3.83-3.74 (m, 1 H), 3.59-3.50
(m, 1 H), 2.77-2.66 (m, 2 H), 2.50 (d, J ) 6.0 Hz, 1 H), 2.17-2.06
(m, 2 H), 2.03-1.86 (m, 1 H), 1.84-1.71 (m, 4 H), 1.69-1.61 (m, 2
H), 1.59-1.48 (m, 1 H), 1.33 (d, J ) 6 Hz, 3 H), 1.32 (d, J ) 6.2 Hz,
3 H), 1.26 (d, J ) 6.2 Hz, 3 H), 1.23 (d, J ) 6.2 Hz, 3 H), 1.22 (d, J
) 6.2 Hz, 3 H), 1.17 (d, J ) 6.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 204.3, 169.0 128.6, 118.2, 82.4, 79.2, 77.3, 73.4, 71.8, 70.4, 62.2,
48.5, 47.0, 39.6, 32.3, 29.2, 29.1, 24.8, 23.0, 22.9, 22.7, 22.4, 16.6,
16.4; MS m/z (M+) calcd 420.2517, obsd 420.2514; [R]22 -48.7° (c
D
0.16, CHCl3).
Anal. Calcd. for C24H36O6: C, 68.53; H, 8.63. Found: C, 68.62;
H, 8.62.

3044 J. Am. Chem. Soc., Vol. 119, No. 13, 1997
Paquette et al.
) 6.1 Hz, 3 H), 1.20 (d, J ) 6.1 Hz, 3 H), 1.17 (d, J ) 6.1 Hz, 3 H),
1.13 (d, J ) 6.1 Hz, 3 H), 1.09 (m, 1 H), 0.97 (d, J ) 5.9 Hz, 3 H),
0.93 (d, J ) 5.8 Hz, 3 H); 13C NMR (75 MHz, C6D6) ppm 202.3,
165.7, 151.4, 132.4, 124.0, 80.5, 78.6, 73.7, 71.7, 71.5, 61.2, 43.34,
43.28, 34.4, 28.4, 22.9, 22.83, 22.78, 22.6, 20.0, 18.8, 17.4; MS m/z
1.20-1.05 (m, 2 H), 0.90 (m, 1 H); 13C NMR (75 MHz, C6D6) ppm
221.8, 201.5, 165.7, 132.4, 84.4, 73.7, 71.7, 56.8, 56.6, 39.9, 38.2, 35.7,
22.9, 22.7, 22.6, 22.55, 22.4, 19.8; MS m/z (M+) calcd 322.1780, obsd
322.1773; [R]22 -16° (c 1.0, CHCl3).
D
(3aS,3bR,4S,6aS,7aS)-3a,3b,4,6,6a,7,7a-Octahydro-3a,4-dihydroxy-
2,3-diisopropoxy-7a-methyl-1H-cyclopenta[a]pentalen-1-one (21).
Sodium borohydride (5.0 mg, 0.132 mmol) was added in one portion
to a solution of 20 (20 mg, 0.62 mmol) in methanol (0.5 mL). The
reaction mixture was left to stir overnight, concentrated, diluted with
saturated NH4Cl solution, and extracted with ether. Drying of the
organic extracts and concentration gave an oil which was purified by
flash chromatography (silica gel, elution with 50% ethyl acetate in
hexanes) to obtain 10 mg (94%) of 21 as a colorless solid: mp 117-
119 °C (from ethyl acetate/hexanes); IR (film, cm-1) 3373, 1693, 1614,
1454, 1381, 1310; 1H NMR (300 MHz, C6D6) δ 5.38 (heptet, J ) 6.1
Hz, 1 H), 5.33 (heptet, J ) 6.1 Hz, 1 H), 4.21 (t, J ) 3.8 Hz, 1 H),
3.75 (s, 1 H), 2.58-2.45 (m, 3 H), 2.15-1.95 (m, 1 H), 1.80-1.35
(series of m, 5 H), 1.31 (s, 3 H), 1.18 (d, J ) 6.1 Hz, 3 H), 1.17 (d, J
) 6.1 Hz, 3 H), 1.15 (d, J ) 6.1 Hz, 3 H), 1.11 (d, J ) 6.1 Hz, 3 H);
13C NMR (75 MHz, C6D6) ppm 203.0, 166.5, 132.0, 84.4, 75.5, 73.5,
71.5, 58.4, 57.3, 44.7, 40.0, 36.7, 29.4, 22.83, 22.78, 22.73, 22.5, 19.1;
(M+) calcd 394.2380, obsd 394.2368; [R]22 -296° (c 0.86, CHCl3).
D
For 16: pale yellow oil; IR (neat, cm-1) 3400, 1695, 1653, 1453,
1380, 1320; 1H NMR (300 MHz, C6D6) δ 5.38 (heptet, J ) 6.1 Hz, 1
H), 5.33 (heptet, J ) 6.1 Hz, 1 H), 4.07 (quint, J ) 6.2 Hz, 1 H), 3.55
(quint, J ) 6.2 Hz, 1 H), 3.05 (br s, 1 H), 2.70-2.60 (m, 1 H), 2.55-
2.40 (m, 2 H), 2.30-2.20 (m, 1 H), 1.80-1.60 (m, 2 H), 1.42 (s, 3 H),
1.40-1.00 (series of m, 2 H), 1.23 (d, J ) 6.1 Hz, 3 H), 1.22 (d, J )
6.1 Hz, 3 H), 1.16 (d, J ) 6.1 Hz, 3 H), 1.10 (d, J ) 6.1 Hz, 3 H),
1.06 (d, J ) 6.2 Hz, 3 H), 0.93 (d, J ) 6.2 Hz, 3 H); 13C NMR (75
MHz, C6D6) ppm 202.6, 165.1, 152.2, 132.3, 120.4, 81.0, 78.3, 74.0,
72.2, 71.6, 61.4, 44.6, 43.4, 36.3, 28.7, 22.9, 22.8, 22.6, 22.5, 20.2,
18.8, 17.7; MS m/z (M+) calcd 394.2355, obsd 394.2355; [R]22D +211°
(c 0.63, CHCl3).
(3aS,6aS,7aS)-4-[(1R,2R)-1,2-Dicyclohexyl-2-hydroxyethoxo]-
3a,5,6,6a,7,7a-hexahydro-3a-hydroxy-2,3-diisopropoxy-7a-methyl-
1H-cyclopenta[a]pentalen-1-one (18) and (3aR,6aR,7aR)-1,2-Dicy-
clohexyl-2-hydroxyethoxo]-3a,5,6,6a,7,7a-hexahydro-3a-hydroxy-
2,3-diisopropoxy-7a-methyl-1H-cyclopenta[a]pentalen-1-one (19).
Reaction of 17 [from 738 mg (2.0 mmol) of the bromo acetal] with 7
(200 mg, 1.0 mmol) (reaction time of 1 h) and then 2-lithiopropene
[from 242 mg (2.0 mmol) of 2-bromopropene] for 14 h at room
temperature followed by the usual workup provided a residual gum
that was subjected to chromatography on silica gel (elution with 15%
ethyl acetate in hexanes containing 1% triethylamine). There was
isolated 205 mg (38%) of 18 and 125 mg (24%) of 19.
MS m/z (M+) calcd 324.1935, obsd 324.1936; [R]22 -263° (c 0.45,
D
CHCl3).
Anal. Calcd. for C18H28O5: C, 66.64; H, 8.70. Found: C, 66.64;
H, 8.69.
(3aS,3bR,3bS,6aS,7aS)-2,3,3a,3b,6,6a,7,7a-Octahydro-3b-hydroxy-
4,5-diisopropoxy-6a-methyl-6-oxo-1H-cyclopenta[a]pentalen-3-yl (R)-
methoxyphenylacetate (22) and (3aS,3bR,4S,6aS,7aS)-1,3b,4,5,6,-
6a,7,7a-Octahydro-4-hydroxy-2,3-diisopropoxy-7a-methyl-1-oxo-
3aH-cyclopenta[a]pentalen-3a-yl (R)-methoxyphenylacetate (23).
(R)-O-Methylmandelic acid (50 mg, 0.3 mmol) was dissolved in 2 mL
of CH2Cl2, and the solution was cooled to 0 °C in advance of the
addition of 0.6 mmol of oxalyl chloride. After overnight stirring at
room temperature, the solvent was evaporated under vacuum and 40
mg (0.12 mmol) of 21 in 2 mL of CH2Cl2 was added, followed by 75
mg of triethylamine and a crystal of 4-(dimethylamino)pyridine. After
2 h, the alcohol could no longer be detected by TLC. The volatile
organics were removed under vacuum, and the resulting mixture was
applied directly to a column of silica gel (elution with 20% ethyl acetate
in hexanes). Esters 23 and 22 were isolated (total 47 mg, 81%) in
order of elution.
For 18: pale yellowish oil; IR (neat, cm-1) 3348, 1684, 1608, 1380,
1332, 1263; 1H NMR (300 MHz, C6D6) δ 5.53 (heptet, J ) 6.1 Hz, 1
H), 5.19 (heptet, J ) 6.1 Hz, 1 H), 4.40 (br s, 1 H), 3.75 (br s, 1 H),
3.69 (t, J ) 4.7 Hz, 1 H), 3.47 (t, J ) 4.7 Hz, 1 H), 2.70-2.40 (m, 3
H), 2.20-2.35 (m, 1 H), 1.80-1.40 (series of m, 12 H), 1.36 (s, 3 H),
1.29 (d, J ) 6.1 Hz, 3 H), 1.26 (d, J ) 6.1 Hz, 3 H), 1.18 (d, J ) 6.1
Hz, 3 H), 1.16 (d, J ) 6.1 Hz, 3 H), 1.40-1.00 (series of m, 12 H),
0.90-0.80 (m, 1 H); 13C NMR (75 MHz, C6D6) ppm 202.2, 166.3,
152.7, 132.9, 120.7, 82.4, 78.8, 76.0, 73.6, 71.7, 65.9, 61.1, 43.7, 43.3,
40.4, 39.8, 33.5, 30.9, 30.6, 28.2, 27.6, 27.4, 26.95, 26.90, 26.8, 26.7,
23.1, 22.9, 22.88, 22.6, 20.1, 15.5; MS m/z (M+) calcd 530.3636, obsd
530.3612; [R]22 -259° (c 0.72, CHCl3).
D
For 22: 28 mg (48%); colorless solid, mp 69-71 °C (from ethyl
acetate); IR (film, cm-1) 3464, 1743, 1698, 1621; 1H NMR (300 MHz,
CDCl3) δ 7.44-7.32 (m, 5 H), 5.40 (heptet, J ) 6.1 Hz, 1 H), 5.30-
5.27 (m, 1 H), 4.95 (heptet, J ) 6.1 Hz, 1 H), 4.75 (s, 1 H), 3.35 (s,
3 H), 3.19 (s, 1 H), 2.71 (m, 1 H), 2.30-2.10 (m, 2 H), 2.05-1.83 (m,
2 H), 1.82-1.70 (m, 1 H), 1.50-1.15 (m, 2 H), 1.36 (d, J ) 6.1 Hz,
3 H), 1.31 (d, J ) 6.1 Hz, 3 H), 1.21 (d, J ) 6.1 Hz, 3 H), 1.20 (d, J
) 6.1 Hz, 3 H), 1.09 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 202.3,
169.6, 162.2, 135.3, 131.5, 129.1, 128.9, 128.9, 127.0, 127.0, 82.6,
83.4, 80.0, 73.9, 71.9, 57.6, 56.9, 55.0, 43.0, 39.8, 34.4, 28.2, 22.7,
22.7, 22.65, 22.4, 17.9; MS m/z (M+) calcd 472.2461, obsd 472.2437.
For 23: 19 mg (33%); colorless oil; IR (neat, cm-1) 3422, 1748,
1700, 1622; 1H NMR (300 MHz, CDCl3) δ 7.45-7.25 (m, 5 H), 5.45-
5.35 (m, 1 H), 5.38 (heptet, J ) 6.1 Hz, 1 H), 4.97 (heptet, J ) 6.1
Hz, 1 H), 4.75 (s, 1 H), 3.41 (s, 3 H), 2.66 (t, J ) 7.3 Hz, 1 H), 2.58
(s, 1 H), 2.16 (q, J ) 6.8 Hz, 2 H), 1.93-1.70 (series of m, 3 H), 1.40
(m, 1 H), 1.35 (d, J ) 6.1 Hz, 3 H), 1.30 (d, J ) 6.1 Hz, 3 H), 1.30-
1.00 (m, 1 H), 1.20 (d, J ) 6.1 Hz, 3 H), 1.19 (d, J ) 6.1 Hz, 3 H),
1.15 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 203.5, 170.1, 166.9,
136.0, 131.3, 128.8, 128.7, 128.7, 127.2, 127.2, 82.9, 82.8, 78.5, 74.0,
71.8, 57.5, 57.2, 55.4, 43.6, 39.5, 34.4, 28.4, 22.7, 22.7, 22.7, 22.4,
18.4; MS m/z (M+) calcd 472.2461, obsd 472.2432.
For 19: thick colorless oil; IR (neat, cm-1) 3560, 3345, 1695, 1614,
1380, 1321, 1259; 1H NMR (300 MHz, C6D6) δ 5.38 (heptet, J ) 6.1
Hz, 1 H), 5.34 (heptet, J ) 6.1 Hz, 1 H), 4.20 (br s, 1 H), 3.96 (dd, J
) 7.1, 3.0 Hz, 1 H), 3.61 (dd, J ) 7.1, 3.0 Hz, 1 H), 2.80-2.60 (series
of m, 2 H), 1.46 (s, 3 H), 1.33 (d, J ) 6.0 Hz, 3 H), 1.26 (d, J ) 6.0
Hz, 3 H), 1.14 (d, J ) 6.0 Hz, 3 H), 1.09 (d, J ) 6.0 Hz, 3 H), 1.40-
0.90 (series of m, 20 H); 13C NMR (75 MHz, C6D6) ppm 202.6, 165.2,
153.6, 132.2, 119.6, 84.5, 78.2, 76.3, 74.4, 71.6, 61.4, 44.1, 43.6, 40.1,
39.7, 35.9, 30.9, 30.6, 29.2, 26.9, 26.85, 26.76, 26.71, 26.6, 26.51, 26.46,
23.1, 22.9, 22.8, 22.52, 22.49, 20.1; MS m/z (M+) calcd 530.3616, obsd
530.3612; [R]22 +100° (c 0.55, CHCl3).
D
(3aS,3bS,6aS,7aS)-3b,4,6,6a,7,7a-Hexahydro-3a-hydroxy-2,3-di-
isopropoxy-7a-methyl-1H-cyclopenta[a]pentalene-1,4-(3aH)-dione
(20). A solution of 15 (40 mg, 0.10 mmol) in 5 mL of wet acetone
was treated with 1 drop of 10% HCl, stirred overnight at room
temperature, and quenched with 1 mL of saturated NaHCO3 solution.
The acetone was evaporated, and the resulting aqueous solution was
extracted with ether. The combined organic extracts were dried and
concentrated. Following a short flash chromatography (silica gel,
elution with 20% ethyl acetate in hexanes) and solvent removal, 32
mg (100% of 20 was obtained as a colorless oil.
The hydrolysis of 18 was slower, and it was necessary to heat the
(1S,4R)-3-Bromo-4-methoxy-2-cyclopentenol (25). A solution of
24 (1.10 g, 3.58 mmol) in THF (24 mL) was cooled to 0 °C and treated
dropwise with tetra-n-butylammonium fluoride (7.2 mL of 1 M in THF,
7.2 mmol), and the mixture was stirred at room temperature for 30
min before the addition of water (10 mL) and extraction with ether (2
× 20 mL). The combined organic phases were washed with water
(20 mL) and brine (20 mL), dried, and concentrated. The residue was
purified by flash chromatography (silica gel, elution with 3:1 hexanes/
reaction mixture at reflux for 2 d to obtain the identical ketone.
For 20: IR (film, cm-1) 3450, 1723, 1698, 1621, 1381, 1300; H
1
NMR (300 MHz, C6D6) δ 5.33 (heptet, J ) 6.1 Hz, 1 H), 5.27 (heptet,
J ) 6.1 Hz, 1 H), 5.12 (s, 1 H), 2.44 (d, J ) 7.5 Hz, 1 H), 2.16 (m, 1
H), 2.03 (m, 1 H), 1.85 (dq, J ) 8.5, 3.6 Hz, 1 H), 1.72 (br dd, J )
8.5, 3.6 Hz, 1 H), 1.26 (s, 2 H), 1.17 (d, J ) 6.1 Hz, 3 H), 1.16 (d, J
) 6.1 Hz, 3 H), 1.15 (d, J ) 6.1 Hz, 3 H), 1.06 (d, J ) 6.1 Hz, 3 H),

Enhanced Channeling of the Squarate Cascade
J. Am. Chem. Soc., Vol. 119, No. 13, 1997 3045
ethyl acetate) to give 25 as a yellowish liquid (0.53 g, 77%): IR (neat,
(3aR,5S,7aS)-6-Bromo-3a,4,5,7a-tetrahydro-5-methoxy-2,2-dim-
ethyl-1,3-benzodioxole (32). A cold (0 °C) solution of 31 (500 mg,
3.0 mmol) in CH2Cl2 (10 mL) was treated dropwise during 5 min with
a CH2Cl2 solution (5 mL) of bromine (0.17 mL, 3.29 mmol), followed
by triethylamine (0.95 mL, 6.82 mmol). After an additional 5 min at
0 °C, the reaction mixture was warmed to room temperature, filtered
through a short pad of silica gel, and freed of solvent. The residue
was chromatographed on silica gel (elution with 20% ethyl acetate in
hexanes containing 0.1% triethylamine) to give 636 mg (87%) of the
bromo enone as a white crystalline solid: mp 108-110 °C; IR (neat,
1
cm-1) 3384, 1689, 1356, 1077; H NMR (300 MHz, CDCl3) δ 6.07
(br, 1 H), 4.45-4.41 (m, 1 H), 4.11-3.96 (m, 1 H), 3.78 (br, 1 H),
3.31 (s, 3 H), 2.62 (dt, J ) 14.0, 7.4 Hz, 1 H), 1.60 (dt, J ) 14.0, 4.0
Hz, 1 H); 13C NMR (75 MHz, CDCl3) ppm 137.3, 126.8, 84.6, 72.5,
56.1, 39.3; MS m/z (M+) calcd 191.9728, obsd 191.9757; [R]22D -36.9°
(c 0.74, CHCl3).
(3S,5R)-1-Bromo-3,5-dimethoxycyclopentene (26). Alcohol 25
(0.51 g, 2.64 mmol) in THF (10 mL) was added dropwise at 0 °C to
a magnetically stirred suspension of sodium hydride (0.17 g of 60%
dispersion in mineral oil, 4.25 mmol) in the same solvent (10 mL).
After 1 h at room temperature, methyl iodide (0.90 mL, 14.5 mmol)
was introduced at 0 °C and stirring was maintained at 22 °C for 2 h.
Water (5 mL) was added, the mixture was extracted with ether (2 x 10
mL), and the combined organic solutions were washed with water (10
mL) and brine (10 mL), dried, and concentrated. The residue was
subjected to flash chromatography (silica gel, elution with 20:1 hexanes/
ethyl acetate) to provide 26 as a pale yellowish liquid (0.40 g, 74%):
IR (neat, cm-1) 1620, 1455, 1358, 1097; 1H NMR (300 MHz, CDCl3)
δ 6.17 (br, 1 H), 4.43-4.16 (m, 1 H), 4.14-4.09 (m, 1 H), 3.31 (s, 3
H), 3.25 (s, 3 H), 2.56 (dt, J ) 13.9, 7.4 Hz, 1 H), 1.72 (dt, J ) 13.9,
4.0 Hz, 1 H); 13C NMR (75 MHz, CDCl3) ppm 134.4, 128.3, 84.1,
80.9, 55.8, 55.4, 35.6; MS m/z (M+) calcd 205.9918, obsd 205.9930;
1
cm-1) 1703, 1613, 1383, 1371, 1226; H NMR (300 MHz, CDCl3) δ
7.08 (dd, J ) 3.0, 1.8 Hz, 1 H), 4.75 (dd, J ) 4.8, 3.0 Hz, 1 H), 4.67
(m, 1 H), 3.16 (dd, J ) 17.4, 2.6 Hz, 1 H), 2.79 (dd, J ) 17.4, 3.6 Hz,
1 H), 1.38 (s, 6 H); 13C NMR (75 MHz, CDCl3) ppm 187.3, 146.1,
124.2, 110.4, 73.3, 72.9, 38.6, 27.7, 26.5; MS m/z (M+ - CH3) calcd
230.9656, obsd 230.9660; [R]22 -20.8° (c 1.09, CHCl3).
D
The bromo enone (76 mg, 0.31 mmol) was dissolved in dry methanol
(1.5 mL) containing cerium trichloride heptahydrate (126 mg, 0.34
mmol) at 0 °C and treated with sodium borohydride (58 mg, 1.5 mmol)
in two portions. After 15 min, saturated NH4Cl solution was introduced
and the products were extracted into CH2Cl2, dried, and concentrated.
The 1.8:1 cis/trans mixture of alcohols (1H NMR analysis) was separated
into its components by chromatography on silica gel (elution with 20%
ethyl acetate in hexanes). There was isolated 48 mg (62%) of the cis
isomer and 27 mg (35%) of the trans isomer, both as white crystalline
solids.
[R]22 -56.7° (c 0.56, CHCl3).
D
(3aR,6aS,6bR,7S,9bR)-4,5,6,6a,6b,7,8,9b-Octahydro-9b-hydroxy-
1,2-diisopropoxy-7-methoxy-3H-dicyclopenta[a,b]pentalen-3-one (28)
and (3aS,6aR,6bS,7S,9bS)-4,5,6,6a,6b,7,8,9b-Octahydro-9b-hydroxy-
1,2-diisopropoxy-7-methoxy-3H-dicyclopenta[a,b]pentalen-3-one (29).
Reaction of 27 [from 0.39 g (1.88 mmol) of 26] in THF (10 mL) with
7 (0.37 g, 1.88 mmol) (reaction time of 1 h) and then cyclopentenyl-
lithium [from 0.74 g (3.81 mmol) of the iodide] for 18 h at 22 °C
followed by the usual workup procedure provided a brown liquid that
was purified by flash chromatography on silica gel (elution with 6:1
hexanes/ethyl acetate). There were isolated 0.12 g (17%) of 28 and
0.13 g (19%) of 29.
For the cis alcohol: colorless crystals, mp 69-70 °C; IR (neat, cm-1
)
1
3512, 1645, 1292, 1227, 1154; H NMR (300 MHz, CDCl3) δ 6.07
(dd, J ) 3.1, 1.1 Hz, 1 H), 4.51 (m, 2 H), 4.14 (s, 1 H), 3.31 (d, J )
9.6 Hz, 1 H), 2.56 (ddd, J ) 15.4, 3.5, 2.4 Hz, 1 H), 2.22 (ddd, J )
15.4, 4.6, 2.1 Hz, 1 H), 1.46 (s, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 128.7, 128.1, 110.2, 74.0, 71.9, 69.4, 32.4, 28.1, 26.5; MS m/z
(M+ - CH3) 232.9813, obsd 232.9813; [R]22D -141° (c 1.03, CHCl3).
For the trans alcohol: colorless crystals, mp 125-126 °C; IR (neat,
1
cm-1) 3589, 1643, 1299, 1212, 1154; H NMR (300 MHz, CDCl3) δ
For 28: pale yellowish oil; IR (neat, cm-1) 3398, 1691, 1613, 1306,
1108; 1H NMR (300 MHz, CDCl3) δ 5.56 (br, 1 H), 5.34 (heptet, J )
6.1Hz, 1 H), 4.85 (heptet, J ) 6.1 Hz, 1 H), 3.77 (q, J ) 6.3 Hz, 1 H),
3.28 (s, 3 H), 2.95-2.90 (m, 1 H), 2.68-2.63 (m, 2 H), 2.50-2.41
(m, 1 H), 2.20-2.10 (m, 2 H), 1.84-1.78 (m, 2 H), 1.75-1.67 (m, 2
H), 1.52-1.45 (m, 1 H), 1.32 (d, J ) 6.1 Hz, 3 H), 1.18 (d, J ) 6.1
Hz, 3 H), 1.14 (d, J ) 6.1 Hz, 3 H), 1.14 (d, J ) 6.1 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) ppm 203.5, 165.6, 150.8, 129.0, 119.6, 90.6,
75.7, 74.1, 71.9, 71.3, 62.2, 57.6, 51.8, 42.1, 33.6, 32.1, 27.5, 23.0,
6.09 (m, 1 H), 4.48 (m, 1 H), 4.38 (m, 1 H), 2.61 (ddd, J ) 14.3, 5.6,
4.3 Hz, 1 H), 2.04 (s, 1 H), 1.87 (ddd, J ) 14.3, 8.9, 2.5 Hz, 1 H),
1.38 (s, 3 H), 1.36 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 130.6,
129.2, 109.3, 73.3, 72.3, 66.2, 33.7, 27.8, 26.4; MS m/z (M+ - CH3)
calcd 232.9813, obsd 232.9807; [R]22 -67.4° (c 1.08, CHCl3).
D
To a THF (10 mL) suspension of sodium hydride (290 mg, 12.0
mmol) at 0 °C under N2 was added over 1 h a THF solution (5 mL) of
the cis alcohol (1.5 g, 6.0 mmol) and methyl iodide (2.23 g, 15 mmol).
The reaction was stirred at 22 °C for 12 h, quenched with saturated
NH4Cl solution, and extracted with ether. The usual workup was
followed by chromatography on silica gel (elution with 40% ethyl
acetate in hexanes) to give 1.5 g (95%) of 32 as a colorless solid: mp
22.8, 22.7, 22.2; MS m/z (M+) calcd 362.2099, obsd 362.2096; [R]22
D
-74.2° (c 0.38, CHCl3).
Anal. Calcd. for C21H30O5: C, 69.57; H, 8.35. Found: C, 69.48;
H, 8.38.
1
64-65 °C; H NMR (300 MHz, C6D6) δ 6.08 (br s, 1 H), 3.96-3.93
(m, 1 H), 3.82-3.77 (m, 1 H), 3.42 (m, 1 H), 3.14 (s, 3 H), 1.96 (m,
1 H), 1.62-1.58 (m, 1 H), 1.40 (s, 3 H), 1.22 (s, 3 H); 13C NMR (75
MHz, C6D6) ppm 129.5, 129.2, 110.1, 76.0, 73.3, 71.0, 56.8, 31.1, 28.3,
26.5; [R]22 -50.5° (c 1.03, CHCl3).
D
Anal. Calcd. for C10H15BrO3: C, 45.65; H, 5.75. Found: C, 45.77;
H, 5.80.
(3aR,5R,7aS)-6-Bromo-3a,4,5,7a-tetrahydro-5-methoxy-2,2-dim-
ethyl-1,3-benzodioxole (33). Analogous O-methylation of the trans
alcohol from above (2.55 g, 10.28 mmol) provided 33 (2.31 g, 86%)
as a faintly yellowish oil: IR (neat, cm-1) 1642, 1379, 1236, 1060; 1H
NMR (300 MHz, CDCl3) δ 6.08 (br, 1 H), 4.42-4.35 (m, 2 H), 3.90-
3.85 (m, 1 H), 3.39 (s, 3 H), 2.31 (dt, J ) 13.9, 5.3 Hz, 1 H), 1.96-
1.84 (m, 1 H), 1.32 (s, 3 H), 1.28 (s, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 129.7, 127.7, 109.1, 75.7, 72.9, 71.4, 57.5, 31.5, 27.7, 26.1; MS
For 29: white solid, mp 108-110 °C; IR (neat, cm-1) 3410, 1693,
1614, 1308, 1104; 1H NMR (300 MHz, CDCl3) δ 5.61 (br, 1 H), 5.28
(heptet, J ) 6.1 Hz, 1 H), 4.90 (heptet, J ) 6.1 Hz, 1 H), 3.97 (q, J )
6.3 Hz, 1 H), 3.22 (s, 3 H), 2.87-2.76 (m, 2 H), 2.60-2.54 (m, 1 H),
2.52-2.40 (m, 1 H), 1.93-1.80 (m, 1 H), 1.78-1.60 (m, 6 H), 1.26
(d, J ) 6.1 Hz, 3 H), 1.21 (d, J ) 6.1 Hz, 3H), 1.17 (d, J ) 6.1 Hz,
3 H), 1.15 (d, J ) 6.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3) ppm
203.2, 165.1, 148.8, 132.8, 121.1, 84.7, 77.0, 73.9, 71.9, 69.7, 57.2,
52.7, 69.7, 57.2, 52.7, 49.8, 42.5, 29.3, 29.0, 27.1, 22.6, 22.5 (2 C),
m/z (M+) calcd 262.0148, obsd 262.0176; [R]22 -35.2° (c 0.72,
D
CHCl3).
(S)-4-Hydroxy-2,3-diisopropoxy-4-[(3S,4R,6S)-3,4-(isopropylidene-
dioxy)-6-methoxy-1-cyclohexen-1-yl]-2-cyclobuten-1-one (36) and
(R)-4-Hydroxy-2,3-diisopropoxy-4-[(3S,4R,6S)-3,4-(isopropylidene-
dioxy)-6-methoxy-1-cyclohexen-1-yl]-2-cyclobuten-1-one (37). tert-
Butyllithium (3.0 mL of 1.7 M in pentane, 5.10 mmol) was added
dropwise at -78 °C to a solution of 32 (0.60 g, 2.29 mmol) in dry
THF (12 mL), and the mixture was stirred at this temperature for 1 h
22.4; MS m/z (M+) calcd 362.2099, obsd 362.2094; [R]22 +20.6° (c
D
0.49, CHCl3).
Anal. Calcd. for C21H30O5: C, 69.57; H, 8.35. Found: C, 69.64;
H, 8.33

3046 J. Am. Chem. Soc., Vol. 119, No. 13, 1997
Paquette et al.
prior to the introduction of 7 (0.23 g, 1.16 mmol) as a solution in THF
(6 mL). One hour later, water (10 mL) was carefully added, and the
products were extracted into ether (2 × 20 mL), washed with water
(20 mL) and brine (20 mL), dried, and concentrated. Chromatography
of the residue on silica gel (elution with 4:1 hexanes/ethyl acetate) gave
36 (0.22 g, 50%), followed by 37 (0.15 g, 34%).
Anal. Calcd. for C24H34O6: C, 68.86; H, 8.19. Found: C, 69.01;
H, 8.23.
For 36: faint yellowish oil; IR (neat, cm-1) 3386, 1769, 1384, 1101;
1H NMR (300 MHz, C6D6) δ 6.47 (d, J ) 3.4 Hz, 1 H), 4.94 (br, 1 H),
4.86 (heptet, J ) 6.0 Hz, 1 H), 4.81 (heptet, J ) 6.0 Hz, 1 H), 4.38-
4.32 (m, 1 H), 4.02-3.97 (m, 1 H), 3.65-3.62 (m, 1 H), 3.06 (s, 3 H),
2.06 (dt, J ) 14.4, 4.9 Hz, 1 H), 1.56 (dt, J ) 14.5, 4.2 Hz, 1 H), 1.41
(s, 3 H), 1.28 (s, 3 H), 1.25-1.14 (m, 12 H); 13C NMR (75 MHz,
C6D6) ppm 183.8, 168.2, 138.0, 132.8, 126.1, 109.4, 88.0, 77.2, 73.2,
72.9, 72.0, 71.3, 56.2, 28.4, 28.3, 26.5, 22.8, 22.7, 22.6, 22.2; MS m/z
(3aS,6aR,6bS,7S,8R,10bS)-5,6,6a,6b,7,8,9,10b-Octahydro-10b-hy-
droxy-1,2-diisopropoxy-7,8-(isopropylidenedioxy)dicyclopent[a,b]-
inden-3(4H)-one (40). tert-Butyllithium (1.4 mL of 1.7 M in pentane,
2.4 mmol) was added dropwise at -78 °C to cyclopentenyl iodide (0.20
g, 1.03 mmol) dissolved in dry THF (5 mL). After 1 h at this
temperature, a solution of 37 (95 mg, 0.24 mmol) in THF (3 mL) was
introduced, allowed to react for 17 h at room temperature, and processed
as described above to give 27 mg (26%) of 40 and 23 mg (22%) of 39.
For 40: faint yellowish oil; IR (neat, cm-1) 3426, 1691, 1613, 1380,
1052; 1H NMR (300 MHz, CDCl3) δ 6.06-6.04 (m, 1 H), 5.31 (heptet,
J ) 6.0 Hz, 1 H), 4.47-4.44 (m, 1 H), 4.39-4.31 (m, 1 H), 2.80-
2.73 (m, 1 H), 2.48-2.40 (m, 1 H), 2.34-2.24 (m, 1 H), 2.14-1.97
(m, 2 H), 1.96-1.63 (m, 5 H), 1.60-0.90 (m, 19 H); 13C NMR (75
MHz, CDCl3) ppm 203.4, 166.1, 144.5, 131.2, 120.9, 108.0, 79.8, 75.0,
73.9, 73.5, 72.0, 68.0, 48.5, 41.2, 30.8, 30.6, 30.4, 27.8, 27.0, 25.2,
22.7 (2 C), 22.4, 22.3; MS m/z (M+) calcd 418.2378, obsd 418.2363;
(M+) calcd 382.1961, obsd 381.1976; [R]22 +63.6° (c 0.55, C6H6).
D
Anal. Calcd. for C20H30O7: C, 62.79; H, 7.91. Found: C, 62.89;
H, 7.94.
For 37: faint yellowish oil; IR (neat, cm-1) 3417, 1769, 1614, 1372,
1098; 1H NMR (30 MHz, C6D6) δ 6.12 (d, J ) 2.4 Hz, 1 H), 5.35 (br,
1 H), 4.89 (heptet, J ) 6.1 Hz, 1 H), 4.76 (heptet, J ) 6.1 Hz, 1 H),
4.12-4.09 (m, 2 H), 3.87-3.83 (m, 1 H), 3.12 (s, 3 H), 1.92-1.83
(m, 1 H), 1.69 (dt, J ) 14.9, 4.5 Hz, 1 H), 1.41 (s, 3 H), 1.23 (s, 3 H),
1.12-1.06 (m, 12 H); 13C NMR (75 MHz, C6D6) ppm 185.3, 164.4,
139.5, 132.6, 124.1, 109.6, 89.1, 76.7, 75.4, 73.4, 71.4, 71.3, 56.4, 29.4,
28.4, 26.4, 22.7, 22.6, 22.4, 22.2; MS m/z (M+) calcd 382.1961, obds
[R]22 +139° (c 0.50, CHCl3).
382.2005; [R]22 +62.2° (c 0.59, C6H6).
D
D
Anal. Calcd. for C24H34O6: C, 68.86; H, 8.19. Found: C, 68.59;
H, 8.25.
Anal. Calcd. for C20H30O7: C, 62.79; H, 7.91. Found: C, 62.71;
H, 7.94.
(3aR,6aS,6bR,7S,8R,10bR)-5,6,6a,6b,7,8,9,10b-Octahydro-10b-hy-
droxy-1,2-diisopropoxy-7,8-(isopropylidenedioxy)dicyclopent[a,b]-
inden-3(4H)-one (38) and (3aS,6aR,6bR,7S,8R,10bS)-5,6,6a,6b,7,8,9,-
10b-Octahydro-10b-hydroxy-1,2-diisopropoxy-7,8-(isopropyli-
denedioxy)dicyclopent[a,b]inden-3(4H)-one (39). tert-Butyllithium
(6.5 mL of 1.7 M in pentane, 11.05 mmol) was added dropwise at
-78 °C to cyclopentenyl iodide (0.96 g, 4.94 mmol) dissolved in dry
THF (25 mL). After 1 h at this temperature, a solution of 36 (0.47 g,
1.23 mmol) in dry THF (13 mL) was introduced, and the reaction was
allowed to proceed at room temperature for 13 h prior to implementation
of the usual workup. Flash chromatography on silica gel (elution with
5:1 hexanes/ethyl acetate) gave 0.12 g (24%) of 39 and 0.29 g (58%)
of 38.
(S)-4-(tert-Butyldimethylsiloxy)-2,3-diisopropoxy-4-[(3S,4R,6R)-
3,4-(isopropylidenedioxy)-6-methoxy-1-cyclohexen-1-yl]-2-cyclobuten-
1-one (43) and (R)-4-(tert-Butyldimethylsiloxy)-2,3-diisopropoxy-
4-[(3S,4R,6R)-3,4-(isopropylidenedioxy)-6-methoxy-1-cyclohexen-1-
yl]-2-cyclobuten-1-one (44). tert-Butyllithium (4.6 mL of 1.7 M in
pentane, 7.8 mmol) was added dropwise at -78 °C to a solution of 33
(0.93 g, 3.5 mmol) in dry THF (18 mL), and the mixture was stirred
at this temperature for 1 h prior to the introduction of 7 (0.35 g, 1.76
mmol) as a solution in THF (9 mL). One hour later, the usual workup
was applied and an inseparable 1:1 mixture (1H NMR analysis) of 41
and 42 was obtained in 88% yield.
For 38: faint yellowish oil; IR (neat, cm-1) 3437, 1692, 1613, 1380,
1054; 1H NMR (300 MHz, CDCl3) δ 5.91-5.86 (m, 1 H), 5.29 (heptet,
J ) 6.1 Hz, 1 H), 4.97 (heptet, J ) 6.1 Hz, 1 H), 4.11 (q, J ) 5.1 Hz,
1 H), 4.05 (t, J ) 4.7 Hz, 1 H), 2.70 (dt, J ) 10.8, 7.3 Hz, 1 H), 2.57
(dt, J ) 17.4, 6.0 Hz, 1 H), 2.52-2.41 (m, 1 H), 2.34-2.24 (m, 2 H),
2.01-1.80 (m, 3 H), 1.76-1.66 (m, 2 H), 1.41 (s, 3 H), 1.34 (s, 3 H),
1.32 (d, J ) 6.1 Hz, 3 H), 1.22 (d, J ) 6.1 Hz, 3 H), 1.20 (d, J ) 6.1
Hz, 3 H), 1.18 (d, J ) 6.1 Hz, 3 H), 1.07-0.99 (m, 1 H); 13C NMR
(75 MHz, CDCl3) ppm 202.7, 165.8, 141.3, 132.3, 119.5, 107.4, 80.0,
75.3, 73.8, 71.7, 71.4, 64.9, 53.3, 49.9, 29.5, 29.4, 28.4, 28.3, 26.4,
25.9, 22.6, 22.5 (2 C), 22.3; MS m/z (M+) calcd 418.2378, obsd
A 0.94 g (2.46 mmol) sample of this mixture was dissolved in DMF
(8 mL), treated with tert-butyldimethylsilyl chloride (0.74 g, 4.91 mmol)
and imidazole (0.50 g, 7.4 mmol), and heated at 70 °C for 14 h. Water
(10 mL) was added and the resulting mixture was extracted with ether
(2 × 20 mL). The combined organic layers were washed with water
(20 mL) and brine (20 mL), dried, and concentrated. Chromatography
of the residue on silica gel (elution with 6:1 hexanes/ethyl acetate gave
0.17 g (14%) of 43 and 0.28 g (23%) of 44, both as yellow liquids.
418.2356; [R]22 -200° (c 0.42, CHCl3).
D
Anal. Calcd. for C24H34O6: C, 68.86; H, 8.19. Found: C, 68.79;
H, 8.26.
1
For 43: IR (film, cm-1) 1770, 1622, 1384, 1099; H NMR (300
MHz, C6D6) δ 6.53 (d, J ) 3.2 Hz, 1H), 4.94 (heptet, J ) 6.1 Hz, 1
H), 4.74 (heptet, J ) 6.1 Hz, 1 H), 4.43-4.38 (m, 2 H), 3.85 (t, J )
3.6 Hz, 1 H), 3.01 (s, 3 H), 2.15-2.06 (m, 1 H), 1.72-1.65 (m, 1 H),
1.45 (s, 3 H), 1.25 (s, 3 H), 1.17 (d, J ) 6.1 Hz, 3 H), 1.15-1.09 (m,
9 H), 1.00 (s, 9 H), 0.35 (s, 3 H), 0.28 (s, 3 H); 13C NMR (75 MHz,
C6D6) ppm 182.9, 166.2, 139.7, 132.9, 125.9, 108.7, 89.5, 76.3, 73.3,
73.1, 71.4, 70.9, 56.1, 30.0, 28.0, 25.8 (3 C), 25.6, 22.6 (2 C), 22.3,
22.0, 18.3, -3.4, -3.5; MS m/z (M+) calcd 496.2828, obsd 496.2842;
For 39: faint yellowish oil; IR (neat, cm-1) 3443, 1694, 1614, 1380,
1053; 1H NMR (300 MHz, CDCl3) δ 6.07-6.03 (m, 1 H), 4.90 (heptet,
J ) 6.1 Hz, 1 H), 4.10 (q, J ) 6.2 Hz, 1 H), 3.79 (t, J ) 6.1 Hz, 1 H),
2.61 (dt, J ) 16.9, 7.1 Hz, 1 H), 2.48-2.17 (m, 3 H), 2.16-2.03 (m,
2 H), 1.99-1.55 (m, 4 H), 1.44 (s, 3 H), 1.40-1.28 (m, 9 H), 1.23-
1.04 (m, 7 H); 13C NMR (75 MHz, CDCl3) ppm 203.0, 165.7, 146.0,
129.3, 119.4, 108.0, 80.8 (2 C), 73.9, 72.6, 71.8, 66.8, 53.9, 50.2, 33.9,
30.8, 27.9, 26.9, 25.4, 25.2, 22.7 (3 C), 22.3; MS m/z (M+) calcd
[R]22 +74.9° (c 0.62, CHCl3).
D
1
For 44: IR (film, cm-1) 1777, 1633, 1383, 1098; H NMR (300
MHz, C6D6) δ 6.50 (d, J ) 3.1 Hz, 1 H), 4.95 (heptet, J ) 6.1 Hz, 1
H), 4.69 (heptet, J ) 6.1 Hz, 1 H), 4.40-4.34 (m, 2 H), 3.91 (t, J )
3.8 Hz, 1 H), 3.06 (s, 3 H), 2.19-2.12 (m, 1 H), 1.76-1.65 (m, 1 H),
1.41 (s, 3 H), 1.24 (s, 3 H), 1.17 (d, J ) 6.1 H, 3 H), 1.14-1.01 (m,
9 H), 0.98 (s, 9 H), 0.33 (s, 3 H), 0.25 (s, 3 H); 13C NMR (75 MHz,
C6D6) ppm 182.6, 163.8, 139.3, 133.3, 125.8, 108.5, 88.9, 76.0, 73.2,
72.9, 71.4, 71.0, 55.8, 30.0, 27.9, 25.7 (3 C), 25.6, 22.7, 22.5, 22.2,
418.2378, obsd 418.2366; [R]22 +27.0° (c 0.57, CHCl3).
D

Enhanced Channeling of the Squarate Cascade
J. Am. Chem. Soc., Vol. 119, No. 13, 1997 3047
22.0, 18.3, -3.4, -3.5; MZ m/z (M+) calcd 496.2828, obsd 496.2862;
Formation of 38 and 39 from 41. A cold (-78 °C), magnetically
stirred solution of cyclopentenyl iodide (0.16 g, 0.82 mmol) in dry
THF (4 mL) was treated dropwise with tert-butyllithium (1.1 mL of
1.7 M in pentane, 1.87 mmol). After 1 h at this temperature, a solution
of 41 (77 mg, 0.20 mmol) of dry THF (2 mL) was introduced. The
resulting solution was then stirred at room temperature for 16 h and
diluted with deoxygenated saturated NH4Cl solution (5 mL) at 0 °C
and, 10 min later, with water (5 mL) and ether (20 mL). The organic
phase was washed with water (10 mL) and brine (10 mL), dried, and
concentrated. Submission of the residue to flash chromatography (silica
gel, elution with 4:1 hexanes/ethyl acetate) gave 30 mg (36%) of 39
and 15 mg (18%) of 38.
[R]22 +30.0° (c 0.96, CHCl3).
D
(S)-4-Hydroxy-2,3-diisopropoxy-4-[(3S,4R,6R)-3,4-(isopropylidene-
dioxy)-6-methoxy-1-cyclohexen-1-yl]-2-cyclobuten-1-one (41). Tetra-
n-butylammonium fluoride (0.65 mL of 1 M in THF, 0.65 mL) was
added to a solution of 43 (0.16 g, 0.32 mmol) in THF (3 mL), and the
reaction mixture was stirred at room temperature for 30 min. Water
(5 mL) was added, and the mixture was extracted with ether (2 × 10
mL). The combined organic layers were washed with water (10 mL)
and brine (10 mL), dried, and concentrated. Chromatography of the
residue on silica gel (elution with 4:1 hexanes/ethyl acetate) gave 41
as a yellow liquid (81 mg, 66%); IR (film, cm-1) 3402, 1769, 1621,
1
Formation of 39 and 40 from 42. When 42 was processed in the
predescribed manner, flash chromatography (silica gel, elution with
5:1 hexanes/ethyl acetate) furnished 34 mg (21%) of 40 and 43 mg
(26%) of 39.
1384, 1099; H NMR (300 MHz, C6D6) δ 6.45 (d, J ) 3.1 Hz, 1 H),
4.95 (heptet, J ) 6.1 Hz, 1 H), 4.72 (heptet, J ) 6.1 Hz, 1 H), 4.33-
4.30 (m, 1 H), 4.27-4.21 (m, 1 H), 4.05 (t, J ) 5.0 Hz, 1 H), 3.02 (s,
3 H), 1.98-1.90 (m, 1 H), 1.86-1.78 (m, 1 H), 1.41 (s, 3 H), 1.26 (s,
3 H), 1.21-1.07 (m, 13 H); 13C NMR (75 MHz, C6D6) ppm 183.3,
166.2, 138.7, 132.6, 125.4, 108.6, 87.9, 76.5, 73.8, 73.1, 71.4, 71.3,
55.8, 29.8, 27.9, 25.9, 22.5, 22.4, 21.9; MS m/z (M+) calcd 382.1961,
Acknowledgment. This contribution is dedicated with
admiration to Prof. Fabian Gerson, a longtime friend and
collaborator, on the occasion of his retirement from the
University of Basel. The authors thank the National Science
Foundation for generous financial support and Dr. Kurt Loening
for nomenclature expertise..
obsd 382.1962; [R]22 -71.9° (c 0.93, C6H6).
D
Anal. Calcd. for C20H30O7: C, 62.79; H, 7.91. Found: C, 62.86;
H, 7.98.
(R)-4-Hydroxy-2,3-diisopropoxy-4-[(3S,4R,6R)-3,4-(isopropylidene-
dioxy)-6-methoxy-1-cyclohexen-1-yl]-2-cyclobuten-1-one (42). Com-
parable treatment of 44 (0.28 g, 0.56 mmol) provided 0.16 g (76%) of
42 as a yellow liquid; IR (film, cm-1) 3405, 1769, 1633, 1384, 1098;
1H NMR (300 MHz, C6D6) δ 6.20 (d, J ) 2.6 Hz, 1 H), 5.37-5.03
(br, 1 H), 4.91 (heptet, J ) 6.1 Hz, 1 H), 4.73 (heptet, J ) 6.1 Hz, 1
H), 4.45-4.41 (m, 1 H), 4.31-4.29 (m, 1 H), 4.18-4.13 (m, 1 H),
3.10 (s, 3 H), 2.09-2.01 (m, 1 H), 1.71-1.63 (m, 1 H), 1.33 (s, 3 H),
1.24 (s, 3 H), 1.18-1.06 (m, 12 H); 13C NMR (75 MHz, C6D6) ppm
184.8, 164.1, 138.5, 132.3, 124.8, 108.5, 88.7, 76.3, 74.8, 73.1, 71.5,
71.4, 56.1, 29.8, 27.9, 26.1, 22.4 (2 C), 22.1, 21.8; MS m/z (M+) calcd
Supporting Information Available: Crystallographic ex-
perimental sections and tables of X-ray crystal data, bond lengths
and angles, final fractional coordinates, and thermal parameters
for 14, 22, and 29 (36 pages). See any current masthead page
for ordering and Internet access instructions. The authors have
deposited the atomic coordinates for the X-ray structures with
the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, U.K.
382.1961, obsd 382.2021; [R]22 -47.5° (c 0.52, C6H6).
D
Anal. Calcd. for C20H30O7: C, 62.79; H, 7.91. Found: C, 62.76;
H, 7.97.
JA964140D