Diastereoselective prins-type reaction of cycloalkenylcyclopropanol silyl ethers and α,β-unsaturated aldehyde acetals

Article abstract of DOI:10.1021/jo071272o

(Chemical Equation Presented) Electrophilic addition of 1-(1-cyclohexenyl)-1-cyclopropanol trimethylsilyl ether to α,β- unsaturated aldehyde acetals under Lewis acidic conditions proceeds with good to excellent diastereoselectivity to afford spirocyclobut

Full text of DOI:10.1021/jo071272o

Diastereoselective Prins-Type Reaction of Cycloalkenylcyclopropanol
Silyl Ethers and r,â-Unsaturated Aldehyde Acetals
Ivan L. Lysenko, Heong-Sub Oh, and Jin Kun Cha*
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202
jcha@chem.wayne.edu
ReceiVed June 13, 2007
Electrophilic addition of 1-(1-cyclohexenyl)-1-cyclopropanol trimethylsilyl ether to R,â-unsaturated
aldehyde acetals under Lewis acidic conditions proceeds with good to excellent diastereoselectivity to
afford spirocyclobutanones containing three contiguous stereocenters. A convenient entry to enantiose-
lective syntheses is available by use of a nonracemic C2-symmetric acetal. Elaboration of the resulting
adducts provides ready access to medium-sized carbocycles.
Introduction
facile addition of the trimethylsilyl ethers of 1-vinylcyclopro-
panols to oxocarbenium ions (generated in situ from acetals).5,6
In the absence of overriding geometrical factors, electrophilic
attack takes place preferentially at the double bond, leading to
formation of the corresponding spirocyclobutanones bearing
three contiguous stereocenters (eq 1). It is not surprising that
diastereocontrol proved to be difficult,5,7 and a handful of known
diastereoselective examples reported have been limited primarily
to intramolecular variants.5,8 We report herein diastereo-
selective Prins-type reactions of 1-(1-cyclohexenyl)-1-cyclo-
propanol trimethylsilyl ether (2) and R,â-unsaturated aldehyde
acetals.
The release of strain arising from cleavage of cyclopropanes
has been frequently utilized in organic synthesis.1 Heteroatom-
substituted cyclopropanes display enhanced nucleophilicity and
provide convenient methods for regio- and stereoselective ring-
opening. For example, ring-opening reactions of cyclopropanols
and siloxy derivatives have been extensively investigated and
render them a “homoenol” or “homoenolate” equivalent.2-4
The juxtaposition of a cyclopropanol and an olefin or an alkyne
generates unique conjunctive functionalities suitable for different
modes of C-C bond formation, and the Trost group documented
(1) For reviews, see: (a) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip,
Y. C.; Tanko, J.; Hudlicky, T. Chem. ReV. 1989, 89, 165. (b) Hudlicky, T.;
Reed, R. W. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 5, pp 899-970. (c) Piers, E.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, U.K., 1991; Vol. 5, pp 971-988. (d) Bronson, J. J.;
Danheiser, R. L. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 5, pp 999-1035.
(e) de Meijere, A.; Kozhushkov, S. I.; Hadjiaraoglou, L. P. Top. Curr. Chem.
2000, 207, 149.
(2) For reviews, see: (a) Gibson, D. H.; DePuy, C. H. Chem. ReV. 1974,
74, 605. (b) Ryu, I.; Murai, S. Houben-Weyl Methods of Organic Chemistry;
Georg Thieme Verlag: Stuttgart, Germany, 1997; Vol. E17c, pp 1985-
2040. (c) Kulinkovich, O. G. Chem. ReV. 2003, 103, 2597. See also: (d)
Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151. (e) Gnad, F.;
Reiser, O. Chem. ReV. 2003, 103, 1603. (f) Yu, M.; Pagenkopf, B. L.
Tetrahedron 2005, 61, 321.
(4) For represenative examples, see: (a) Carey, J. T.; Knors, C.; Helquist,
P. J. Am. Chem. Soc. 1986, 108, 8313. (b) O’Neil, K. E.; Kingree, S. V.;
Minbiole, K. P. C. Org. Lett. 2005, 7, 515. (c) Epstein, O. L.; Lee, S.; Cha.
J. K. Angew. Chem., Int. Ed. 2006, 45, 4988. (d) Lee, H. G.; Lysenko, I.
L.; Cha. J. K. Angew. Chem., Int. Ed. 2007, 46, 3326.
(5) For reviews, see: (a) Trost, B. M. Top. Curr. Chem. 1986, 133, 3.
(b) Salau¨n, J. Top. Curr. Chem. 1988, 144, 1. (c) Trost, B. M.; Brandi, A.
J. Am. Chem. Soc. 1984, 106, 5041. (d) Trost, B. M.; Lee, D. C. J. Am.
Chem. Soc. 1988, 110, 6556. (e) Trost, B. M.; Chen, D. W. C. J. Am. Chem.
Soc. 1996, 118, 12541.
(6) (a) Wasserman, H. H.; Cochoy, R. E.; Baird, M. S. J. Am. Chem.
Soc. 1969, 91, 2375. (b) Wasserman, H. H.; Hearn, M. J.; Cochoy, R. E. J.
Org. Chem. 1980, 45, 2874. (c) Gassman, P. G.; Riehle, R. J. J. Am. Chem.
Soc. 1989, 111, 2319.
(7) (a) Oh, H.-S.; Lee, H. I.; Cha, J. K. Org. Lett. 2002, 4, 3707. (b) Oh,
H.-S.; Cha, J. K. Tetrahedron: Asymmetry 2003, 14, 2911. (c) Manivannan,
E.; Oh, H.-S.; Cha, J. K. Org. Lett. 2007, 9, 2693.
(3) Kuwajima, I.; Nakamura, E. Top. Curr. Chem. 1990, 155, 1.
(8) Youn, J.-H.; Lee, J.; Cha, J. K. Org. Lett. 2001, 3, 2935.
10.1021/jo071272o CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/13/2007
J. Org. Chem. 2007, 72, 7903-7908
7903

Lysenko et al.
SCHEME 1. Coupling of 2 and Acetals 3a-e
Results and Discussion
Cyclopropanol 1, which was readily prepared by the Kulink-
ovich cyclopropanation of methyl 1-cyclohexene-1-carboxy-
late,9,10 was selected for a vinylogous homo-Prins- or homo-
Mukaiyama-type reaction11 with acetals under Lewis acidic
conditions (Scheme 1). Ring expansion induced by addition of
an oxocarbenium ion to a trisubstituted olefin (e.g., 1-cyclo-
hexenyl moiety) should provide ready access to a quaternary
center.12 This straightforward procedure was applicable to a full
range of acetals derived from aliphatic, R,â-unsaturated, aro-
matic aldehydes and alkynals to give the corresponding spiro-
cyclobutanones in excellent yields. Diastereoselectivity was
found to be not only sensitive to the reaction parameters (e.g.,
reaction temperatures, Lewis acids, the presence of lutidine, etc.),
but also modest (typically 3-4:1).
SCHEME 2. Coupling Reactions of 2 with Aliphatic and
Aryl Aldehyde Acetals7
However, the use of R,â-unsaturated aldehyde acetals was
shown to be an exception. Treatment of a mixture of trimeth-
ylsilyl ether 2 and dimethyl acetals 3a-e with TiCl4 at -78 °C
afforded spirobutanones 4a-e in 93-99% (combined) yield and
with good diastereoselectivity. Only the stereochemistry of the
major isomers is shown in Scheme 1, where the product ratios
1
were determined by GC-MS and also analysis of H NMR
spectra. Formation of two (e.g., 4a and 4c) or three (e.g., 4b,
4d, and 4e) isomers was usually observed out of four possible
diastereomers. Fortuitously, the major isomers were easily
separated by silica gel chromatography from the remaining
isomers in all cases. Cyclopropanols could also be used directly
without silylation, but the resulting diastereoselectivity was often
different from that obtained for the corresponding trimethylsilyl
ethers. For example, coupling of 1 and 3a afforded a 1:3 mixture
of two products epimeric at the quaternary carbon in 85% yield,
and the minor isomer corresponded to 4a.
The unequivocal stereochemical determination of 4e was
established by single-crystal X-ray analysis.13 The stereochem-
ical assignment of 4a-d was then made by the correlation study
(9) (a) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 4198.
(b) Kim, S. H.; Sung, M. J.; Cha, J. K. Org. Synth. 2003, 80, 111.
(10) For reviews, see: (a) Kulinkovich, O. G.; de Meijere, A. Chem.
ReV. 2000, 100, 2789. (b) Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV.
2000, 100, 2835. (c) Kulinkovich, O. G. Eur. J. Org. Chem. 2004, 4517.
(11) (a) Mukaiyama, T. Org. React. 1982, 28, 203. (b) Murata, S.; Suzuki,
M.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 3248. (c) Mahrwald, R. Chem.
ReV. 1999, 99, 1095. (d) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu,
G. Chem. ReV. 2000, 100, 1929.
(12) For reviews, see: (a) Martin, S. F. Tetrahedron 1980, 36, 419. (b)
Fuji, K. Chem. ReV. 1993, 93, 2037. (c) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388. (d) Christoffers, J.; Mann, A. Angew.
Chem., Int. Ed. 2001, 40, 4591. (e) Christoffers, J.; Baro, A. Angew. Chem.,
Int. Ed. 2003, 42, 1688. (f) Barriault, L.; Denissova, I. Tetrahedron 2003,
59, 10105.
(13) We thank Dr. Mary Jane Heeg for single-crystal X-ray analysis.
The X-ray data have been deposited with the Cambridge Structural
Database: please refer to CSD nos. 265946 (4e), 256733 (5A), and 263915
(10a). X-ray structures are also secured for 6 (cf. 239454 and 239496), 7A
(cf. 232509), 7B (232508), and 8 (232506).
involving oxidative cleavage of the double bond of 4e (subse-
quent to desilylation) and 4a-d, in addition to difference NOE
measurements or comparison of key coupling constants. TLC
behavior of these isomers was also informative because of
regular patterns apparent among several related spirobutanones
(Scheme 2), the stereochemistry of which had previously been
secured by single-crystal X-ray analysis: Rf values of the
indicated (S,R)-products (e.g., 4a-e) were lower than those of
7904 J. Org. Chem., Vol. 72, No. 21, 2007

DiastereoselectiVe Prins-Type Reaction
SCHEME 3. Reactions of (Z)-r,â-Unsaturated Aldehyde
Acetals
SCHEME 5. Reactions of 12 and Acetals 3a-c
availability and ease of removal. The coupling reaction of 2
and 9a,b resulted in both 1,2- and 1,4-addition, and no attempt
was made to assign the stereochemistry of 11a,b. The placement
of a bulky substituent at the â-position precluded 1,4-addition,
as shown in the stereoselective (11:1) formation of 10c. The
stereochemistry of the major products 10b,c was assigned by
analogy to that of 10a, which had been secured by X-ray
analysis.13 The observed 1,3-diastereofacial selectivity by the
chiral C2-symmetric acetal is consistent with literature prece-
dents.16
SCHEME 4. Use of Nonracemic C2-Symmetric Acetals
To probe the scope of the key coupling reaction, we next
studied the reactions of 12 and 3a-c (Scheme 5). The
diastereoselectivity exerted by 12 was considerably lower than
that by 2, where the stereochemistry of 13a-c was tentatively
assigned by analogy to that of 4a-c. The observed decrease in
selectivity with the cyclopentene system 12 reflects a smaller
difference in energy between the two transition states leading
to cis and trans addition. As the final step involves rehybrid-
ization from the sp2 carbon to the sp3 quaternary carbon, both
transition states involving cyclopentanes contain an increasing
number of eclipsing interactions. On the other hand, cyclohex-
anes, in which a staggered arrangement is possible, presumably
display a larger difference in energy between the two transition
states corresponding to cis and trans addition. Acyclic di- and
trisubstituted alkenylcyclopropanols gave only low diastereo-
selectivity.
the respective (R,R)-isomers. The observed (S,R)-stereochemistry
can be rationalized by synclinal approach of the vinylcyclo-
propanol to the oxocarbenium ion to avoid nonbonded interac-
tions between the cyclopropane ring and the alkenyl substituent,
as shown in the Newman projection I in Scheme 1.
Conspicuous is the cis-stereochemical relationship between
the two newly formed C-C bonds of 4a-e, which is indicative
of the intermediacy of the stable tertiary cyclopropylcarbinyl
cations II.7,14 The diastereofacial bias of ring expansion appears
to be steric in origin; depending on the substrates (e.g., 4a-e
and 5A vs 6 and 7A), both net “cis” and net “trans” additions
are observed. The preferential formation of 4a-e (cis addition)
might be attributed in part to the minimization of torsional strain
during ring expansion (1,2-alkyl shift): as 1,2-alkyl shift occurs,
trans addition would have to go through a fully eclipsed
arrangement between the newly introduced side chain and the
CsCdO bond.15
When (Z)-R,â-unsaturated aldehyde acetals were employed,
complete isomerization to the (E)-double bond was observed,
and this result is in accord with generation and subsequent
trapping of oxocarbenium ions (Scheme 3). Diminished dias-
tereoselectivity was observed for formation of 8.
As was the case with 7A/7B,7b,c a straightforward entry to
enantioselective synthesis was available by utilizing a nonra-
cemic C2-symmetric acetal (Scheme 4). Hydrobenzoin was
chosen as a chiral auxiliary primarily because of its commercial
These addition products possess useful functionalities and are
well suited for subsequent elaboration such as annulation of
various ring sizes. To demonstrate the synthetic versatility of
these products, functionalized seven- and eight-membered
carbocycles 19-21 were next prepared from 4a by radical-
induced fragmentation of the spirocyclobutanone moiety (Scheme
6).7a,b,17,18 Treatment of 4a with iodine in acetic acid provided
a separable 2.5:1 mixture of 14 and 15 in 90% yield and with
high diastereofacial selectivity. However, the low regiocontrol
was surprising. The stereochemical assignment of 14 and 15
was supported by not only ample literature examples on
electrophilic addition of allylic alcohol derivatives,19 but also
several correlation studies (including preparation and elaboration
of 16 and 17).20 The free radical-mediated cyclization-
fragmentation reaction of 15 was next achieved by slow addition
(16) See, inter alia: (a) Alexakis, A.; Mangeney, P. Tetrahedron:
Asymmetry 1990, 1, 477. (b) Denmark, S. E.; Almstead, N. G. J. Am. Chem.
Soc. 1991, 113, 8089. (c) Sammakia, T.; R. S. Smith, J. Am. Chem. Soc.
1992, 114, 10998.
(14) In our initial studies (ref 7a) involving cognate reactions of alkanal
acetals, antiperiplanar trans addition was mistakenly assumed in their
tentative assignment of the ring junction stereochemistry by extrapolation
of 6 and 7A. Subsequent studies, as documented in this work, clearly indicate
a stepwise reaction pathway.
(17) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, Germany, 2001.
(18) (a) Dowd, P.; Zhang, W. J. Am. Chem. Soc. 1991, 113, 9875. (b)
Dowd, P.; Zhang, W. Chem. ReV. 1993, 93, 2091. (c) Zhang, W. Curr.
Org. Chem. 2002, 6, 1015.
(15) Cf. von R. Schleyer, P. J. Am. Chem. Soc. 1967, 89, 701.
(19) Chamberlin, A. R.; Mulholland, R. L. Tetrahedron 1984, 40, 2297.
J. Org. Chem, Vol. 72, No. 21, 2007 7905

Lysenko et al.
SCHEME 6. Free Radical-Mediated Annulation of
Medium-Sized Rings
-78 °C for 15 min and then quenched by sequential addition of
saturated NaCl (20 mL) and ether (40 mL). The organic layer was
separated, and the aqueous layer was extracted with ethyl ether (2
× 10 mL). The combined organic extracts were passed through a
short pad of Na2SO4-Al2O3, and the filtrate was concentrated under
reduced pressure. Purification of the residue by column chroma-
tography (30 g SiO2, 15:1 to 10:1 hexanes-EtOAc) afforded 4d
(491 mg, 84%) as a colorless oil, in addition to two diastereomers
(64 mg, 11%): IR (film) 1777 cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.59 (dt, J ) 15.5, 6.6 Hz, 1H), 5.18 (ddt, J ) 15.5, 9.1, 1.6 Hz,
1H), 3.19 (t, J ) 9.1 Hz, 1H), 3.15 (s, 3H), 2.95-2.84 (m, 2H),
2.04 (qd, J ) 6.6, 1.4 Hz, 2H), 1.98 (tdd, J ) 11.3, 7.6, 1.6 Hz,
1H), 1.78 (ddd, J ) 13.5, 9.7, 3.7 Hz, 1H), 1.59 (m, 1H), 1.40-
1.10 (m, 15H), 0.88 (t, J ) 7.0 Hz, 3H), 0.82 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 215.4, 136.8, 129.1, 85.2, 66.9, 55.1, 45.5,
41.2, 33.8, 32.2, 31.6, 29.1, 28.8, 25.8, 25.1, 22.6, 22.0, 18.3, 14.0;
HRMS m/z calcd for C19H32O2 (M+) 292.2402, found 292.2412.
Data for 4a: IR (film) 1778 cm-1; 1H NMR 1H NMR (500 MHz,
CDCl3) δ 5.60 (dq, J ) 15.2, 6.6 Hz, 1H), 5.19 (ddq, J ) 15.2,
9.1, 1.5 Hz, 1H), 3.18 (t, J ) 9.1 Hz, 1H), 3.12 (s, 3H), 2.96-2.84
(m, 2H), 1.95 (m, 1H), 1.80-1.66 (m, 2H), 1.72 (dd, J ) 6.6, 1.5
Hz, 3H), 1.66-1.60 (m, 2H), 1.59-1.56 (m, 2H), 1.46 (m, 1H),
1.28-1.10 (m, 2H), 0.81 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
215.4, 131.1, 130.5, 85.1, 66.9, 55.1, 45.5, 41.2, 33.8, 25.7, 25.1,
22.0, 18.2, 17.7; HRMS m/z calcd for C14H42O2 (M+) 222.1620,
found 222.1623.
Data for 4b: IR (film) 1778 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.58 (dt, J ) 15.4, 6.9 Hz, 1H), 5.19 (ddt, J ) 15.4, 8.9, 1.4 Hz,
1H), 3.19 (t, J ) 8.9 Hz, 1H), 3.13 (s, 3H), 2.97-2.83 (m, 2H),
2.04 (m, 2H), 1.96 (tdd, J ) 11.4, 7.7, 1.6 Hz, 1H), 1.78 (ddd, J )
13.4, 9.7, 3.7 Hz, 1H), 1.74-1.35 (m, 8H), 1.31-1.10 (m, 2H),
0.89 (t, J ) 7.7 Hz, 3H), 0.82 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 215.3, 136.5, 129.2, 85.2, 66.9, 55.1, 45.5, 41.2, 34.3, 33.8, 25.8,
25.1, 22.4, 22.1, 18.3, 13.7; HRMS m/z calcd for C16H26O2 (M+)
250.1933, found 250.1938.
of n-tributyltin hydride in the presence of AIBN to give 19 as
an easily separable mixture of two epimers (4.4:1, 82% yield),
where the trans-ring junction stereochemistry resulted from 1,5-
hydrogen transfer. Similarly, free radical-mediated cyclization-
fragmentation of 14 and 18 proceeded smoothly to afford 20
and 21 in 84% and 75% yield, respectively. It is interesting to
note that 20 was isolated as a mixture of all four diastereomers,
whereas 21 was obtained as a ∼2:1 mixture of two
isomers.
Data for 4c: IR (film) 1777 cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.58 (dt, J ) 15.5, 6.5 Hz, 1H), 5.19 (ddt , J ) 15.5, 9.0, 1.5 Hz,
1H), 3.18 (t, J ) 9.0 Hz, 1H), 3.14 (s, 3H), 2.97-2.85 (m, 2H),
2.08-2.03 (m, 2H), 1.96 (m, 1H), 1.78 (ddd, J ) 12.5, 10.0, 3.5
Hz, 1H), 1.70 (m, 1H), 1.67-1.61 (m, 2H), 1.60-1.55 (m, 2H),
1.47 (m, 1H), 1.42-1.11 (m, 7H), 0.93-0.78 (m, 5H); 13C NMR
(125 MHz, CDCl3) δ 215.4, 136.8, 129.1, 85.2, 66.9, 55.1, 45.5,
41.2, 33.8, 32.1, 31.3, 28.9, 25.8, 25.1, 22.4, 22.0, 18.3, 14.0; HRMS
m/z calcd for C18H30O2 (M+) 278.2246, found 278.2247.
Conclusions
In summary, a family of coupling reactions between 1-(1-
cyclohexenyl)-1-cyclopropanol trimethylsilyl ether (2) and R,â-
unsaturated aldehyde acetals have been developed to quickly
assemble spirocyclobutanones containing three contiguous ste-
reocenters. Particularly noteworthy is high diastereoselectivity
obtained by employing R,â-alkenal acetals in marked contrast
to modest selectivity (3-4:1) observed for other acetals. The
resulting products contain useful functionalities such as a
cyclobutanone and an allylic ether, which are well suited for
elaboration. Mechanistic studies to elucidate dominant factors
for diastereocontrol and other methods for diastereoselective
functionalization of the coupling products will be reported in
due course.
Data for 4e: IR (film) 1779 cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.82 (d, J ) 18.5 Hz, 1H), 5.74 (dd, J ) 18.5, 7.5 Hz, 1H), 3.20
(dd, J ) 9.5, 7.5 Hz, 1H), 3.15 (s, 3H), 2.97-2.86 (m, 2H), 1.97
(m, 1H), 1.80 (ddd, J ) 13.0, 10.0, 3.5 Hz, 1H), 1.71 (ddd, J )
13.0, 5.0, 3.0 Hz, 2H), 1.67-1.56 (m, 2H), 1.56-1.43 (m, 2H),
1.30-1.12 (m, 2H), 0.85 (m, 1H), 0.06 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 215.3, 144.7, 136.4, 87.9, 66.8, 55.6, 45.0, 41.2,
33.8, 25.6, 25.1, 22.0, 18.3, -1.3; HRMS m/z calcd for C16H28O2-
Si (M+) 280.1859, found 280.1863.
Data for 5A: IR (film) 1774 cm-1; 1H NMR (360 MHz, CDCl3)
δ 3.44 (dd, J ) 8.1, 7.3 Hz, 2H), 3.28 (s, 3H), 3.18 (dt, J ) 9.0,
4.0 Hz, 1H), 2.87-3.01 (m, 2H), 2.26 (m, 1H), 2.07 (m, 1H), 1.85-
1.99 (m, 2H), 1.59-1.73 (m, 5H), 1.47 (m, 1H), 1.26 (m, 2H),
0.97 (m, 1H); 13C NMR (90 MHz, CDCl3) δ 215.0, 81.3, 67.1,
56.5, 44.3, 41.5, 34.3, 34.2, 28.8, 26.3, 25.4, 22.0, 18.6.
Experimental Section
Representative Procedure for Vinylogous Mukaiyama- or
Prins-Type Reactions of Cycloalkenylcyclopropanol Silyl Ethers.
To a cooled (-78 °C) solution of silyl ether 2 (421 mg, 2 mmol)
and acetal 3d (559 mg, 3 mmol) in dichloromethane (20 mL) was
added dropwise a solution of TiCl4 (570 mg, 3 mmol) in
dichloromethane (3 mL). The reaction mixture was stirred at
Data for 5B: IR (film) 1766 cm-1; 1H NMR (360 MHz, CDCl3)
δ 3.44-3.57 (m, 3H), 3.33 (s, 3H), 2.91 (t, J ) 8.4 Hz, 2H), 2.25
(dt, J ) 11.0, 8.4 Hz, 1H), 1.74-1.82 (m, 2 H), 1.48-1.68 (m,
9H), 1.22 (m, 1H); 13C NMR (90 MHz, CDCl3) δ 215.2, 80.2, 67.1,
58.2, 46.3, 41.6, 36.1, 35.8, 31.1, 25.9, 25.7, 23.3, 23.1.
Data for 5C (third isomer; structure not shown in Scheme
2): IR (film) 1770 cm-1; 1H NMR 1H NMR (500 MHz, CDCl3) δ
3.35-3.46 (m, 2H), 3.32 (s, 3H), 3.28 (td, J ) 6.8, 3.2 Hz, 1H),
3.00 (ddd, J ) 18.4, 10.0 Hz, 6.8 Hz, 1H), 2.90 (ddd, J ) 18.4,
10.0, 6.4 Hz, 1H), 2.34 (m, 1H), 2.08 (m, 1H), 1.97 (m, 1H), 1.68-
(20) Treatment of 14 and 15 with guanidine furnished the identical
erythro-(E)-epoxide, which was also secured by acidic hydrolysis of 17
and subsequent epoxide formation. On the other hand, the threo-(E)-epoxide
was obtained from 16. Additionally, iodohydrin formation gave 18 as the
major product, along with a mixture of the two (E)-epoxides.
7906 J. Org. Chem., Vol. 72, No. 21, 2007

DiastereoselectiVe Prins-Type Reaction
1
1.77 (m, 4H), 1.60-1.68 (m, 2H), 1.48 (m, 1H), 1.34 (m, 1H),
1.15-1.30 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 216.5, 80.8,
69.1, 57.8, 43.2, 42.2, 35.6, 34.6, 30.1, 25.6, 23.0, 22.0, 19.9.
Data for 10a: IR (film) 1778 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.20-7.24 (m, 3H), 7.10-7.14 (m, 3H), 6.95-7.02 (m, 4H),
5.16-5.27 (m, 2H), 4.72 (d, J ) 8.0 Hz, 1H), 4.70 (br s, 1H, -OH),
4.41 (d, J ) 8.0 Hz, 1H), 3.38 (t, J ) 9.5 Hz, 1H), 3.23 (ddd, J )
18.0, 10.0, 5.0 Hz, 1H), 3.15 (ddd, J ) 18.0, 10.0, 7.5 Hz, 1H),
2.01 (m, 1H), 1.88 (ddd, J ) 12.6, 9.5, 3.7 Hz, 1H), 1.77 (m, 1H),
1.58-1.70 (m, 3H), 1.68 (d, J ) 5.2 Hz, 3H). 1.44-1.54 (m, 2H),
1.28 (m, 1H), 1.16 (m, 1H), 0.73 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 218.3, 139.5, 137.2, 132.5, 130.3, 128.2, 128.1, 127.9,
127.7, 127.3, 127.1, 83.3, 79.6, 77.9, 66.9, 45.4, 41.9, 33.9, 25.9,
25.0, 22.0, 18.1, 17.7.
Data for 14: IR (film) 1776, 1739 cm-1; H NMR (400 MHz,
CDCl3) δ 5.17 (dq, J ) 9.7, 6.1 Hz, 1H), 4.13 (dd, J ) 9.7, 1.2
Hz, 1H), 3.36 (s, 3H), 2.98 (ddd, J ) 17.8, 9.7, 6.9 Hz, 1H), 2.85
(ddd, J ) 17.8, 9.7, 4.9 Hz, 1H), 2.55 (dd, J ) 9.3, 1.2 Hz, 1H),
2.10 (s, 3H), 1.99 (ddd, J ) 12.2, 9.3, 3.4 Hz, 1H), 1.89 (dddd, J
) 11.4, 9.7, 6.9, 1.6 Hz, 1H), 1.60-1.80 (m, 6H), 1.52 (d, J ) 6.1
Hz, 3H), 1.20-1.40 (m, 2H), 1.12 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 213.2, 169.4, 80.5, 72.6, 66.5, 59.2, 46.8, 43.1, 41.1,
33.8, 27.6, 24.9, 22.0, 21.9, 21.3, 19.4.
1
Data for 15: IR (film) 1776, 1743 cm-1; H NMR (400 MHz,
CDCl3) δ 5.37 (dd, J ) 4.9, 1.8 Hz, 1H), 4.48 (qd, J ) 6.9, 4.9
Hz, 1H), 3.38 (s, 3H), 3.34 (dd, J ) 9.3, 1.8 Hz, 1H), 2.94 (ddd,
J ) 17.0, 9.7, 6.9 Hz, 1H), 2.81 (ddd, J ) 17.0, 9.7, 5.3 Hz, 1H),
2.18 (s, 3H), 2.03 (m, 1H), 1.99 (d, J ) 6.9 Hz, 3H), 1.85-1.58
(m, 7H), 1.08-1.36 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 213.6,
170.0, 84.8, 78.7, 66.6, 59.1, 43.6, 41.0, 33.9, 27.8, 25.1, 24.6, 23.5,
21.7, 21.0, 18.9.
Data for 10b: IR (film) 1769 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.18-7.22 (m, 3H), 7.10-7.16 (m, 3H), 6.95-7.04 (m, 4H),
5.12-5.27 (m, 2H), 4.71 (d, J ) 8.5 Hz, 1H), 4.45 (d, J ) 8.5 Hz,
1H), 3.39 (dd, J ) 9.3, 8.5 Hz, 1H), 3.24 (ddd, J ) 18.0, 9.7, 4.9
Hz, 1H), 3.15 (ddd, J ) 18.0, 9.7, 7.7 Hz, 1H), 1.98-2.03 (m,
2H), 1.89 (m, 1H), 1.76 (m, 1H), 1.58-1.72 (m, 3H), 1.42-1.57
(m, 2H), 1.10-1.40 (m, 10H), 0.88 (t, J ) 7.3 Hz, 3H), 0.74 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 218.1, 139.5, 137.9, 137.1,
128.9, 128.2, 128.0, 127.8, 127.6, 127.2, 127.1, 83.2, 79.6, 77.9,
67.0, 45.5, 42.0, 33.9, 32.2, 31.4, 28.8, 25.7, 25.1, 22.5, 22.1, 18.2,
14.1.
1
Data for 16: IR (film) 2934, 2859 cm-1; H NMR (400 MHz,
CDCl3) δ 4.54 (hept, J ) 6.1 Hz, 1H), 4.43 (dq, J ) 10.1, 6.9 Hz,
1H), 3.80 (dd, J ) 2.5, 0.8 Hz, 1H), 3.68 (dd, J ) 10.1, 0.8 Hz,
1H), 3.59 (s, 3H), 2.14-2.28 (m, 2H), 2.04 (d, J ) 6.9 Hz, 3H),
1.96 (m, 1H), 1.60-1.80 (m, 4H), 1.40-1.53 (m, 5H), 1.29 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 103.3, 78.9, 78.3, 68.9 (q, J
) 32.8 Hz), 68.6 (q, J ) 32.8 Hz), 62.0, 47.2, 43.6, 32.0, 31.0,
26.3, 26.2, 25.5, 24.4, 22.2, 21.3 (2C).
Data for 10c: IR (film) 3565, 1778 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.20-7.24 (m, 3H), 7.05-7.12 (m, 3H), 6.98-7.12 (m,
2H), 6.94-6.97 (m, 2H), 5.71 (dd, J ) 18.7, 8.1 Hz, 1H), 5.50 (d,
J ) 18.7 Hz, 1H), 4.72 (d, J ) 8.1 Hz, 1H), 4.38 (d, J ) 8.1 Hz,
1H), 3.57 (dd, J ) 9.6, 9.1 Hz, 1H), 3.22 (dd, J ) 17.7, 9.6, 5.1
Hz, 1H), 3.15 (ddd, J ) 17.7, 9.6, 7.1 Hz, 1H), 1.99 (m, 1H), 1.92
(ddd, J ) 13.0, 9.6, 3.5 Hz, 1H), 1.78 (m, 1H), 1.55-1.70 (m,
4H), 1.51 (m, 1H), 1.42 (m, 1H), 1.29 (m, 1H), 1.17 (m, 1H), 0.75
(m, 1H), 0.06 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 218.3, 144.4,
139.7, 138.3, 137.0, 128.3, 128.1, 128.0, 127.8, 127.4, 127.0, 83.5,
82.3, 77.9, 66.9, 44.7, 42.0, 33.9, 25.4, 25.0, 22.0, 18.2, -1.4.
Data for 13a: IR (film) 1771 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.63 (dq, J ) 15.4, 6.5 Hz, 1H), 5.22 (ddq, J ) 15.4, 8.5, 1.6
Hz, 1H), 3.32 (dd, J ) 10.1, 8.5 Hz, 1H), 3.15 (s, 3H), 2.93 (t, J
) 8.3 Hz, 2H), 2.14-2.30 (m, 2H), 1.98 (m, 1H), 1.55-1.84 (m,
5H), 1.71 (dd, J ) 6.5, 1.6 Hz, 3H), 1.19 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 216.3, 130.5, 129.8, 84.3, 71.9, 55.2, 50.3, 42.9,
37.7, 28.1, 23.2, 21.1, 17.7; HRMS m/z calcd for C12H17O2 (M+-
Me) 193.1229, found 193.1233.
Data for 17: IR (film) 2934, 2859 cm-1; H NMR (400 MHz,
1
CDCl3) δ 4.46 (hept, J ) 6.1 Hz, 1H), 4.26-4.34 (m, 2H), 3.80
(br s, 1H), 3.43 (s, 3H), 2.72 (m, 1H), 2.22 (m, 1H), 2.05 (dd, J )
12.6, 2.4 Hz, 1H), 1.95 (ddd, J ) 13.0, 10.1, 3.7 Hz, 1H), 1.52-
1.78 (m, 5H), 1.43 (d, J ) 6.5 Hz, 3H), 1.34-1.48 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 109.3, 94.7, 94.5, 73.4, 69.7 (q, J )
33 Hz), 69.3 (q, J ) 33 Hz), 59.3, 53.9, 39.5, 39.3, 34.3, 30.9,
29.3, 26.4, 21.6, 21.4, 19.5.
1
Data for 18: IR (film) 3434, 1764 cm-1; H NMR (400 MHz,
CDCl3) δ 4.18 (dq, J ) 9.3, 6.5 Hz, 1H), 4.01 (dd, J ) 9.3, 1.8
Hz, 1H), 3.48 (s, 3H), 3.03 (dd, J ) 9.3, 1.8 Hz, 1H), 2.84-3.00
(m, 2H), 2.06 (ddd, J ) 11.8, 9.3, 3.2 Hz, 1H), 1.98 (m, 1H), 1.47-
1.78 (m, 7H), 1.54 (d, J ) 6.5 Hz, 3H), 1.18-1.38 (m, 2H), 1.07
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 214.0, 80.3, 70.0, 66.8,
58.8, 46.8, 46.5, 41.1, 33.9, 27.8, 25.0, 25.0, 21.9, 19.5.
Representative Procedure for Free Radical Cyclization. A
solution of 15 (20 mg, 0.049 mmol) in benzene (5.0 mL) was heated
at reflux under an argon atmosphere. A solution of n-Bu3SnH (30
mg, 0.1 mmol) and AIBN (1.6 mg, 0.01 mmol) in benzene (1.0
mL) was added over 6 h. The solvent was evaporated under reduced
pressure, and the residue was treated with Et3N·3HF complex (0.5
mL) in ether (3.0 mL). The resulting mixture was stirred for 1 h at
room temperature and passed through a pad of SiO2. The filtrate
was concentrated under reduced pressure. The crude product was
purified by SiO2 (1.0 g) column chromatography using 10:1
hexanes-ethyl acetate as the eluent to give 19 (11.3 mg, 82%) as
a 4.4:1 mixture of diastereomers. Data for the major diastereomer:
Data for 13b: IR (film) 1778 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.61 (dt, J ) 15.4, 6.9 Hz, 1H), 5.20 (ddt, J ) 15.4, 8.5, 1.6 Hz,
1H), 3.34 (dd, J ) 10.1, 8.5 Hz, 1H), 3.17 (s, 3H), 2.95 (t, J ) 8.3
Hz, 2H), 2.14-2.32 (m, 2H), 1.93-2.04 (m, 2H), 1.80 (m, 1H),
1.55-1.68 (m, 3H), 1.35-1.45 (m, 2H), 1.18 (m, 1H), 0.89 (t, J )
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 216.3, 135.2, 129.4,
84.4, 72.0, 55.3, 50.4, 42.9, 37.8, 34.3, 28.2, 23.2, 22.4, 21.2, 13.6;
HRMS m/z calcd for C15H24O2 (M+) 236.1776, found 236.1779.
Data for 13c: IR (film) 1778 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.61 (dt, J ) 15.4, 6.9 Hz, 1H), 5.20 (ddt, J ) 15.4, 8.5, 1.6 Hz,
1H), 3.33 (dd, J ) 10.1, 8.5 Hz, 1H), 3.18 (s, 3H), 2.94 (t, J ) 8.3
Hz, 2H), 2.06-2.32 (m, 2H), 1.94-2.04 (m, 3H), 1.81 (m, 1H),
1.56-1.68 (m, 4H), 1.05-1.23 (m, 7H), 0.88 (t, J ) 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 216.3, 135.5, 129.2, 84.4, 72.0,
55.3, 50.4, 42.9, 37.8, 32.2, 31.3, 28.9, 28.2, 23.2, 25.5, 21.8, 14.1;
HRMS m/z calcd for C17H28O2 (M+) 264.2089, found 264.2096.
Preparation of 14 and 15. A mixture of cyclobutanone 4a (178
mg, 0.8 mmol), Hg(OAc)2 (318.7 mg, 1.0 mmol), and iodine (254
mg, 1.0 mmol) in acetic acid (4.0 mL) was stirred at room
temperature for 4 h. The solvent was evaporated under reduced
pressure. The residue was dissolved in ether, washed with brine
and an aqueous sodium bicarbonate solution, dried over Na2SO4,
and concentrated under reduced pressure. The crude product was
purified by preparative TLC to afford 14 (209.3 mg, 64%) and 15
(84.1 mg, 26%).
IR (film) 1740, 1702 cm-1; H NMR (400 MHz, CDCl3) δ 5.08
1
(dd, J ) 5.0, 2.8 Hz, 1H), 3.41 (dq, J ) 6.5, 5.0 Hz, 1H), 3.35 (s,
3H), 3.24 (d, J ) 2.8 Hz, 1H), 2.72 (m, 1H), 2.30 (ddd, J ) 19.1,
6.5, 3.2 Hz, 1H), 2.12 (s, 3H), 1.55-1.80 (m, 7H), 1.05-1.22 (m,
5H), 1.01 (d, J ) 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
213.2, 170.5, 87.8, 79.6, 61.0, 44.7, 42.9, 38.5, 36.4, 36.0, 34.0,
26.6, 26.2, 21.1, 12.5 (there is an overlap corresponding to 2C);
HRMS m/z calcd for C16H26O4 (M+) 282.1831, found 282.1838.
Data for 21 (higher Rf, trans-ring junction isomer): IR (film)
3435, 1693 cm-1; H NMR (400 MHz, CDCl3) δ 3.97 (apparent
1
quintet, J ) 6.1 Hz, 1H), 3.64 (d, J ) 6.1 Hz, 1H), 3.40 (s, 3H),
3.30 (d, J ) 4.5 Hz, 1H), 2.79 (dd, J ) 6.1, 4.5 Hz, 1H), 2.73
(ddd, J ) 15.0, 10.1, 2.8 Hz, 1H), 2.39 (ddd, J ) 15.0, 10.1, 2.8
Hz, 1H), 1.95 (m, 1H), 1.45-1.56 (m, 6H), 1.03-1.40 (m, 3H),
1.27 (d, J ) 6.5 Hz, 3H), 0.96-1.02 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 216.5, 84.0, 67.7, 60.7, 59.1, 45.5, 41.8, 37.1, 34.5, 32.9,
30.9, 26.5, 26.1, 21.7.
J. Org. Chem, Vol. 72, No. 21, 2007 7907

Lysenko et al.
Data for 21 (lower Rf, cis-ring junction isomer): IR (film)
Acknowledgment. We thank the National Institutes of
Health (Grant GM35956) and the National Science Foundation
(Grant CHE0615604) for generous financial support.
1
3454, 1697 cm-1; H NMR (400 MHz, CDCl3) δ 4.22 (qd, J )
6.5, 2.4 Hz, 1H), 3.79 (dd, J ) 10.9, 2.4 Hz, 1H), 3.42 (s, 3H),
2.57 (ddd, J ) 12.2, 12.2, 2.8 Hz, 1H), 2.46 (dd, J ) 10.9, 2.4 Hz,
1H), 2.40 (d, J ) 6.5 Hz, 1H), 2.34 (ddd, J ) 12.2, 6.5, 2.0 Hz,
1H), 2.12 (ddd, J ) 12.6, 6.5, 2.8 Hz, 1H), 1.74-2.00 (m, 3H),
1.50-1.65 (m, 5H), 1.20-1.50 (m, 2H), 1.25 (d, J ) 6.5 Hz, 3H),
1.07 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 213.3, 82.3, 68.2,
60.5, 57.4, 43.6, 42.6, 38.5, 33.6, 26.8, 26.6, 21.6, 21.2, 20.7.
Supporting Information Available: 1H and 13C NMR spectra
of key intermediates. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO071272O
7908 J. Org. Chem., Vol. 72, No. 21, 2007