Scope and facial selectivity of the prins-pinacol synthesis of attached rings

Article abstract of DOI:10.1021/jo0522862

Using a β-alkyl Suzuki cross-coupling as a key step, a concise and stereocontrolled synthesis of five- to eight-membered triisopropylsiloxy ethers having (2Z)-(6,6-dimethoxyhexylidene) or (2Z)-(5,5-dimethoxypentylidene) side chains was developed. Prins-pinacol reactions of these precursors promoted by SnCl₄ provide bicyclic products in which 5-, 6-, or 7-membered rings are joined by a C-C single bond. Synthetically challenging attached ring systems in which both rings are chiral can be prepared in this fashion with high stereo- and enantioselectivity. Stabilizing through-space electrostatic interactions between the α-alkoxycarbenium ion and an axially positioned oxygen substituent are believed to play a significant role in organizing the transition structure of the Prins cyclization. copy; 2006 American Chemical Society.

Full text of DOI:10.1021/jo0522862

Scope and Facial Selectivity of the Prins-Pinacol Synthesis of
Attached Rings
Larry E. Overman* and Emile J. Velthuisen
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine, California 92697-2025
leoVerma@uci.edu
ReceiVed NoVember 3, 2005
Using a B-alkyl Suzuki cross-coupling as a key step, a concise and stereocontrolled synthesis of five- to
eight-membered triisopropylsiloxy ethers having (2Z)-(6,6-dimethoxyhexylidene) or (2Z)-(5,5-dimethoxy-
pentylidene) side chains was developed. Prins-pinacol reactions of these precursors promoted by SnCl4
provide bicyclic products in which 5-, 6-, or 7-membered rings are joined by a C-C single bond.
Synthetically challenging attached ring systems in which both rings are chiral can be prepared in this
fashion with high stereo- and enantioselectivity. Stabilizing through-space electrostatic interactions between
the R-alkoxycarbenium ion and an axially positioned oxygen substituent are believed to play a significant
role in organizing the transition structure of the Prins cyclization.
Introduction
features of several classes of natural products, with representa-
tive examples being depicted in Figure 1.5 When the attached
carbons are stereogenic, this motif of rings poses a formidable
challenge for stereocontrolled total synthesis.6,7
In our earlier study, we found that reaction of SnCl4 with
(Z)-alkylidene cyclohexane 5a promoted Prins cyclization and
subsequent pinacolic ring-contraction to form 1-(cyclohexyl)-
cyclopentanecarbaldehyde 6, as a mixture of methoxy epimers,
in useful yield (Scheme 1).4 In contrast, similar treatment of
the corresponding E stereoisomer 5b produced a mixture of
A central objective in synthetic organic chemistry is to
discover new methods for constructing complex molecules from
relatively simple starting materials. One powerful method for
accomplishing this feat is to combine two distinct reactions into
a single transformation, often referred to as a cascade or tandem
reaction.1 For a number of years, we have been developing
cascade reactions that combine a Prins cyclization with a pinacol
rearrangement.2,3 Using this strategy, a variety of architecturally
complex fused or bridged oxacyclic and carbocyclic ring systems
can be assembled in good yield and high stereoselectivity.3
Several years ago we described the first use of a Prins-pinacol
reaction to assemble rings joined by a C-C σ-bond, hereafter
referred to as attached rings.4 Such rings are prominent structural
(4) Overman, L. E.; Pennington, L. D. Can. J. Chem. 2000, 78, 732-
738.
(5) (a) Nozoe, S.; Machida, Y. Tetrahedron Lett. 1970, 31, 2671-2674.
(b) Desilva, E. D.; Morris, S. A.; Miao, S.; Dumdei, E.; Andersen, R. J. J.
Nat. Prod. 1991, 54, 993-997. (c) Iliopoulou, D.; Mihopoulos, N.; Vagias,
C.; Papazafiri, P.; Roussis, V. J. Org. Chem. 2003, 68, 7667-7674. (d)
Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Chem. Commun. 1968,
23-25.
(6) For a review of methods to make carbocyclic attached ring systems,
see: Wills, M. In Second Supplements to the 2nd Edition of Rodd’s
Chemistry of Carbon Compounds; Sainsbury, M. Ed.; Elsevier: New York,
1994; Vol. II B (Partial), C, D, and E, pp 181-204.
(7) For representative examples of how this architectural motif has been
addressed, see: (a) Lange, G. L.; Furlan, L.; MacKinnon, M. C. Tetrahedron
Lett. 1998, 39, 5489-5492. (b) Lemieux, R. M.; Meyers, A. I. J. Am. Chem.
Soc. 1998, 120, 5453-5457. (c) Gilbert, J. C.; Selliah, R. D. J. Org. Chem.
1993, 58, 6255-6265. (d) Sakai, K.; Tanaka, M. Tetrahedron Lett. 1991,
32, 5581-5584. (e) Ley, S. V.; Gutteridge, C. E.; Pape, A. R.; Spilling, C.
D.; Zumbrunn, C. Synlett 1999, 1295-1297. (f) Lebsack, A. D.; Overman,
L. E.; Valentekovich, R. J. J. Am. Chem. Soc. 2001, 123, 4851-4852. (g)
Kishi, Y.; Wang, W. Org. Lett. 1999, 7, 1129-1132.
(1) For recent reviews, see: (a) Tietze, L. F. Chem. ReV. 1996, 96, 115-
136. (b) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137-165.
(c) Winkler, J. D. Chem. ReV. 1996, 96, 167-176. (d) Ryu, I.; Sonoda, N.;
Curran, D. P. Chem. ReV. 1996, 96, 177-194. (e) Parsons, P. J.; Penkett,
C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195-206. (f) Wang, K. K. Chem.
ReV. 1996, 96, 207-222. (g) Padwa, A.; Weingarten, M. D. Chem. ReV.
1996, 96, 223-269. (h) Malacria, M. Chem. ReV. 1996, 96, 289-306. (i)
Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307-338. (j) Tietze,
L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131-163. (k)
Ho, T.-L. Tandem Organic Reactions; Wiley & Sons: New York, 1992.
(2) (a) Martinet, P.; Mousset, G.; Michel, M. C. R. Acad. Sci. Paris,
Ser. C 1969, 268, 1303-1306. (b) Martinet, P.; Mousset, G. Bull. Soc.
Chim. Fr. 1970, 1071-1076.
(3) For a recent review, see: Overman, L. E.; Pennington, L. D. J. Org.
Chem. 2003, 68, 7143-7157.
10.1021/jo0522862 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/17/2006
J. Org. Chem. 2006, 71, 1581-1587
1581

Overman and Velthuisen
SCHEME 2
FIGURE 1. Representative natural products containing attached rings.
SCHEME 1
Results
Stereoselective Synthesis of 2(Z)-Alkylidenecycloalkanols.
In our previous study, 2-(Z)-alkylidene-1-siloxycyclohexane 5a
was prepared by a nonstereoselective Wittig reaction, with
tedious chromatography being required to obtain isomerically
pure material. As a result, an improved synthesis of 2(Z)-
alkylidenecycloalkanols that utilizes a B-alkyl Suzuki cross-
coupling as the pivotal step was developed (Scheme 2).9 This
sequence was refined initially in the cyclohexyl series. The (Z)-
vinyl triflate 11 was generated by rapid addition of t-BuLi to a
hexanes solution of 2-(hydroxymethylene)cyclohexanone (8) at
-78 °C, followed by quenching at -78 °C with Tf2O.10 Because
of the instability of triflate 11, it was used immediately without
purification. Suzuki cross-coupling of crude 11 with alkyl borane
23, generated by hydroboration of 4,4-dimethoxybut-1-ene with
9-BBN, provided (Z)-alkylidenecyclohexanone 14 in 65%
overall yield from ketone 8. Reduction of this product with
LiAlH4 yielded alcohol 17, which upon silylation with triiso-
propylsilyl trifluoromethanesulfonate provided Prins-pinacol
precursor 20.11 The Z configuration of 20 was confirmed by
observing 1H NMR NOE enhancements between the C1 siloxy
hydrogen and the allylic hydrogens of the side chain. The
cycloheptyl and cyclooctyl congeners of 20, 21, and 22 were
prepared by identical sequences (Scheme 2).
products resulting from a competition between ring-contraction
and hydride migration in the pinacolic-rearrangement step. The
clean formation of 1-(cyclohexyl)cyclopentanecarbaldehydes 6
in the former case was attributed to Prins cyclization occurring
by chair conformer A in which A1,3 interactions8 are minimized
by placing the siloxy group axial. If pinacol rearrangement
occurred more rapidly than conformational equilibration, only
ring bond a in the resulting cyclohexyl cation B would have
sufficient overlap with the vacant p-orbital to undergo a pinacol
rearrangement. Face selectivity in the Prins cyclization of the
oxocarbenium ion derived from 5a cannot be ascertained from
the relative configuration of 1-(cyclohexyl)cyclopentanecarbox-
aldeyde 6 because C1 is not stereogenic.
Cyclization precursors having four methylene units between
the alkene and acetal functional groups were prepared in similar
fashion from the corresponding 2-(hydroxymethylene)cycloal-
kanones and alkyl borane 34, derived from 5,5-dimethoxypent-
1-ene (Scheme 3). As with the substrates reported in Scheme
2, the alkene configuration of 47, 48, and 49 was confirmed by
1H NMR NOE experiments.
Although our previous study pointed to the potential of Prins-
pinacol reactions to construct attached rings,4 several aspects
of this strategy required further study. This paper addresses three
issues: (1) development of a stereoselective synthesis of (Z)-
2-alkylidene-1-siloxycycloalkanes; (2) investigation of the scope
of the Prins-pinacol approach for assembling attached rings of
varying sizes and ring substitution; and (3) exploration of facial
stereoselection in the Prins cyclization, which, if high, would
allow for the stereocontrolled construction of attached stereo-
genic rings by Prins-pinacol cyclizations.
To explore the effect of ring substitution upon the Prins-
pinacol synthesis of attached rings, three geminally disubstituted
ring precursors were investigated. Starting from 2,2-dimethyl-
(9) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-321.
(10) Bru¨ckner, R.; Scheuplein, S. W.; Suffert, J. Tetrahedron Lett. 1991,
32, 1449-1452.
(11) Unless preceded by a stereochemical descriptor, all compounds are
racemic.
(8) Eliel, E. L.; Wilen, S. H. In Stereochemistry of Organic Compounds;
John Wiley & Sons: New York, 1994, 738.
1582 J. Org. Chem., Vol. 71, No. 4, 2006

Prins-Pinacol Synthesis of Attached Rings
TABLE 1. Prins-Pinacol Reactions To Form Various Attached
Ring Systems
SCHEME 3
entry
substrate
n
m
yield, %
cis/trans (product)
1
2
3
4
5
20
21
22
32
33
1
1
1
2
2
1
2
3
2
3
69
75
71
82
68
1.0:3.4 (50a + 50b)
1.0:1.0 (51a + 51b)
1.2:1.0 (52a + 52b)
1.5:1.0 (53a + 53b)
2.4:1.0 (54a + 54b)
cycloalkanecarbaldehydes 53 and 54 in 82% and 68% yield,
respectively (Table 1, entries 4 and 5). In contrast, attempted
construction of a 1-(2-methoxycyclohexyl)cyclobutanecarbalde-
hyde by Prins-pinacol conversion of the alkylidenecyclopentyl
precursor 31 gave cyclopentanone 55 as the sole isolated product
(eq 1). Only in this latter case wherein ring contraction would
have generated a four-membered ring was Prins cyclization
followed by hydride migration.
SCHEME 4
In the reactions summarized in Table 1, the methoxy epimers
of the products were separable by flash column chromatography;
1
epimer ratios were ascertained by H NMR experiments. For
the Prins-pinacol products reported in entries 1-3 of Table 1,
the relative configuration of these epimers was determined by
1H NMR NOE enhancements. A cis relationship of the methoxy
methine hydrogen and the vicinal methine hydrogen was
indicated by a positive NOE correlation, whereas in the epimeric
series this enhancement was absent. For the products of Prins-
pinacol rearrangements reported in entries 4 and 5 of Table 1,
relative configuration followed directly from 1H NMR spectra.
A diagnostic triplet of doublets for the downfield methine
hydrogen [53b: δ 2.84 ppm (J ) 10.3, 4.2 Hz), 54b: δ 2.78
ppm (J ) 10.5, 4.4 Hz)] established an equatorial disposition
of the methoxy substituent; whereas the trans isomers showed
a broad singlet for this hydrogen (53a: δ 3.58 ppm, 54a: δ
3.53 ppm).
(35),12 3,3-dimethyl- (36),13 and 4,4-dimethyl-6-(hydroxymeth-
ylene)cyclohexanone (37),14 the corresponding Prins-pinacol
precursors were synthesized by similar sequences (Scheme 4).
Prins-Pinacol Reactions. Although nitromethane was used
as solvent in our earlier study,4 in early phases of this
investigation (vide infra) we found that these Prins-pinacol
reactions were equally efficient in CH2Cl2. As CH2Cl2 is easier
to obtain anhydrous, this solvent is preferred. Exposure of a
CH2Cl2 solution of the alkylidenecyclohexyl Prins-pinacol
substrates 20, 21, and 22 to 0.5 equiv of SnCl4 for 2 h at 0 °C
afforded 1-(cyclopentyl)cycloalkanecarbaldehydes 50-52 in
69-75% yield (Table 1, entries 1-3). Identical reaction of
Prins-pinacol substrates 32 and 33 provided the 1-(cyclohexyl)-
The effect of substitution in the starting siloxy alkylidene
ring was explored in the cyclohexyl series. Exposure of substrate
47, which contains gem-dimethyl substitution adjacent to the
siloxy substituent, to 0.5 equiv of SnCl4 at 0 °C for 2 h in
MeNO2 provided a mixture of products. Similar results were
obtained when CH2Cl2 was employed as the solvent. From this
complex reaction mixture, the 1-(cyclohexyl)cyclopentanecar-
baldehyde 56 was isolated in 8% yield (eq 2). Additionally,
bicyclohexyl-2-one 57, which arises from hydride migration
following Prins cyclization, was isolated in 21% yield. The
equatorial disposition of the methoxy group in both 56 and 57
followed from the diagnostic apparent triplet of doublets
observed for the ether methine hydrogen: 56: δ 2.98 ppm (J
) 10.3, 4.2 Hz), 57: δ 3.38 ppm (J ) 9.5, 3.9 Hz). Because of
(12) Johnson, W. S.; Posvic, H. J. Am. Chem. Soc. 1947, 69, 1361-
1366.
(13) Seifert, S. HelV. Chim. Acta 1951, 34, 728-735.
(14) Tietze, L. F.; Peterson, S. Eur. J. Org. Chem. 2001, 9, 1619-1624.
J. Org. Chem, Vol. 71, No. 4, 2006 1583

Overman and Velthuisen
SCHEME 5 a
SCHEME 7 a
a Reagents and conditions: (a) SnCl4, MeNO2, 0 °C (48%); (b)
NH2NHTs, AcOH (50%).
SCHEME 6 a
a Reaction conditions: (a) NaBH4, MeOH; (b) Ac2O, pyridine (67% over
2 steps for 62, 85% for 63); (c) RuCl3‚xH2O, NaIO4, CCl4, MeCN, pH 7
buffer (50% for both 62 and 71% for 63).
SCHEME 8
a Reagents and conditions: (a) SnCl4, MeNO2, 0 °C (84%); (b)
NH2NHTs, AcOH (84%).
the low yield of these products, the relative configuration at
the carbon adjacent to the carbonyl group was not determined.
1
the H NMR spectrum as a broad singlet at δ 3.46 ppm. The
constitution and relative configuration of aldehyde 60a was
confirmed by single-crystal X-ray analysis of tosylhydrazone
derivative 61.15
To establish that Prins-pinacol products 60a and 60b were
indeed methoxy epimers, 60a and 60b were chemically cor-
related as summarized in Scheme 7. After transforming the
formyl group of these two products to acetoxymethyl substit-
uents, derivatives 62 and 63 were both converted to cyclohex-
anone 64 upon oxidation with RuO4.
The desired Prins-pinacol conversion was more efficient when
the gem-dimethyl group was present at C3 or C4 of the
cyclohexyl ether precursor. For example, exposure of substrate
48 to 0.5 equiv of SnCl4 at 0 °C for 2 h in MeNO2 gave a 1:2
mixture of 1-(2-methoxycyclohexyl)-3,3-dimethylcyclopentan-
ecarbaldehydes 58a and 58b in 48% yield (Scheme 5). Several
other unidentified products were apparent in the 1H NMR
spectrum of the crude reaction product. Similar results were
realized using CH2Cl2 as the solvent. The relative configuration
To survey the potential of Prins-pinacol cyclizations for the
stereo- and enantioselective construction of attached rings in
which the attached carbons are both stereogenic, cyclization
substrate 49 was prepared in enantiomerically enriched form.
By design, the route we employed for the synthesis of racemic
cyclization substrates was easily adapted to this task (Scheme
8). Thus, using the (R)-CBS catalyst, oxazaborolidine-mediated
reduction of enone 43 provided allylic alcohol (S)-46 in 74%
yield and 87% ee.16,17 This product was assigned the S absolute
configuration on the basis of strong precedent17 and the
established facial selectivity of the CBS reagents.16 Silylation
of alcohol (S)-46 provided rearrangement substrate (S)-49.
Exposure of siloxy acetal (S)-49 to 0.5 equiv of SnCl4 for 2
h at 0 °C in MeNO2 provided 1-(2-methoxycyclohexyl)-4,4-di-
methylcyclopentanecarbaldehydes (1S,1′S,2′S)-60a and (1S,1′S,
2′R)-60b in high yields (Scheme 9). The epimers were separated,
and (1S,1′S,2′S)-60a was allowed to react with acetic acid and
tosylhydrazine to provide tosylhydrazone (1S,1′S,2′S)-61. The
1
of the two methoxy epimers of 58 was apparent from their H
NMR spectra [58a: triplet of doublets at δ 2.60 ppm (J ) 10.4,
4.3 Hz), 58b: broad singlet at δ 3.43 ppm]. Additionally, the
constitution and relative configuration of aldehyde 58b was
confirmed by single-crystal X-ray analysis of tosylhydrazone
derivative 59.15
The most efficient Prins-pinacol conversion was realized with
the 4,4-dimethyl-substituted substrate 49 (Scheme 6). When this
precursor was exposed to 0.5 equiv of SnCl4 for 2 h at 0 °C in
MeNO2, a 1.4:1 mixture of 1-(2-methoxycyclohexyl)-4,4-
dimethylcyclopentanecarbaldehydes 60a and 60b was isolated
in 84% yield. The equatorial disposition of the methoxy group
in 60b was apparent from the diagnostic triplet of doublets
observed for the ether methine hydrogen: δ 2.70 ppm (J )
10.5, 4.3 Hz). Conversely, this hydrogen of 60a appeared in
(16) For a review of oxazaborolidine mediated reductions with the CBS
reagents, see: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986-2012.
(17) Simpson, A. F.; Szeto, P.; Lathbury. D. C.; Gallagher, T. Tetrahe-
dron: Asymmetry 1997, 8, 673-676.
(15) Crystallographic data for this compound was deposited at the
Cambridge Crystallographic Data Centre: 59, CCDC 287233; 61, CCDC
287232. (1S,1′S,2′S)-61, 287234.
1584 J. Org. Chem., Vol. 71, No. 4, 2006

Prins-Pinacol Synthesis of Attached Rings
SCHEME 9 a
SCHEME 10
a Reagents and conditions: (a) SnCl4, MeNO2, 0 °C (82%); (b)
NH2NHTs, AcOH (81%).
SCHEME 11
identified. First, if the starting ring is five-membered, the cation
67 produced upon Prins cyclization of acetal 31 does not
undergo pinacol ring-contraction, but rather hydride migration
to produce 2-cyclohexylcyclopentanone 55 (Scheme 10). Ring
strain associated with the formation of the cyclobutane ring of
1-(2-methoxycyclohexyl)cyclobutanecarbaldehyde (68) is un-
doubtedly responsible for this outcome. Second, attached ring
systems containing contiguous quaternary carbons apparently
cannot be assembled efficiently by Prins-pinacol reactions. Thus,
1-(2-methoxycyclohexyl)-2,2-dimethylcyclopentanecarbalde-
hyde (56) was produced in low yield from Prins-pinacol reaction
of precursor 47 (eq 2). Pinacol ring contraction of carbocation
69 is apparently disfavored by developing steric interactions
between the axial methyl and pseudoaxial cyclohexyl substit-
uents (Scheme 11).
FIGURE 2. ORTEP representation of the X-ray model of (1S,1′S,2′S)-
61.
enantiomeric excess of this product was determined to be 70%
by HPLC analysis using a chiral phase, establishing that the
Prins-pinacol reaction occurs with 80% transfer of chirality in
this example.18
The absolute configuration of (1S,1′S,2′S)-61 was determined
by single-crystal X-ray analysis (Figure 2). A value of -0.25
for the Flack parameter established the absolute configuration
of this sample to be 1S,1′S,2′S as depicted in Scheme 9.15,19
Similar circular dichroism (CD) spectra were obtained for the
single-crystal employed in the X-ray analysis and the bulk
sample of (1S,1′S,2′S)-61.
A primary objective of the present study was to ascertain
whether attached rings in which both rings are chiral could be
prepared stereoselectively by Prins-pinacol reactions. Such an
outcome would require that the initial Prins cyclization takes
place with high facial selectivity and that pinacol ring contrac-
tion occurs from a single chair conformation of the resulting
cyclohexyl carbenium ion.4 The results summarized in Schemes
5 and 6 demonstrate that such ring systems can be assembled
with high stereocontrol as mixtures of methoxy epimers.20
An analysis of the potential stereochemical outcome of the
Prins-pinacol reaction of precursor 49 is presented in Scheme
12. Prins cyclization of the derived R-alkoxycarbenium ion could
take place either syn or anti to the siloxy group in two possible
Discussion
Scope and Limitations. Using a B-alkyl Suzuki cross
coupling as a key step, a concise and stereocontrolled synthesis
of 5- to 8-membered triisopropylsiloxy ethers having (2Z)-(6,6-
dimethoxyhexylidene) or (2Z)-(6,6-dimethoxyhexylidene) side
chains was developed. As the results reported in Table 1 and
Schemes 5 and 6 show, SnCl4-promoted Prins-pinacol reactions
of these precursors can be employed to assemble a range of
bicyclic products 66 in which 5-, 6-, or 7-membered rings are
joined by a C-C single bond (eq 3). Two limitations have been
(18) The HPLC analysis employed the p-nitrobenzoyl derivative of the
corresponding alcohol.
(19) Flack, H. D. Acta Crystallogr. 1983, A39, 876-881.
(20) The observed stereochemical outcome of the Prins-pinacol trans-
formation is similar in the formation of the attached ring systems 58 (Scheme
5) and 60 (Scheme 6).
J. Org. Chem, Vol. 71, No. 4, 2006 1585

Overman and Velthuisen
SCHEME 12
chair conformations of the alkylidenecyclohexane ring. If one
assumes that pinacol rearrangements occur more rapidly than
interconversion of chair cyclohexyl cations B/D and F/H,21-23
the exclusive formation of rel-1R,1′R methoxy epimers 60a and
60b from precursor 49 is consistent with Prins cyclization taking
place either anti to the siloxy substituent if this group were
equatorial (C f D), or syn to the siloxy group (E f F) if this
substituent were axial. Carrying out the Prins-pinacol reaction
with an enantiomerically enriched precursor can differentiate
these two scenarios. Thus, the transformation of (S)-49 to the
1S,1′S enantiomer of (1-cyclohexyl)cyclopentanecarbaldehyde
60, which proceeded with only slight erosion in enantiomeric
purity, establishes that this reaction takes place largely by the
49 f E f F f 60 pathway. The small loss of absolute chirality
observed in this reaction likely originates from a minor amount
of Prins cyclization taking place by the C f D pathway.24
Several factors potentially contribute to the preference for
Prins cyclization to occur syn to the siloxy group in the chair
conformation depicted in E. As noted earlier,4 the chair
conformation of allylic siloxy ether 49 having the siloxy group
equatorial suffers from a severe allylic (A1,3) interaction between
the alkylidene and siloxy substituents.8 One factor disfavoring
cyclization from the face opposite the axial siloxy group (A f
B) would be a steric interaction between the C5 axial methyl
and the methoxy substituents. However, this interaction does
not appear to be decisive as the related Prins-pinacol conversion
of the C3-dimethyl congener 48, in which this steric interaction
would be absent, proceeds by a pathway similar to that followed
by precursor 49 to provide attached-ring products 58a and 58b.25
A stabilizing through-space electrostatic interaction between the
R-alkoxycarbenium ion and the axial oxygen substituent are
most likely responsible for Prins cyclization occurring prefer-
entially syn to the axial siloxy group.26 The importance of such
interactions in organizing transition structures for the reaction
of nucleophiles with oxocarbenium ions has been demonstrated
by recent incisive studies by Woerpel and co-workers.27
In conclusion, we demonstrated that Prins-pinacol reactions
of cyclohexyl- and cyclopentyl triisopropylsiloxy ethers having
(2Z)-(6,6-dimethoxyhexylidene) or (2Z)-(6,6-dimethoxyhexyl-
idene) side chains can be employed to construct a variety of
attached ring systems. Moreover, attached rings in which both
rings are chiral can be prepared in this fashion with high
stereoselectivity and moderate enantiospecificity. Stabilizing
(21) This assumption has considerable experimental justification.3
(22) Minor, K. P.; Overman, L. E. Tetrahedron 1997, 53, 8927-8940.
(23) In the absence of stereoelectronic constraints, pinacol rearrangements
have extremely low activation barriers; see: (a) Bartok, M.; Molnar, A. In
Chemistry of Ethers, Crown Ethers, Hydroxyl Compounds and Their Sulfur
Analogues; Patai, S., Ed.; Wiley: New York, 1980; Part 2, pp 722-732.
(b) Rickborn, B. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 721-732.
(24) To determine if siloxy acetal (S)-49 partially racemizes during the
course of this reaction sequence, the reaction was stopped prematurely and
the entaniomeric excess of recovered acetal (S)-49 was measured. HPLC
analysis employing the p-nitrobenzoyl derivative of the corresponding
alcohol indicated an 87% ee for this material, indicating that no loss of
absolute chirality had occurred.
(25) These products would be produced if this cyclization proceeded by
the E f F pathway.
(26) (a) Kahn, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, W. J. J. Am.
Chem. Soc. 1987, 109, 650-663. (b) Kahn, S. D.; Hehre, W. J. J. Am.
Chem. Soc. 1987, 109, 666-671.
(27) Chamberland, S.; Ziller, J. W.; Woerpel, K. A. J. Am. Chem. Soc.
2005, 127, 5322-5323.
1586 J. Org. Chem., Vol. 71, No. 4, 2006

Prins-Pinacol Synthesis of Attached Rings
H), 1.44-1.39 (m, 3 H), 1.28-1.25 (m, 1 H); 13C NMR (125 MHz,
CDCl3) δ 140.5, 124.8, 104.7, 65.5, 52.9, 52.8, 34.1, 32.4, 32.1,
28.2, 26.6, 25.3, 20.6; IR (neat) 3420, 1444 cm-1; HRMS (CI) m/z
211.1698 (M - OH, 211.1692 calcd for C13H24O3). Anal. Calcd
for C13H24O3: C, 68.38; H, 10.59. Found: C, 67.91; H, 10.81.
General Procedure for Silylation. Preparation of (Z)-[[2-(5,5-
Dimethoxypentylidene)cyclohexyloxy]triisopropylsilane] (20).
Pyridine (0.60 mL, 7.4 mmol), triisopropylsilyl trifluoromethane-
sulfonate (0.86 mL, 3.2 mmol), and 2,6-(dimethylamino)pyridine
(30 mg, 0.25 mmol) were added sequentially to a solution of alcohol
49 (0.56 g, 2.5 mmol) and CH2Cl2 (3 mL). After being stirred for
18 h at room temperature, the reaction mixture was partitioned
between pentane (20 mL) and saturated aqueous NaHCO3 (20 mL).
The aqueous layer was extracted with pentane (2 × 10 mL), and
the combined organic layers were washed with brine (40 mL), dried
(Na2SO4), and concentrated. The residue was purified by flash
column chromatography on silica gel (1% ethyl acetate-hexanes)
to yield 20 (0.64 g, 68%) as a pale yellow oil: 1H NMR (500 MHz,
CDCl3) δ 5.02 (t, J ) 6.7 Hz, 1 H), 4.72 (bs, 1 H), 4.36 (t, J ) 5.7
Hz, 1 H), 3.32 (s, 6 H), 2.56-2.45 (m, 1 H), 2.11-1.83 (m, 5 H),
1.79-1.73 (m, 1 H), 1.66-1.54 (m, 2 H), 1.48-1.32 (m, 3 H),
1.30-1.22 (m, 1 H), 1.09-1.02 (m, 22 H); 13C NMR (125 MHz,
CDCl3) δ 142.4, 121.5, 104.7, 66.3, 52.8, 36.3, 32.7, 32.3, 29.1,
27.1, 25.3, 20.8, 18.3, 18.2, 12.6; IR(neat) 2936, 2862 cm-1; HRMS
(ESI) m/z 384.3059 (M, 384.3059 calcd for C22H44O3Si). Anal.
Calcd for C22H44O3Si: C, 68.69; H, 11.53. Found: C, 68.84; H,
11.68.
General Procedure for Prins-Pinacol Reactions. Preparation
of 50a and 50b. Stannic chloride32 (60 µL, 0.33 mmol) was added
dropwise to a stirring solution of unsaturated siloxy acetal 20 (0.25
g, 0.65 mmol) and CH2Cl2 (7 mL, 0.1 M) at 0 °C. After the reaction
was maintained at 0 °C for 2 h, the reaction mixture was poured
into saturated aqueous NaHCO3 (5 mL), and the aqueous phase
was extracted with CH2Cl2 (3 × 5 mL). The combined organic
layers were washed with brine (10 mL), dried (Na2SO4), filtered,
and concentrated. The residue was purified on silica gel (2% ethyl
acetate-hexanes) to give the following fractions. 50a (38 mg, 30%)
as a clear pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 9.66 (s,
1 H), 3.62-3.61 (m, 1 H), 3.16 (s, 3 H), 2.24-2.18 (m, 1 H), 1.97-
1.91 (m, 2 H), 1.78-1.68 (m, 4 H), 1.63-1.48 (m, 8 H); 13C NMR
(125 MHz, CDCl3) δ 205.2, 83.3, 57.9, 56.1, 55.0, 33.6, 33.2, 30.3,
25.6, 25.1, 22.6, 17.9; IR(neat) 1722 cm-1; HRMS (CI) m/z
165.1273 (M-OCH3, 165.1279 calcd for C12H20O2-OCH3). 50b
(50 mg, 39%) as a clear pale yellow oil: 1H NMR (500 MHz,
CDCl3) δ 9.48 (s, 1 H), 3.47-3.45 (m, 1 H), 3.23 (s, 3 H), 2.21-
2.19 (m, 1 H), 2.05-1.95 (m, 1 H), 1.94-1.93 (m, 1 H), 1.83-
1.76 (m, 1 H), 1.68-1.49 (m, 7 H), 1.48-1.27 (m, 3 H), 1.25-
1.06 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 204.9, 84.8, 60.2,
57.1, 50.6, 31.6, 31.0, 28.8, 27.0, 25.9, 25.6, 23.5; IR(neat) 1699
cm-1; HRMS (CI) m/z 196.1470 (M+, 196.1463 calcd for C12H20O2).
through-space electrostatic interactions between the R-alkoxy-
carbenium ion and an axially positioned oxygen substituent are
believed to play a significant role in organizing the transition
structure of the Prins cyclization (e.g., E f F, Scheme 12).
Experimental Section28
General Procedure for Enol Triflate Formation, Suzuki
Coupling, and LiAlH4 Reduction. Preparation of (Z)-[2-(5,5-
Dimethoxypentylidene)cyclohexanol] (17). A pentane solution of
t-BuLi (4.8 mL, 8.7 mmol, 1.8 M) was added in a rapid dropwise
manner to a solution of 2-(hydroxymethylene)cyclohexanone 829
(1.0 g, 7.9 mmol) in hexanes (70 mL) at -78 °C.10 The reaction
was maintained at -78 °C for 10 min, and freshly prepared
trifluoromethanesulfonic anhydride (1.5 mL, 8.7 mmol) was
added.30 After being stirred for 10 min, the reaction mixture was
partitioned between Et2O (50 mL) and a mixture of saturated
aqueous NaHCO3 (125 mL) and brine (125 mL). The organic layer
was separated, and the aqueous layer was extracted with Et2O (2
× 50 mL). The combined organic layers were washed with brine
(100 mL), dried (MgSO4), filtered, and concentrated in the presence
of 2,4,6-collidine (0.5 mL). Diagnostic characterization data: LRMS
(ESI) m/z 281 (M + Na, 281 calcd for C8H9F3O4S). The crude
triflate 11 was used immediately without further purification.
A solution of 9-borabicyclo[3.3.1]nonane (9-BBN, 13 mL, 6.5
mmol, 0.5 M in THF) was added to a solution of 4,4-dimethoxybut-
1-ene31 (0.9 g, 7.5 mmol) and THF (10 mL) at 0 °C. After 6 h,
aqueous NaOH (2.3 mL, 7.0 mmol, 3.0 M) was added, and the
mixture was stirred vigorously for 15 min. The crude organoborane
23 was cannulated into a solution of crude triflate 11 (1.3 g, 5.0
mmol), 2,4,6-collidine (0.3 mL, 2.5 mmol), PdCl2(dppf)‚CH2Cl2
(0.4 g, 0.5 mmol), and degassed THF (18 mL). After being stirred
for 3 h at room temperature, the reaction mixture was partitioned
between Et2O (50 mL) and H2O (50 mL), and the layers were
separated. The aqueous layer was extracted with Et2O (2 × 15 mL),
and the combined organic layers were washed sequentially with
saturated aqueous CuSO4 (2 × 50 mL), saturated aqueous NaHCO3
(25 mL), and brine (25 mL). The organic layer was dried (MgSO4),
filtered, and concentrated. The residue was absorbed onto silica
gel and purified by flash column chromatography on silica gel (10%
ethyl acetate-hexanes) to yield 1.2 g (65% from 8) of enone 14 as
a pale yellow oil. Diagnostic characterization data: 1H NMR (500
MHz, CDCl3) δ 5.55 (ddd, J ) 9.0, 7.5, 1.5 Hz, 1 H), 4.34 (t, J )
5.7 Hz, 1H), 3.29 (s, 6H); IR (neat) 1687 cm-1
.
A 1.1 g portion of sample 14 (4.8 mmol) was immediately
dissolved in THF (25 mL) and cooled to 0 °C. Lithium aluminum
hydride (2.4 mL, 2.4 mmol, 1.0 M in THF) was added dropwise,
and the stirred reaction mixture was maintained for 1 h at 0 °C.
The reaction then was quenched by the dropwise addition of
saturated aqueous sodium/potassium tartrate (20 mL). The mixture
was partitioned between Et2O (50 mL) and H2O (25 mL), and the
organic layer was separated. The aqueous layer was extracted with
Et2O (2 × 25 mL), and the combined organic layers were washed
with brine (40 mL), dried (MgSO4), and concentrated. This residue
was absorbed onto silica gel and purified by flash column
chromatography on silica gel (30% ethyl acetate-hexanes) to yield
0.70 g of 17 (64%) as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 5.17 (ddd, J ) 9.2, 7.5, 0.7 Hz, 1 H), 4.69 (bs, 1 H), 4.36 (t, J
) 5.7 Hz, 1 H), 3.30 (s, 6 H), 2.42-2.39 (m, 1 H), 2.10-2.08 (m,
2 H), 1.98-1.91 (m, 2 H), 1.79-1.74 (m, 2 H), 1.61-1.57 (m, 4
Acknowledgment. This research was supported by the NIH
Neurological Disorders & Stroke Institute (NS-12389); fellow-
ship support for E.J.V. from Amgen is gratefully acknowledged.
We thank Dr. Joe Ziller for X-ray analyses. NMR and mass
spectra were obtained at UC Irvine using instrumentation
acquired with the assistance of NSF and NIH Shared Instru-
mentation programs.
Supporting Information Available: Experimental procedures
and tabulated characterization data for new compounds not reported
1
in the Experimental Section, copies of H and 13C NMR spectra
for all new compounds, and X-ray crystallographic files (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
(28) General experimental details have been described: MacMillan, D.
W. C.; Overman, L. E.; Pennington, L. D. J. Am. Chem. Soc. 2001, 123,
9033-9044.
(29) Donohoe, T. J.; Raoof, A.; Linney, J. D.; Helliwell, M. Org. Lett.
2001, 3, 861-864.
JO0522862
(30) Triflic anhydride (Tf2O) was prepared according to a known
procedure. Stang, P. J.; Dueber, T. E. Org. Synth. 1974, 54, 79-84.
(31) Chiang, Y.; Eliason, R.; Guo, G. H.; Kresge, J. A. Can. J. Chem.
1994, 72, 1632-1636.
(32) Stannic chloride (SnCl4) was distilled twice from phosphorus
pentoxide (P2O5) at atmospheric pressure under an N2 atmosphere and stored
in a sealed tube.
J. Org. Chem, Vol. 71, No. 4, 2006 1587