Studies in stereoselective [2+2]-cycloadditions with dichloroketene

Article abstract of DOI:10.1016/j.tet.2006.02.014

During the investigation of the reaction of dichloroketene with cyclic enoxy-lactones and acyclic enoxy-ester substrates it was found that only the acylic variants effectively participated in the [2+2]-cycloaddition. Although a complete understanding of the reasons for this are lacking, molecular mechanics calculations do suggest that an out of plane twist of the cabonyl group in the acyclic compounds may be partially responsible. After screening a variety of chiral auxiliaries it was found that useful levels of diastereoselectivity (2.6-10.8:1) could be obtained in this cycloaddition reaction when (R)-2,2-diphenylcyclopentanol was used as the chiral auxiliary.

Full text of DOI:10.1016/j.tet.2006.02.014

Tetrahedron 62 (2006) 4153–4161
Studies in stereoselective [2D2]-cycloadditions
with dichloroketene
a
a
b
David I. MaGee,a, Tammy C. Mallais, Peter D. M. Mayo and George M. Strunz
*
aDepartment of Chemistry, University of New Brunswick, PO Box 45222, Fredericton, NB, Canada E3B 6E2
bCanadian Forestry Service-Atlantic Forestry Centre, Natural Resources Canada, PO Box 4000, Fredericton, NB, Canada E3B 5P7
Received 27 October 2005; revised 1 February 2006; accepted 2 February 2006
Available online 3 March 2006
Abstract—During the investigation of the reaction of dichloroketene with cyclic enoxy-lactones and acyclic enoxy-ester substrates it was
found that only the acylic variants effectively participated in the [2C2]-cycloaddition. Although a complete understanding of the reasons for
this are lacking, molecular mechanics calculations do suggest that an out of plane twist of the cabonyl group in the acyclic compounds may be
partially responsible. After screening a variety of chiral auxiliaries it was found that useful levels of diastereoselectivity (2.6–10.8:1) could be
obtained in this cycloaddition reaction when (R)-2,2-diphenylcyclopentanol was used as the chiral auxiliary.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
enol ether as one of the key steps. The new strategy provided
a quick and efficient route to the carbon framework of this
group of natural products, and importantly, in contrast to the
original ring contraction approach, opened the way to an
asymmetric synthesis. In this context, it should be noted that
in a quantitative bioassay, the racemic product was only half
as active as the natural material, suggesting that the
dextrorotatory enantiomer alone was endowed with the
bioactivity.4
(C)-Cryptosporiopsin 1, a chlorine containing fungal
metabolite was isolated in 1969 from Sporormia affinis,
Cryptosporiopsis sp. and Periconia macrospinosa.
Bio-assay1–3 of this natural product against a variety of
wood-rotting and other filamentous fungi2 demonstrated
that (C)-cryptosporiopsin was comparable to nystatin in its
antibiotic activity. These results strongly suggested that
cryptosporiopsin could be used to control microorganisms
associated with tree diseases and wood decay.2
Upon examination of the Kabanyane route, it is apparent
that the crucial stereochemistry is introduced at the [2C2]-
cycloaddition stage (Fig. 1). In considering methods to
achieve an asymmetric [2C2]-cycloaddition, two options
presented themselves; the chirality could be introduced via a
substrate-based approach, that is, an optically pure chiral
auxiliary covalently bonded to the ketene or the olefin, or,
alternatively, the chirality could be derived from an additive
such as a chiral Lewis acid. The literature contains examples
of each of these strategies. 7–10 Excellent enantioselectivity
was achieved in some of the methods described, however,
none of the substrate types employed seemed to be directly
applicable per se, to the synthesis of our target chlorine
The first total synthesis of racemic cryptosporiopsin was
reported by Strunz and Court in 1973 by a formally
biomimetic route.4 Although the synthesis had the merit of
being very concise, the key ring contraction step was a
capricious and low yielding process. An improved synthesis
was reported by Henderson and Hill a decade later,
however, it was rather lengthy.5
As a result of the difficulties in the original syntheses,
Kabanyane and co-workers6 recently revisited this natural
product, and in 2000, accomplished a new concise synthesis
of related chlorine containing fungal metabolites. This
synthesis consisted of a total of eight steps and involved a
[2C2]-cycloaddition between dichloroketene and a silyl
Keywords: [2C2]-Cycloaddition; Diastereoselective; Chiral auxiliaries;
Dioxolanones.
*
Corresponding author. Tel.: C1 506 453 4870; fax: C1 506 453 4981;
e-mail: dmagee@unb.ca
Figure 1. Attempted Kabanyane route to the synthesis of cryptosporiopsin.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.014

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D. I. MaGee et al. / Tetrahedron 62 (2006) 4153–4161
containing metabolites since the substrates studied were
either of limited scope or under functionalized.
With five different olefin substrates made, each was
subjected to standard cycloaddition conditions (Cl3CCOCl,
Zn, Et2O, rt)15 (Scheme 2). The results are summarized in
Table 1. The cyclobutanone obtained from cycloaddition
with the dioxolanone olefin 16, derived from lactic acid 6,
was a 2:1 diastereomeric mixture, as clearly evidenced by
1H NMR. Thus, for example, the protons on the
cyclobutanone gave rise to an AB quartet with the signals
for the major diastereomer at d 3.82 and 3.64 and those for
the minor one at d 2.95 and 2.75. Given the low
stereoselectivity one comes to the disappointing conclusion
that the t-butyl group is not providing facial discrimination
to the same extent as in other cycloaddition chemistry. This
was very surprising.
To produce an optically enriched cyclobutanone like 4
(Fig. 1), it was clear that an optically pure equivalent of the
enol-ether ester 2 (a tri-substituted olefin) must be employed
as the precursor. To achieve this end, we realized that some
type of rigid cyclic substrate such as a dioxolanone or
lactone might be exploited with advantage, or drawing upon
Greene11 and Kabanyane’s6 work, presumably a suitable
acyclic chiral analogue of 2 could be developed (Fig. 2).
The following work describes our efforts in trying to design
an appropriate substrate to achieve this goal.
Figure 2. Potential substrates for asymmetric [2C2]-cycloaddition.
2. Results and discussion
Scheme 2. (a) Cl3CCOCl, Zn, Et2O, 0 8C–rt.
It is well established that asymmetric induction tends to be
much higher when the ‘chiral inducer’ is held in a fixed
position. With this in mind, it appeared that optimum
selectivity could be obtained by using a chiral dioxolanone
substrate possessing the appropriate latent functionality,
such as that depicted in Figure 2. Compounds of this type
are well known in the literature and have served as excellent
substrates in [4C2]-cycloadditions.12 Examples of their use
in [2C2]-cycloaddition chemistry, however, are unknown
so it was hoped that dichloroketene would be sufficiently
reactive to add to the dioxolanone olefin with similar
excellent stereoselectivity.
Table 1. Cycloaddition results of the dioxolanone olefins
R0
R00
Olefin
dioxolanone
dr
Yield (%)
16
17
18
19
20
H
H
Me
H
H
H
2:1
—
—
1.4:1
O95:1
33
0
0
13
7
Me
Me
iPr
nPr
The olefin 17 derived from 2-hydroxy-3-methylbutanoic
acid did not undergo cycloaddition; only starting dioxola-
none olefin was recovered. This was perhaps not astonishing
since 17 is a tetra-substituted alkene and therefore much less
reactive towards cycloaddition. Like 17, the tri-substituted
alkene 18 also failed to react. On the other hand, tri-
substituted dioxolanone olefins 19 and 20 reacted with
dichloroketene to give cycloadducts in very modest yields,
ranging from poor (1.4:1) to excellent (O95:5), diastereos-
electivity. The reason for the differences in stereoselectivity
with these tri-substituted alkenes was not obvious, however,
the alkyl chain may confer a preference for a particular
rotamer that gives rise to higher levels of selectivity.
To initiate this study, a variety of chiral a-hydroxy acids,
6–10, were condensed with pivaldehyde13 under acidic
catalysis to give a mixture of cis and trans-dioxolanones
11–15 (c and t) (4–8:1, 66–74% yields) with the cis-isomer
always predominating (Scheme 1). The two isomers in each
case were easily separated by silica gel column chromato-
graphy. The stereochemistry of the major diastereomer was
assigned as the cis-dioxolanone by NOE difference
experiments and by comparing with literature results.13
The cis-dioxolanones were readily transformed14 into the
requisite olefins 16–20 by bromination with N-bromosucci-
nimide (NBS, 97–99% yields) followed by dehydrobromi-
nation with DBU (30–65% yields).
Although the dioxolanone olefin cycloaddition approach
was conceptually attractive, all cycloadditions were plagued
with extremely low yields (0–33%). Attempts to eliminate
side reactions16 in the cycloaddition by using solvents such
as dichloromethane or hexane proved fruitless. Addition-
ally, efforts to increase the yield of the cycloadduct by using
an excess of trichloroacetyl chloride and zinc, added all at
once or in aliquots over a period of time, or using ultrasound
and TMSCl17 also failed.
To explain the reluctance of these cyclic olefins to participate
in [2C2]-cycloadditions it was considered that geometric
constraints in the rigid ring system might prevent appropriate
alignment of the lone pair on the ether oxygen for activation of
Scheme 1. (a) (CH3)3CCHO, H2SO4, pTSA, pentane, D; (b) NBS, CCl4, D;
(c) DBU, C6H6, rt.

D. I. MaGee et al. / Tetrahedron 62 (2006) 4153–4161
4155
the olefin. To gain insight, energy minimization of 20 was
done at the MMFF94 (molecular mechanics force field 1994)
level. The results indicate that the five-membered ring was
essentially planar and co-planar with the olefin (a 28 deviation
from co-planarity was not considered significant). Accord-
ingly, adequate donation indeed appeared to be possible.
dioxolanones or lactones. That said, the effect of the silyl
group could not be completely dismissed. These results
seemed to indicate that we could not take advantage of a
rigid cyclic structure to achieve enhanced chiral induction
and were thus limited to the use of chiral modifications of the
acyclic Kabanyane alkene.
In view of the demonstrated efficiency of dichloroketene
cycloaddition to 2-silyloxy-2-enoate esters6 and because of
potential difficulties associated with introduction of chir-
ality into the enol ether moiety in these compounds, we were
encouraged to focus on installation of chirality in the ester
group. In order to furnish the appropriate compounds the
respective a-keto esters had to be first generated.
Although it was initially believed that sterics might not
affect reactivity in a major way, it appears that in fact it
does. While the unsubstituted dioxolanone 16 gave the
highest yield of cycloadduct, tri-substituted olefins 19 and
20 gave diminished product whereas tetra-substituted olefin
17 did not react at all. Coupled with this steric effect was the
fact that all alkene substrates studied here contained an alkyl
enol-ether, rather than a trimethylsilyloxy-derivative as
used by Kabanyane.6 This change, although minor, might
have contributed to the reduced reactivity of these olefins
since the ether oxygen would be expected to have less
electron density, and therefore be less reactive. To
investigate these subtle electronic effects, an alternative
cyclic substrate 24 was considered (Scheme 3). This
substrate separated the two electronic factors that were
potentially influencing the cycloaddition, namely the
electron withdrawing nature of the carbonyl and the electron
donating nature of the acyclic enol ether.
There were numerous literature reports that described the
synthesis of a-keto esters,27–31 many of which we initially
used to generate the various chiral compounds, 44–51,
shown in Scheme 4. However, we eventually found that
these compounds could be most conveniently produced via
a Grignard addition to oxalates 36–43.32 The oxalates
themselves were generated in a straightforward manner
from oxalyl chloride 35 and enantioenriched alcohols
27–34. Once synthesized the a-keto esters were then
converted to their respective silyl enol ethers following
Kabanyane’s protocol6 (Scheme 4). Notably in each case
only the Z-alkene was formed, this was important since it
helped simplify analysis of the cycloaddition products.
Scheme 3. (a) Concd H2SO4, 0 8C–rt; (b) P2O5, dimethoxymethane, rt;
(c) AgO, CH3I, CH3CN, D.
Although several asymmetric routes to this substrate can be
envisaged, including oxidation of the Mori lactone18 or
degradation of D-ribose19 or D-mannose,20 it was considered
prudent to test the reactivity of this type of compound first
using racemic models. Accordingly, pyruvic acid was
condensed with propanal under acidic conditions21 to give
lactone 23 in 17% yield (Scheme 3). Attempts to protect the
hydroxyl group under basic conditions resulted in the
complete decomposition of starting material. Fortunately
the MOM-ether, 24, and methyl-ether, 25, could be formed
under acid conditions in 57 and 38% yields, respect-
ively.22,23 Unfortunately, all endeavors aimed at producing
silyl ether 26 under acidic24 or neutral25,26 conditions failed.
Subjection of lactones 24 and 25 to the standard
cycloaddition conditions once again proved unsuccessful
and only the starting material was recovered.
Scheme 4. (a)Pyridine,CH2Cl2, rt, 24 h;(b)1.5 equivnBuMgCl, THF,40 8C,
2 h; (c) TBSCl, DBU, C6H6, D, 2 h; (d) Cl3CCOCl, Zn, Et2O, 0 8C–rt.
With the chiral ester silyl enol ethers synthesized, their
utility in the asymmetric [2C2]-cycloaddition reaction was
probed. The TBS-enol ethers (44–51) were allowed to react,
with dichloroketene to give cycloadducts in yields ranging
from 31 to 88% (Table 2). The dramatic rise in yield
realized with these substrates leant credence to our earlier
observations and predictions concerning the influence of
electronic effects. Examination of Table 2 shows that simple
terpene based auxiliaries gave moderate levels of selecti-
vity, 1-phenylethanol and ‘synthetic’ auxiliary derived
Table 2. Cycloaddition results of the enoxy-ester olefins
Given the reluctance of both classes of cyclic compounds
investigated above to undergo cycloaddition, it appeared that
the electron withdrawing ability of the carbonyl group was
overriding any electron donating effect of the ether oxygen.
Simple molecular mechanics (MMFF94) calculations on the
Kabanyane alkene, methyl 2-trimethylsilyloxyhex-2-enoate,
showed that the carbonyl carbon was twisted slightly out of
plane (ca. 58), and although this was only a minimal amount
of twisting it would help render the alkene less electron
deficient. This twisting effect is not possible in the
Entry
R*
dr
Yield
(%)
1
2
3
4
5
6
7
8
Menthyl
Fenchyl
(R)-2-Methoxy-1-phenylethyl
(S)-1-Phenylethyl
1.7:1
2.2:1
1.3:1
1.2:1
88
77
35
31
83
79
31
65
(S)-1-(2,4,6-Triisopropylphenyl)ethyl 4:1
(R)-2,2-Diphenylcyclopentyl
3-Phenyl-isoborneol
(R)-trans 2-Phenyl-1-cyclohexyl
7.5:1
2.4:1
2.8:1

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D. I. MaGee et al. / Tetrahedron 62 (2006) 4153–4161
Table 3. Cycloaddition results of different alkyl substituted dioxolanone
olefins
substrates ranged from poor (entries 3 and 4) to moderate
(entries 7 and 8) to acceptable levels of selectivities (entries
5 and 6).
R0
R00
Olefin
dioxolanone
dr
Yield (%)
(product)
It was observed that the trans 2-phenyl-1-cyclohexanol
derivative, entry 8, was consumed immediately after
complete addition of trichloroacetyl chloride. This was not
observed in any of the other cycloadditions: in fact, all other
cycloadditions took 18–24 h to go to completion. Since this
cycloaddition occurred at a significantly greater rate, a
temperature study was done to see if the stereoselectivity
could be improved. It was found that at 0 8C a 3.5:1 dr was
obtained while at K30 8C no observable reaction was
detected, even after 24 h.
61
62
63
64
65
66
67
H
H
Me
H
H
H
3.5:1
3.8:1
—
2.6:1
—
80 (68)
68 (69)
No reaction
44 (72)
No reaction
94 (70)
32 (71)
Me
Me
Vinyl
Ph
iBu
tBu
H
H
10.8:1
8.2:1
increases in size, at least to a point. This suggests that the
observed good levels of diasteroselectivities in this reaction
are the result of a balancing of nonbonding steric
interactions between the chiral auxiliary, the silyl ether
and the alkyl group attached to the alkene.
It was gratifying to find that Denmark’s diphenylcyclopen-
tanol auxiliary,33 present in entry 6, gave acceptable levels
of asymmetric induction. Since the cycloadduct was
crystalline, simple recrystallization from hexane increased
the diasteromeric ratio to 11.5:1. Although not pursued,
presumably further recrystallizations would produce a
diastereomerically pure cycloadduct.
Molecular modeling of the (R)-2,2-diphenylcyclopentyl
chiral enol ether† using the MMFF94 force field was
performed in order to ascertain some type of transition state
model. These calculations allowed prediction that Si-face
addition of dichloroketene should be more favorable than
the Re-face addition when using (R)-2,2-diphenylcyclopen-
tanol as the chiral auxiliary (Fig. 3). Although there were
many low energy conformations (approximately 20 within
2.5 kcal/mol) 15 of them adopted the s-trans conformation
with all having the Si-face more accessible for cyclo-
addition. Of the remaining five low energy conformations
they all had the s-cis arrangement, again with the Si-face
most accessible.
Since it was not evident how important a role the silyloxy
function played in determining the course of the cyclo-
addition, either in rate or stereoselectivity, a quick
investigation into the use of other silyl groups was pursued.
Upon changing to the less robust trimethylsilyl ether (TMS)
no change in reaction rate or stereoselectivity was observed.
However, when the t-butyldiphenylsilyl ether (TBDPS) was
used only starting silyl enol ether was recovered. This was
surprising but presumably meant that both faces of the
alkene were now effectively blocked from reaction.
Given the success of the diphenylcyclopentyl auxiliary it
remained to be seen how limited the scope of this
cycloaddition was. To probe this a variety of substrates
were generated that explored both the electronic and steric
limitations of this reaction (Scheme 5). When compounds
61–67 were subjected to the standard cycloaddition several
trends became abundantly clear (Table 3). First, successful
cycloaddition is only possible if the olefin is not overly
hindered. For example, when the olefin is tetrasubstituted or
R is very bulky (tBu) then either no reaction is observed or
the rate is greatly diminished. Second, if alternative alkenes
are present in the molecule then they react in preference to
the enoxy-alkene. Third, additional conjugation of the
enoate with a phenyl group completely inactivates the
reaction. Finally, diastereomeric ratios improve as R
Figure 3. Molecular mechanics (MMFF94) calculated structures of
S-diphenylcyclopentyl TMS-enol ester.
Of particular interest in these calculations was that a
dihedral angle of 1398 between the carbonyl and the
carbon–carbon double bond (O]C–C]C) was observed.
This twist, reducing the electron-attracting effect of the
ester carbonyl, once again helps to explain the enhanced
reactivity of this alkene towards [2C2]-cycloaddition.
Although these calculations were not performed on the
other enoxy-ester models we believe that the same
subtleties exist, but to varying degrees, and thus account
for the reactivities and stereoselectivities that were
observed.
Lastly, the absolute stereochemistry was shown to
coincide with our transition state model by conversion34
Scheme 5. (a) 1.5 equiv RMgCl, THF, 40 8C, 2 h; (b) TBSCl, DBU, C6H6,
D, 2 h; (d) Cl3CCOCl, Zn, Et2O, 0 8C–rt.
† A modified version of enoxy-ester 62 was used in order to simplify the
calculations; the TBS-group was replaced with a TMS-group.

D. I. MaGee et al. / Tetrahedron 62 (2006) 4153–4161
4157
of cycloadduct 52 into (K)-cryptosporiopsin, a known
natural product.35 Since the (K)-enantiomer was gener-
ated this indeed meant that dichloroketene added to the
Si-face of 49, consistent with the molecular mechanics
calculations.
mixture was heated at reflux for 3 h, cooled and then
filtered. The solvent was removed in vacuo to provide the
bromo-dioxolanones as pale green oils of sufficient purity to
be used directly in the next step.
To a solution of brominated dioxolanone (5 mmol) in
benzene (20 mL) was added DBU (0.85 mL, 5.75 mmol)
dropwise over 5 min at rt. After complete addition, the
mixture was stirred for 20 min then filtered and the solvent
was removed. The crude product was purified by SiO2
chromatography using 20:1 hexane/ethyl acetate to furnish
the olefins as pale yellow oils.
3. Conclusion
During the investigation of the reaction of dichloroketene
with cyclic enoxy-lactones and acyclic enoxy-ester sub-
strates it was found that only the acylic variants effectively
participated in the [2C2]-cycloaddition. Although complete
understanding of this discrepancy is lacking at this time,
molecular mechanics calculations do suggest that an out of
plane twist of the cabonyl group (up to 418 see Fig. 3) in the
acyclic compounds may be partially responsible. An
additional factor may be the nucleophilicty of the enoxy
oxygen since only the silyloxy derivatives gave efficient
reaction. Acyclic silyl enol ether substrates bearing a chiral
auxiliary on the ester proved to be viable candidates for the
production of optically enriched cycloadducts with diaster-
eomeric ratios ranging from 1.5–10.8:1. Effort to further
improve the diastereoselection is currently in progress.
4.2.1. (S)-2-tert-Butyl-5-methylene-[1,3]dioxolan-4-one,
16. 39% overall yield from (S)-lactic acid. 1H NMR
(CDCl3): d 1.00 (s, 9H), 4.86 (d, JZ2.6 Hz, 1H), 5.13 (d,
JZ2.6 Hz, 1H), 5.44 (s, 1H). 13C NMR (CDCl3): d 22.8,
35.9, 90.8, 144.2, 162.5. IR (NaCl plates, cmK1): 3020,
2972, 2940, 2883, 1796, 1670, 1475, 1311, 1133, 992. MS:
mC/zZ156.0787 (calculated 156.0787). [a]2D2 K1.9 (c 1.1,
CH2Cl2).
4.2.2. (Z)-(S)-2-tert-Butyl-5-ethylidene-[1,3]dioxolan-4-
one, 17. 22% yield from (S)-2-hydroxybutanoic acid. H
1
NMR (CDCl3): d 0.97 (s, 9H), 1.77 (d, JZ7.8 Hz, 3H), 5.42
(s, 1H), 5.60 (q, JZ7.6 Hz, 1H). 13C NMR (CDCl3): d 10.7,
22.8, 35.8, 105.0, 109.5, 139.2, 163.0. IR(NaCl plates, cmK1):
2970, 2924, 2876, 1798, 1702, 1478, 1342, 1240, 1134,
1086, 968. MS: mC/zZ170.0941 (calculatedZ170.0943).
[a]2D2 C33.7 (c 1.55, CH2Cl2).
4. Experimental
4.1. General experimental procedures
All reactions except those stated otherwise were performed
under inert atmospheres of either argon or nitrogen in flame
dried glassware (Pyrex). All solvents were dried according
to established procedures prior to use.36 Standard techniques
were used in handling air sensitive reagents. All commer-
cially available reagents and solvents were used without
further purification. All oxalates required for the preparation
of 2-enoxy-esters 44–51 and 61–67 were synthesized
according to literature,32 Silicycle Ultra Pure Silica Gel
was used for all flash chromatography. All 1H and 13C NMR
spectra were performed on a Varian UNITY 400 MHz or
Varian (INOVA 300 MHz) spectrometer. Optical rotation
measurements were taken on a Perkin-Elmer 241 Polari-
meter using the Na lamp. All IR spectra were recorded on a
Bruker IFS 25 instrument and all mass spectra were run on a
Kratos MS50 instrument and were done under electron
impact conditions at 80 eV unless stated otherwise.
4.2.3. (Z)-(S)-2-tert-Butyl-5-(2-methylpropylidene)-1,3-
dioxolan-4-one 18. 44% yield from (S)-2-hydroxy-4-
methylpentanoic acid. H NMR (CDCl3): d 0.92 (s, 9H)
1
1.79 (s, 3H), 2.04 (s, 3H), 5.29 (s, 1H). 13C NMR (CDCl3) d
16.7, 19.2, 23.0, 35.8, 108.3, 121.5, 133.4, 162.9. IR (NaCl
plates, cmK1): 2958, 2912, 2876, 1774, 1678, 1490, 1276,
1216, 1158, 1074, 980, 730. MS: mC/zZ184.1094
(calculated 184.1099). [a]2D5 K16.6 (c 2.7, CH2Cl2).
4.2.4. (Z)-(S)-2-tert-Butyl-5-(3-methylbutylidene)-1,3-
dioxolan-4-one, 19. 21% yield from (S)-2-hydroxy-5-
methylhexanoic acid. H NMR (CDCl3): d 0.99 (s, 9H)
1
1.10 (d, JZ6.1 Hz, 6H), 2.72 (d of heptet, JZ4.4, 6.2 Hz,
1H), 5.42 (s, 1H), 5.49 (d, JZ4.5 Hz, 1H). 13C NMR
(CDCl3): d 22.1, 23.0, 25.8, 36.2, 109.7, 116.9, 137.0, 163.7.
IR (NaCl plates, cmK1): 2958, 2918, 2854, 1794, 1690,
1478, 1362, 1302, 1216, 1150, 1076, 988, 732. MS: mC/zZ
198.1254 (calculatedZ198.1256). [a]2D5 K34.0 (c 1.72,
CH2Cl2).
4.2. General preparation of olefin dioxolanone, 16–20
A mixture of a-hydroxy acid (10 mmol), pivaldehyde
(2.2 mL, 20 mmol), pTSA (50 mg), and concd H2SO4
(2 drops) in pentane (70 mL) was heated to reflux with
azeotropic removal of the water using a Dean Stark
apparatus. After complete reaction, the mixture was diluted
with ether and washed with H2O (1!), brine (1!), dried
over MgSO4 and the solvent evaporated. Purification by
SiO2 chromatography using hexane/ethyl acetate as eluant
furnished the cis-dioxolanones as colorless oils.
4.2.5. (Z)-(S)-2-tert-Butyl-5-butylidene-[1,3]dioxolan-4-
one 20. 31% yield from (S)-2-hydroxyhexanoic acid. H
1
NMR (CDCl3): d 0.95 (t, JZ7.3 Hz, 3H), 0.98 (s, 9H), 1.49
(heptet, JZ7.4 Hz, 2H), 2.19 (q, JZ7.1 Hz, 2H), 5.42 (s,
1H) 5.59 (t, JZ7.7 Hz, 1H). 13C NMR (CDCl3): d 13.9,
22.0, 23.0, 27.5, 36.1, 109.7, 110.2, 138.7, 163.4. IR (NaCl
plates, cmK1): 2978, 2918, 2854, 1794, 1690, 1478, 1406,
1368, 1310, 1208, 1090, 974, 740. MS: mC/zZ198.1260
(calculatedZ198.1256). [a]2D5 K28.4 (c 1.02, CH2Cl2).
N-Bromosuccinimide (1.33 g, 7.4 mmol) in carbon tetra-
chloride (20 mL) was combined with cis-dioxolanone
(5 mmol) in carbon tetrachloride (5 mL). The reaction
4.2.6. Preparation of 5-ethyl-3-methoxymethoxy-5H-
furan-2 one, 24. In a flask cooled in an ice bath was put

4158
D. I. MaGee et al. / Tetrahedron 62 (2006) 4153–4161
concd H2SO4 (30 mL) followed by a mixture of pyruvic acid
(7.85 mL, 0.114 mol) and propanal (8.19 mL, 0.11 mol)
dropwise over 30 min. The temperature of the reaction
mixture was maintained below 5 8C. After complete
addition the dark colored mixture was poured into cold
H2O (60 mL) and extracted with ether (3!). The combined
organic extracts were washed with H2O, 5% HCl, brine,
dried over MgSO4 and solvent evaporated. The residue was
purified by SiO2 chromatography (3:1 hexane/ethyl acetate)
to give lactone 23 (2.54 g, 17%) as a brown oil.
140.7, 165.1. IR (NaCl plates, cmK1): 2958, 2874, 1720,
1640, 1464, 1252, 1150, 842. MS: [mC/zKC6H15Si]Z
265.1804 (calculatedZ265.1804). [a]2D5 C14.9 (c 2.37,
EtOH).
4.3.3. (Z)-(R)-2-Methoxy-1-phenylethyl 2-tert-butyldi-
methylsilyloxyhex-2-enoate, 46. Colorless oil, 67% yield.
1H NMR (CDCl3): d 0.09 (s, 3H), 0.14 (s, 3H), 0.93 (t, JZ
3.6 Hz, 3H), 0.94 (s, 9H), 1.43 (q, JZ7.5 Hz, 2H), 2.17 (q,
JZ7.3 Hz, 2H), 3.36 (s, 3H), 3.59 (d of d, JZ4.1, 10.9 Hz,
1H), 3.75 (d of d, JZ7.9, 10.8 Hz, 1H), 6.01 (d of d, JZ3.9,
7.9 Hz, 1H), 6.11 (t, JZ7.5 Hz, 1H), 7.30 (m, 5H). 13C
NMR (CDCl3): d K4.4, 14.0, 18.5, 22.0, 25.8, 27.9, 59.0,
74.7, 75.3, 123.5, 126.7, 128.2, 137.5, 140.6, 164.1. IR
(NaCl plates, cmK1): 2936, 1728, 1648, 1456, 1150, 834,
702. MS: [mC/zKC6H15Si]Z378.2226 (calculatedZ
378.2226). [a]2D5 K28.4 (c 1.05, EtOH).
To a solution of enol lactone 23 (500 mg) and CH2Cl2
(20 mL) was added dimethoxymethane (23 mL, 264 mmol)
and P2O5 (1.95 g, 17.0 mmol). The reaction mixture was
stirred overnight, diluted with ether and then poured into a
cold Na2CO3 solution. The organic layer was then washed
with brine, dried over Na2SO4 and the solvent evaporated.
The oily residue was purified by SiO2 chromatography (3:1
hexane/ethyl acetate) to give MOM-lactone 24 (510 mg,
76%) as a tan colored oil. 1H NMR (CDCl3): d 1.00 (t, JZ
7.5 Hz, 3H), 1.76 (dq, JZ7.2, 11.0 Hz, 2H), 3.50 (s, 3H),
4.90 (dt, JZ1.9, 6.3 Hz, 1H), 5.11 (s, 2H) 6.38 (d, JZ
1.9 Hz, 1H). 13C NMR (CDC13): d 8.8, 27.2, 56.6, 80.0,
96.0, 121.0, 143.7, 168.2. IR (NaCl plates, cmK1): 2958,
2901, 2832, 1772, 1654, 1456, 1236, 1156, 1128, 1084, 958.
MS: mC/zZ172.0739 (calculatedZ172.0736).
4.3.4. (Z)-(R)-1-Phenylethyl2-tert-butylydimethylsilyloxy-
hex-2-enoate, 47. Colorlessoil, 77% yield. 1H NMR(CDCl3):
d 0.09 (s, 3H), 0.13 (s, 3H), 0.95 (t, JZ7.5 Hz, 3H), 0.95 (s,
9H), 1.43 (sextet, JZ7.5 Hz, 2H), 1.58 (d, JZ5.0 Hz, 3H),
2.17(d of q, JZ0.9, 7.2 Hz, 2H), 5.94(q, JZ6.3 Hz, 1H), 6.08
(t, JZ7.5 Hz, 1H), 7.25–7.4 (m, 5H). 13C NMR (CDCl3): d
K3.98, K3.93, 14.3, 18.9, 22.4, 22.5, 26.2, 28.2, 73.2, 123.5,
126.5, 128.2, 128.8, 141.2, 141.9, 164.6. IR (NaCl plates,
cmK1): 2946, 2855, 1720, 1640, 1456, 1368, 1258, 1142, 834.
MS: [mC/zKC12H18]Z186.0717 (calculatedZ186.0712),
[C8H9]CZ105.0705 (calculatedZ105.0704). [a]2D5 C2.2 (c
1.08, CH2Cl2).
4.3. General preparation of TBS-enoxy esters 44–51
and 60–67
A mixture of a-keto ester32 (1.9 g, 5.5 mmol) and TBS-Cl
(1.0 g, 6.6 mmol) in THF (35 mL) was added dropwise to a
solution of DBU (1.24 mL, 8.3 mmol) in THF (5 mL). The
reaction mixture was stirred at rt for 12 h then diluted with
ether and filtered through Celitew. The filtrate was washed
with cold HCl (5%, 2!), H2O (1!), brine (1!), dried over
MgSO4 and the solvent removed in vacuo. Purification by
SiO2 chromatography provided silyl enol ethers 44–51 and
61–67.
4.3.5. (Z)-(R)-1-(2,4,6-Triisopropylphenyl)ethyl 2-tert-
butyldimethylsilyloxyhex-2-enoate, 48. Colorless waxy
solid, 72% yield. H NMR (DMSO, 80 8C): d 0.06 (s, 3H)
1
0.12 (s, 3H), 0.88 (t, JZ7.3 Hz, 3H), 0.92 (s, 9H), 1.19 (d,
JZ7.0 Hz, 12H) 1.24 (d, JZ6.8 Hz, 6H), 1.37 (h, JZ
7.5 Hz, 2H), 1.59 (d, JZ7.0 Hz, 3H), 2.13 (q, JZ7.5 Hz,
2H), 2.84 (heptet, JZ6.8 Hz, 1H), 3.52 (broad heptet, JZ
6.7 Hz, 2H) 5.96 (t, JZ7.5 Hz, 1H), 6.47 (q, JZ6.8 Hz,
1H), 7.00 (s, 2H). 13C NMR (DMSO, 80 8C): d K4.8, K4.7,
13.1, 17.7, 21.0, 21.4, 23.21, 23.24, 23.7, 24.1, 25.3, 26.8,
28.3, 32.9, 35.9, 68.2, 121.2, 121.4, 131.4, 140.3, 147.3,
163.1. IR (NaCl plates, cmK1): 2948, 2855, 1722, 1644,
1452, 1367, 1268, 1060, 834. MS: (30 eV): [mC/z]Z
473.3451 (calculatedZ473.3451). [a]2D5 C3.2 (c 1.45,
CH2Cl2).
4.3.1. (Z)-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexy 2-
tert-butyldimethylsilyloxyhex-2-enoate, 44. Colorless oil,
65% yield. 1H NMR (CDCl3): d 0.15 (s, 3H), 0.17 (s, 3H),
0.75 (d, JZ6.8 Hz, 3H), 0.89 (t, JZ6.3 Hz, 3H), 0.92 (d,
JZ7.5 Hz, 3H), 0.94 (d, JZ7.4 Hz, 3H), 0.96 (s, 9H), 1.02
(m, 2H), 1.43 (q, JZ2.7 Hz, 1H), 1.68 (m, 2H), 1.88 (m,
1H), 2.00 (m, 1H), 2.17 (m, 2H), 4.73 (t of d, JZ4.4,
10.9 Hz, 1H), 5.98 (t, JZ7.4 Hz, 1H). 13C NMR (CDCl3): d
K4.3, K4.2, 14.0, 16.4, 18.6, 20.6, 22.0, 22.1, 23.3, 25.9,
26.3, 27.8, 31.4, 34.3, 40.8, 47.1, 74.8, 122.5, 140.9, 164.5.
IR (NaCl plates, cmK1): 2936, 2854, 1712, 1648, 1464,
1150, 834. MS: [mC/zKC6H15Si]Z267.1960 (calculatedZ
267.1964). [a]2D5 K36.5 (c 2.6, EtOH).
4.3.6. (Z)-(R)-2,2-Diphenylcyclopentyl 2-tert-butyldi-
methylsilyloxyhex-2-enoate, 49. Colorless oil, 70% yield.
1H NMR (CDCl3): d 0.108 (s, 3H), 0.11 (s, 3H), 0.79 (t, JZ
7.4 Hz, 3H), 0.92 (s, 9H), 1.24 (m, 2H) 1.57 (m, 1H), 1.75
(m, 1H), 1.95 (m, 1H), 2.23 (m, 1H) 2.47 (m, 1H), 2.63 (m,
1H), 5.33 (t, JZ7.9 Hz, 3H), 6.01 (m, 1H), 7.17 (m, 10H).
13C NMR (CDCl3): d K4.4,K4.3, 13.8, 14.1, 18.5, 20.4,
21.8, 22.7, 25.8, 27.5, 30.6, 31.6, 35.5, 59.1, 80.3, 123.0,
125.8, 126.1, 127.88, 127.9, 128.4, 140.4, 145.0, 145.6,
164.4. IR (NaCl plates, cmK1) 2936, 1720, 1648, 1376,
1252, 1150, 834. MS: [mC/zKC6H15Si]Z349.1791 (calcu-
latedZ349.1804). [a]2D5 K37.0 (c 3.0, CH2Cl2).
4.3.2. (Z)-(1R)-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-yI
2-tert-butyldimethylsilyloxyhex-2-enoate, 45. Colorless
oil, 42% yield. H NMR (CDCl3): d 0.17 (s, 3H), 0.17 (s,
1
3H), 0.78 (s, 3H), 0.94 (t, JZ7.4 Hz, 3H), 0.97 (s, 9H), 1.05
(s, 2H), 1.11 (s, 2H), 1.21 (m, 2H), 1.4 (m, 3H), 1.59 (d of d,
JZ1.7, 10.3 Hz, 1H), 1.74 (m, 3H), 2.19 (q, JZ7.4 Hz, 2H),
4.44 (d, JZ1.9 Hz, 1H), 6.00 (t, JZ7.4 Hz, 1H). 13C NMR
(CDCl3): d K4.3, 13.9, 18.6, 19.4, 20.4, 22.1, 25.5, 25.9,
26.8, 27.7, 29.8, 39.8, 41.4, 48.3, 48.5, 76.3, 86.4, 122.2,
4.3.7. (Z)-(1R,2R,3S,4S)-4,7,7-Trimethyl-3-phenylbicy-
clo[2.2.1]heptan-2-yl 2-tert-butyldimethylsilyloxyhex-2-
enoate, 50. Colorless of 77% yield. 1H NMR (CDCl3):

D. I. MaGee et al. / Tetrahedron 62 (2006) 4153–4161
4159
d K0.05 (s, 3H), 0.04 (s, 3H), 0.61 (t, JZ7.4 Hz, 3H), 0.82
(s, 9H), 0.88 (m, 2H), 1.01 (s, 3H), 1.30 (s, 3H), 1.32 (s, 3H),
1.55 (m, 2H), 1.71 (m, 3H), 1.94 (m, 1H), 2.03 (d, JZ
5.1 Hz, IH), 4.09 (d, JZ8.7 Hz, 1H), 4.25 (t, JZ7.0 Hz,
1H), 5.39 (d, JZ8.7 Hz, 1H), 7.41 (m, 3H), 7.66 (m, 2H),
7.76 (d of d, JZ1.4, 8.0 Hz, 1H), 8.00 (d, JZ8.4 Hz, 1H).
13C NMR (CDCl3): d K4.8, K4.5, 13.7, 14.8, 18.4, 21.6,
21.7, 23.9, 23.93, 25.8, 26.1, 27.2, 42.6, 48.2, 49.3, 51.1,
55.4, 76.3, 80.3, 122.4, 123.3, 124.3, 125.0, 126.1, 126.6,
126.8, 128.8, 133.4, 133.5, 135.9, 139.9, 163.7. IR (NaCl
plates, cmK1): 2948, 1726, 1632, 1466, 1252, 1146, 836,
778. MS: [mC/zKC6H15Si]Z391.2274 (calculatedZ
391.2273). [a]2D5 K53.5 (c 1.05, EtOH).
20.7, 25.9, 30.8, 35.0, 59.2, 80.9, 125.7, 126.1, 126.4, 128.8,
127.9, 128.0, 128.4, 136.2, 145.10, 145.13, 165.3. IR (NaCl
plates, cmK1): 3059, 3023, 2955, 2929, 2857, 1704,
1634, 1472, 1463, 1371, 1300, 1250, 1192, 1090. MS:
[mC/zKC6H15Si]Z335.1645 (calculatedZ335.1647).
[a]2D5 K63 (c 0.40, EtOH).
4.3.12. (Z)-(R)-2,2-Diphenlycyclopentyl 2-(tert-butyldi-
methylsilyloxy)penta-2,4-dienoate, 64. Colorless oil,
16%: H NMR (CDCl3): d 0.14 (s, 3H), 0.143 (s, 3H),
1
0.94 (s, 9H), 1.56–1.82 (m, 2H), 1.92 (m, 1H), 2.26 (m, 1H),
2.48 (m, 1H), 2.67 (dt, JZ12.9, 9.3 Hz, 1H), 5.13 (m, 2H),
5.83 (d, JZ11.0 Hz, 1H), 6.03 (dd, JZ5.7, 3.1 Hz, 1H),
6.60 (ddd, JZ17.0, 11.0, 10.0 Hz, 1H), 7.09–7.34 (m, 10H).
13C NMR (CDCl3): d K4.3, K4.1, 18.6, 20.4, 25.8, 30.7,
35.5, 59.1, 80.6, 120.2, 120.6, 125.9, 126.2, 126.6, 127.9,
128.0, 128.4, 130.4, 140.3, 144.9, 145.6, 164.4. IR (NaCl
plates, cmK1): 3060, 3024, 2956, 2929, 2857, 1726, 1645,
1599, 1495, 1471, 1390, 1362, 1255, 1151. MS: [mC/zK
C6H15Si]Z333.1489 (calculatedZ333.1491). [a]2D5 K40 (c
0.70, EtOH).
4.3.8. (Z)-(1R,2S)-2-Phenylcyclohexyl 2-tert-butyldi-
methylsilyloxyhex-2-enoate, 51. Colorless oil 75% yield.
1H NMR (CDCl3): d K0.04 (s, 3H), 0.02 (s, 3H), 0.86 (t,
JZ9.8 Hz, 3H), 0.91 (s, 9H), 1.23–1.65 (m, 4H), 1.31 (q,
JZ9.8 Hz, 2H), 1.78–2.21 (m, 4H), 2.02 (dq, JZ1.1,
10.1 Hz, 2H), 2.72 (ddd, JZ5.0, 17.2, 16.4 Hz, 1H) 4.96 (dt,
JZ6.1, 14.0 Hz, 1H), 5.66 (t, JZ9.9 Hz, 1H), 7.18 (m, 5H).
13C NMR (CDCl3): d K4.4, K4.2, 10.7, 14.0, 18.7, 22.1,
24.9, 26.0, 27.7, 32.5, 34.1, 50.0, 122.7, 126.5, 127.1, 128.4,
140.7, 143.3, 164.4. IR (NaCl plates, cmK1): 2946, 1730,
1630, 1456, 1250, 1146, 832, 778. MS: (30 eV): [mC/zK
C4H9]Z345.1886 (calculatedZ345.1886). [a]2D5 K11.6 (c
3.1, CH2Cl2).
4.3.13. (Z)-(R)-2,2-Diphenlycyclopentyl 2-(tert-butyldi-
methylsilyloxy)-3-phenylacrylate, 65. Colorless oil, 44%.
1H NMR (CDCl3): d 0.12 (s, 3H), 0.13 (s, 3H), 0.91 (s, 9H),
1.66 (m, 1H), 1.77–1.98 (m, 2H), 2.30 (m, 1H), 2.51 (m,
1H), 2.72 (dt, JZ12.3, 9.1 Hz, IH), 6.05 (t, JZ2.9 Hz, 1H),
6.07 (s, 1H), 7.13–7.33 (m, 13H), 7.49 (d, JZ7.0 Hz, 2H).
13C NMR (CDCl3): d K3.9, K3.8, 18.6, 20.4, 25.8, 30.6,
35.6, 59.1, 80.7, 118.5, 125.9, 126.1, 126.6, 127.8, 127.9,
128.0, 128.4, 129.7, 129.8, 134.1, 140.3, 144.9, 145.6,
164.9. IR (NaCl plates, cmK1): 3058, 3024, 2956, 2929,
2883, 2857, 1717, 1634, 1598, 1494, 1463, 1386, 1321,
1254, 1130, 1071, 1006. MS: [mC/zKC6H15Si]Z383.1643
(calculatedZ383.1647). [a]2D5 K81 (c 0.99, EtOH).
4.3.9. (R)-2,2-Diphenlycyclopentyl 2-(tert-butyldimethyl-
silyloxy)acrylate, 61. Colorless oil, 71%. 1H NMR
(CDCl3): d 0.00 (s, 3H), 0.04 (s, 3H), 0.84 (s, 9H), 1.54
(m, 1H), 1.67–1.89 (m, 2H), 2.14 (m, 1H), 2.45–2.62 (m,
2H), 4.60 (d, JZ1.0 Hz, 1H), 4.95 (d, JZ1.0 Hz, 1H), 6.04
(dd, JZ2.6, 0.9 Hz, 1H), 7.01–7.26 (m, 10H). 13C NMR
(CDCl3): d K5.1, K5.0, 18.2, 20.4, 25.5, 30.5, 35.1, 59.2,
80.7, 103.6, 125.8, 126.1, 126.5, 127.8, 127.9, 128.4, 144.8,
145.4, 147.3, 163.8. IR (NaCl plates, cmK1): 3059, 3032,
2955, 2884, 2857, 1730, 1624, 1599, 1485, 1463, 1447,
1377, 1322, 1253, 1169, 1031, 1005. MS: [mC/zK
C6H15Si]Z307.1330 (calculatedZ307.1334). [a]2D5 K76
(c 0.48, EtOH).
4.3.14. (Z)-(R)-2,2-Diphenlycyclopentyl 2-(tert-butyldi-
methylsilyloxy)-4-methylpent-2-enoate, 66. Colorless oil,
61%. 1H NMR (CDCl3): d 0.12 (s, 3H), 0.13 (s, 3H), 0.77 (d,
JZ6.7 Hz, 3H), 0.86 (d, JZ6.7 Hz, 3H), 0.93 (s, 9H), 1.59
(m, 1H), 1.78 (m, 1H), 1.90 (m, 1H), 2.27 (m, 1H), 2.45
(ddd, JZ12.3, 7.9, 1.7 Hz, 1H), 2.59–2.72 (m, 2H), 5.08 (d,
JZ9.7 Hz, 1H), 6.00 (dd, JZ5.7, 2.7 Hz, 1H), 7.08–7.34
(m, 10H). 13C NMR (CDCl3): d K4.4, K4.3, 18.6, 20.5,
22.0, 22.1, 24.8, 25.8, 30.7, 35.6, 59.3, 80.3, 125.8, 126.1,
126.6, 127.9, 128.0, 128.3, 129.8, 138.5, 145.0, 145.6,
164.6. IR (NaCI, plates, cmK1): 3088, 3060, 3025, 2957,
2857, 1716, 1643, 1599, 1494, 1471, 1447, 1387, 1362,
1303, 1257, 1157, 1113, 1032, 1007. MS: [mC/zK
C6H15Si]Z349.1802 (calculatedZ349.1804). [a]2D5 K66
(c 0.92, EtOH).
4.3.10. (Z)-(R)-2,2-Diphenlycyclopentyl 2-(tert-butyldi-
methylsilyloxy)but-2-enoate, 62. Colorless oil, 69%. H
1
NMR (CDCl3): d 0.11 (s, 3H), 0.13 (s, 3H), 0.94 (s, 9H),
1.56 (d, JZ7.1 Hz, 3H), 1.61–1.79 (m, 2H), 1.91 (m, 1H),
2.20 (m, 1H), 2.48–2.67 (m, 2H), 5.49 (q, JZ7.1 Hz, 1H),
6.04 (dd, JZ5.3, 2.6 Hz, 1H), 7.07–7.31 (m, 10H). 13C
NMR (CDCl3): d K4.37, K4.28, 11.3, 18.5, 20.4, 25.8,
30.5, 35.3, 59.1, 80.3, 117.6, 125.8, 126.1, 126.6, 127.9,
128.4, 141.5, 144.9, 145.6, 164.1. IR (NaCl plates, cmK1):
3087, 3059, 3024, 2956, 2884, 2857, 1717, 1648, 1598,
1494, 1472, 1447, 1389, 1343, 1264, 1145, 1090. MS: [mC/
zKC6H15Si]Z321.1503 (calculatedZ321.1491). [a]D25
K73 (c 0.95, EtOH).
4.3.15. (Z)-(R)-2,2-Diphenlycyclopentyl 2-(tert-butyldi-
methylsilyloxy)-4,4-dimethylpent-2-enoate, 67. White
Solid, 21%. Mp: 94–96 8C. H NMR (C6D6): d 0.16 (s,
1
3H), 0.18 (s, 3H), 0.92 (s, 9H), 0.96 (s, 9H), 1.68–1.98 (m,
2H), 2.27 (m, 1H), 2.44 (m, 1H), 2.64 (m, 1H), 4.99 (s, 1H),
5.95 (dd, JZ2.3, 5.5 Hz, 1H), 7.08–7.28 (m, 10H). 13C
NMR (C6D6): d 165.4, 146.1, 145.5, 139.9, 129.3, 128.7,
126.4, 126.1, 80.8, 59.6, 36.0, 31.7, 31.1, 30.0, 29.9, 26.7,
20.7, 19.4, K2.6, K2.7. IR (NaCl, plates, cmK1): 3088,
3050, 3022, 2950, 2863, 1716, 1645, 1601, 1495, 1471,
1447, 1377, 1361, 1303, 1027, 1005. MS: [mC/zK
4.3.11. (R)-2,2-Diphenlycyclopentyl 2-(tert-butyldi-
methylsilyloxy)-3-methylbut-2-enoate, 63. White solid,
44%. Mp: 56–58 8C. 1H NMR (CDCl3): d 0.07 (s, 3H), 0.09
(s, 3H), 0.93 (s, 9H), 1.43 (s, 3H), 1.59 (m, 1H), 1.68 (s, 3H),
1.75–1.99 (m, 2H), 2.18 (m, 1H), 2.53–2.69 (m, 2H), 6.27
(d, JZ4.9 Hz, 1H), 7.05–7.27 (m, 8H), 7.36 (d, JZ8.2 Hz,
2H). 13C NMR (CDCl3): d K4.3, K4.2, 18.4, 19.2, 20.3,

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D. I. MaGee et al. / Tetrahedron 62 (2006) 4153–4161
C6H15OSi]Z347.2011 (calculatedZ347.2024). [a]D25
K123 (c 2.2, CH2Cl2).
4.4.3. Preparation of 1-tert-butyldimethylsilyloxy-2,2-
dichloro-4-methyl-3-oxo-cyclobutanecarboxylic acid
(S)-(2,2-diphenyl)cyclopentyl ester, 69. Starting with
alkene 62 a colorless oil was produced in 68% as a 3.8:1
4.4. General cycloaddition reaction
1
ratio of inseparable diastereoisomers. H NMR (CDCl3): d
7.10–7.33 (m, 10H), 6.19 (d, JZ5.3 Hz, 0.79H), 6.06 (m,
0.21H), 3.50 (q, JZ7.2 Hz, 0.21H), 3.07 (q, JZ7.6 Hz,
0.79H), 2.44–2.60 (m, 2H), 2.22–2.34 (m, 1H), 1.97–2.07
(m, 1H), 1.80–1.92 (m, 1H), 1.47–1.66 (m, 1H), 1.02 (d, JZ
7.2 Hz, 0.63H), 0.89 (s, 7.11H), 0.87 (s, 1.89H), 0.81 (d, JZ
7.5 Hz, 2.37H), 0.34 (s, 3H), 0.15 (s, 2.37H), 0.08 (s,
0.63H). 13C NMR (CDCl3): Major diastereomer d 195.0,
167.4, 144.8, 144.3, 128.5, 128.4, 127.5, 126.4, 126.3,
126.1, 90.7, 83.4, 80.4, 59.7, 58.6, 35.3, 30.4, 26.4, 20.6,
19.6, 9.5, K2.8, K3.0. Minor diastereomer (visible peaks) d
194.2, 162.0, 145.0, 144.2, 128.5, 128.2, 127.9, 126.5, 89.8,
82.7, 80.9, 58.9, 57.2, 35.5, 30.7, 26.0, 20.1, 19.1, 7.6,
K3.0, K3.6. IR (NaCl plates, cmK1): 3059, 2958, 2932,
2884, 2858, 1817, 1744, 1494, 1472, 1463, 1448, 1258,
1252, 1207, 1156, 1111, 1054, 1031. MS: [mC/zK
C6H15Si]Z325.0431 (calculatedZ325.0430). [a]2D5 K45
(c 1.10, EtOH).
4.4.1. Preparation of 1-tert-butyldimethylsilyloxy-2,2-
dichloro-3-oxo-4-n-propyl-cyclobutanecarboxylic acid
(S)-(2,2-diphenyl)cyclopentyl ester, 52. Zn dust was
activated by vigorously stirring with HCl (10%) for
1–2 min, filtered, then washed with H2O (3!) followed
by acetone (3!). The activated Zn was stored in an oven
heated at approximately 140–150 8C. To a flask of activated
Zn dust (1.12 g, 17.1 mmol) and ether (10 mL) was added a
mixture of trichloroacetyl chloride (1.53 mL, 13.7 mmol)
and alkene 49 (3.20 g, 6.9 mmol) dropwise over 4–5 h. The
heterogeneous solution was stirred for 16 h at rt, diluted
with diethyl ether and filtered through Celitew. The filtrate
was concentrated to 1–5 mL by rotary evaporation, diluted
with pentane (15 mL) then vigorously stirred for 5 min to
induce precipitation of Zn salts. After allowing the
precipitate to settle, the pentane solution was decanted
from the Zn salts. This decanting/washing protocol was
repeated twice more. The combined pentane extracts were
washed with cold saturated NaHCO3 (5%, 2!), H2O (1!),
brine (1!), dried over Na2SO4, and the solvent evaporated.
The crude residue was purified by filtration through SiO2
(20:1 hexane/ethyl acetate) followed by recrystallization
from hexanes to furnish cycloadduct 52 (3.07 g, 79% yield)
as a colorless solid. Mp: 76–78 8C. 1H NMR (CDCl3). d 0.22
(s, 3H), 0.36 (s, 3H), 0.73 (t, JZ7.3 Hz, 3H), 0.92 (s, 9H),
1.29 (m, 2H), 1.51 (m, 3H), 1.87 (m, 1H), 2.04 (m, 1H), 2.31
(m, 1H), 2.47 (m, 1H), 2.65 (m, 1H), 2.95 (t, JZ7.7 Hz, lH),
6.24 (d, JZ4.8 Hz, 1H), 7.23 (m, 10H). 13C NMR (CDCl3):
d K2.8, 14.1, 19.9, 20.7, 21.2, 26.3, 26.7, 28.8, 30.3, 35.2,
59.9, 64.3, 83.9, 126.3, 126.5, 126.7, 126.8, 127.6, 128.4,
128.5, 128.7, 128.8, 144.5, 145.1, 168.2, 194.8. IR (NaCl
plates, cmK1): 3030, 2878, 1818, 1735, 1518, 1460, 1225,
920. [a]2D5 K65.2 (c 2.5, CH2Cl2).
4.4.4. Preparation of 1-tert-butyldimethylsilyloxy-2,2-
dichloro-3-oxo-4-isopropyl-cyclobutanecarboxylic acid
(S)-(2,2-diphenyl)cyclopentyl ester, 70. Starting with
alkene 66 a colorless oil was produced in 94% as a 10.8:1
1
ratio of inseparable diastereoisomers. H NMR (CDCl3) d
7.22 (m, 1H), 6.21 (d, JZ5.0 Hz, 0.92H), 6.03 (dd, JZ5.9,
3.4 Hz, 0.08H), 3.32 (d, JZ10.6 Hz, 0.08H), 2.44–2.63 (m,
2H), 2.40 (d, JZ10.6 Hz, 0.92H), 1.98–2.26 (m, 3H), 1.80–
1.91 (m, 1H), 1.49–1.64 (m, 1H), 0.98 (s, 0.72H), 0.91 (s,
8.28H), 0.82 (d, JZ6.8 Hz, 2.76H), 0.71 (d, JZ6.3 Hz,
0.24H), 0.62 (d, JZ6.3 Hz, 0.24H), 0.41 (d, JZ6.4 Hz,
2.76H), 0.33 (s, 2.76H), 0.27 (s, 2.76H), 0.18 (s, 0.24H),
0.04 (s, 0.24H). 13C NMR (CDCl3): Major diastereomer d
193.5, 168.3, 144.8, 144.3, 128.57, 128.55, 127.4, 126.4,
126.2, 83.7, 80.7, 70.8, 59.6, 35.0, 30.0, 28.0, 26.6, 26.0,
21.8, 20.4, 20.3, 19.7, K2.6, K2.8. Minor diastereomer
(visible peaks) d 193.8, 167.0, 144.7, 144.1, 128.8, 128.4,
128.3, 128.2, 128.1, 126.6, 91.1, 82.4, 68.1, K3.4, K3.7. IR
(NaCl plates, cmK1): 2960, 2927, 2847, 1808, 1754, 1722,
1643, 1568, 1494, 1470, 1388, 1362, 1254, 1200, 1110,
1031. MS: [mC/zKC6H15Si]Z459.1130 (calculatedZ
459.1130). [a]2D5 K31 (c 0.60, EtOH).
4.4.2. Preparation of 1-tert-butyldimethylsilyloxy-2,2-
dichloro-3-oxocyclobutanecarboxylic acid (S)-(2,2-
diphenyl)cyclopentyl ester, 68. Starting with alkene 61 a
clear yellow oil was produced in 80% as a 3.5:1 ratio of
diastereoisomers. 1H NMR (CDCl3): d 7.12–7.37 (m, 10H),
6.29 (d, JZ4.6 Hz, 0.78H), 6.16 (dd, JZ5.2, 2.8 Hz,
0.22H), 3.49 (d, JZ17.6 Hz, 0.22H), 3.20 (d, JZ17.7 Hz,
0.2H), 3.03 (d, JZ17.1 Hz, 0.78H), 2.57–2.65 (m, 1H),
2.16–2.48 (m, 2H), 2.06 (d, JZ17.5 Hz, 0.78H), 1.82–2.07
(m, 2H), 1.44–1.62 (m, 1H), 0.95 (s, 7.02H), 0.93 (s, 1.98H),
0.26 (s, 2.34H), 0.16 (s, 0.66H), 0.06 (s, 0.66H), K0.01 (s,
2.34H). 13C NMR (CDCl3): Major diastereomer d 188.8,
167.9, 145.1, 144.1, 128.54, 128.52, 127.3, 126.4, 126.2,
126.0, 91.8, 83.6, 78.1, 59.8, 53.8, 34.9, 29.9, 25.7, 20.5,
18.5, K3.6, K4.0. Minor diastereomer (visible peaks) d
189.1, 168.0, 145.2, 143.8, 128.5, 128.2, 128.0, 126.5,
126.3, 91.2, 83.3, 78.6, 58.6, 53.7, 30.6, 25.8, 25.6, 19.8,
18.4, K3.7. IR (NaCl plates, cmK1): 3088, 3059, 3024,
2955, 2931, 2885, 2858, 1813, 1756, 1598, 1472, 1463,
1388, 1300, 1252, 1220, 1181, 1132, 1103, 1032. MS: [mC/
zKC6H15Si]Z417.0670 (calculatedZ417.0660). [a]D25
K36 (c 0.99 EtOH).
4.4.5. Preparation of 1-tert-butyldimethylsilyloxy-2,2-
dichloro-4,4-dimethyl-3-oxo-cyclobutanecarboxylic acid
(S)-(2,2-diphenyl)cyclopentyl ester 71. Starting with
220 mg (0.46 mmol) of alkene 67, a 4:1 inseparable mixture
of starting material and cycloadduct was produced. Based
on consumed starting material (determined by 1H NMR) 71
was produced as a colorless oil in 32% yield in a 8.2:1 ratio
1
of inseparable diastereosiomers. H NMR (C6D6): Major
diastereosiomer d 6.87–7.21 (m, 10H), 6.16 (d, JZ3.6 Hz,
1H), 3.45 (s, 1H), 1.23–2.61 (m, 6H), 1.08 (s, 9H), 0.92 (s,
9H), 0.55 (s, 3H), 0.53 (s, 3H). 13C NMR (C6D6): Major
diastereomer d 194.6, 169.0, 145.3, 144.7, 129.0, 128.9,
127.9, 127.6, 126.54, 126.5, 84.5, 83.9, 73.4, 35.1, 34.6,
32.4, 30.2, 30.1, 29.9, 28.7, 28.5, 27.2, 23.2, 20.3, 14.4,
K1.8. IR (NaCl plates, cmK1); most distinguishable peak
for cycloadduct 71: 1814.

D. I. MaGee et al. / Tetrahedron 62 (2006) 4153–4161
4161
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butyldimethylsilyloxy)-3-(3,3-dichloro-2-oxocyclobut-
yl)acrylate, 72. Starting with alkene 64, a colorless oil was
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1
isomers. H NMR (CDCl3): d 7.05–7.27 (m, 10H), 6.01–
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6.06 (m, 1H), 5.33 (d, JZ9.2 Hz, 0.28H) 5.08 (d, JZ9.5 Hz,
0.72H), 3.80 (d, JZ4.8 Hz, 0.28H), 3.46 (m, 0.72H), 3.38
(dd, JZ17.8, 10.1 Hz, 0.72H), 3.00 (dd, JZ17.9, 8.6 Hz,
0.28H), 2.86 (dd, JZ18.0, 4.9 Hz, 0.28H), 2.78 (dd, JZ
17.8, 8.6 Hz, 0.72H), 2.59–2.71 (m, 1H), 2.45–2.56 (m, 1H),
2.23–2.41 (m, 1H), 2.07 (m, 0.28H), 1.77–1.96 (m, 1.72H),
1.36–1.47 (m, 1H), 1.01 (s, 2.52H), 0.94 (s, 6.48H), 0.38 (s,
0.84H), 0.30 (s, 0.84H), 0.19 (s, 2.16H), 0.18 (s, 2.16H). 13C
NMR (CDCl3): Major diastereomer d 192.2, 163.4, 145.1,
144.3, 143.7, 130.9, 128.8, 128.4, 128.2, 127.8, 126.5,
126.3, 81.5, 68.1, 59.6, 48.7, 41.8, 35.7, 30.4, 25.8, 20.7,
18.6, K4.2. Minor diastereomer (visible peaks) d 132.5,
128.7, 128.1, 127.3, 126.2, 125.8, 81.1, 66.4, 59.5, 45.9,
44.1, 35.7, 30.2, 25.8, 20.5, K2.2, K2.5. IR (NaCl plates,
cmK1): 3060, 3024, 2957, 2930, 2858, 1815, 1760, 1725,
1645, 1599, 1495, 1447, 1386, 1291, 1254, 1212, 1162,
1124, 1071. MS: [mC/zKC6H15Si]Z337.0417 (calcula-
tedZ337.0430). [a]2D5 K69 (c 0.26, EtOH).
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We wish to thank the Natural Sciences and Engineering
Research Council of Canada (NSERC) for a Discovery grant
to carry out this research. T.C.M. would like to thank the New
Brunswick Women’s Doctoral Fellowship for financial
support. We would like to thank Mr. Gilles Vautour with
assistance in running the mass spectra and Dr. Larry Calhoun
for assistance in some NMR experiments.
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