Transition metal catalyzed stereospecific intramolecular [3 + 2] cycloadditions of methylenecyclopropanes with alkynes

Article abstract of DOI:10.1021/ja9611809

Palladium catalyzed intramolecular [3 + 2] cycloadditions of diastereomerically pure methylenecyclopropanes MCPs have been investigated. The reaction was found to be stereospecific and occurred with retention of configuration at the carbon center undergoi

Full text of DOI:10.1021/ja9611809

J. Am. Chem. Soc. 1996, 118, 9597-9605
9597
Transition Metal Catalyzed Stereospecific Intramolecular
[3 + 2] Cycloadditions of Methylenecyclopropanes with
Alkynes
Mark Lautens* and Yi Ren
Contribution from the Department of Chemistry, UniVersity of Toronto,
Toronto, Ontario, Canada M5S 3H6
ReceiVed April 10, 1996X
Abstract: Palladium catalyzed intramolecular [3 + 2] cycloadditions of diastereomerically pure methylenecyclo-
propanes MCPs have been investigated. The reaction was found to be stereospecific and occurred with retention of
configuration at the carbon center undergoing reaction. A variety of substitution patterns were tolerated on and
around the MCP. Deuterium labeling studies have been conducted, and information about the rate of the reaction
was obtained. A mechanism has been proposed involving π-allyl intermediates. Pd2(dba)3/P(OiPr)3 was a suitable
catalyst for most cycloadditions, but molecular sieves or Pd(PPh3)4 improved the reaction with some substrates.
1,4-Addition of hydride or a carbanion to the enoate was achieved with high selectivity at the newly formed
stereocenter. The allylic alcohol was selectively epoxidized with VO(acac)2/t-BuOOH.
Introduction
Many additional examples of this reaction have been reported,
and improved catalysts were developed in the intervening years.5
In particular Binger’s comprehensive investigation of nickel and
palladium catalyzed intermolecular cycloadditions between
MCPs and alkenes or alkynes provided important insights into
the reaction and revealed some limitations associated with a
lack of regio- and stereoselectivity.3a,d
An attractive strategy for the synthesis of five-membered rings
is a transition metal mediated [3 + 2] cycloaddition reaction.1
A variety of different three-carbon units has been employed in
this process including trimethylenemethane (TMM)2 synthons
generated from bifunctional conjunctive reagents and methyl-
enecyclopropanes MCPs.3 In their seminal study, Noyori and
Takaya reported that a Ni0 complex catalyzed a [3 + 2]
cycloaddition between MCP and an electron deficient alkene.4
The regiochemical outcome of MCP cycloadditions was
shown to depend on the substitution pattern of the substrate
and the catalyst.1,3 The trends that can be generalized from
previous studies are as follows: (a) in the presence of Pd0, all
types of MCPs undergo distal ring opening regardless of the
substitution pattern and (b) with Ni0 catalysts the parent MCP
undergoes proximal ring opening, whereas reaction of mono-
substituted MCPs leads to distal and proximal ring opening and
MCPs which bear dialkyl substituents at the cyclopropyl or
vinylic carbon undergo distal ring opening preferentially.
Exclusive distal ring opening occurs if the MCP is substituted
with a diaryl moiety at the cyclopropane carbon or vinylic
carbon.
X Abstract published in AdVance ACS Abstracts, September 1, 1996.
(1) For a review of transition metal mediated cycloadditions, see:
Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. For a review
of [3 + 2] cycloadditions, see: Chan, D. M. T. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; vol. 5, p 271;
For examples of transition metal-mediated cycloaddition approaches toward
five-membered ring-formation, see: (a) Herndon, J. W. J. Am. Chem. Soc.
1987, 109, 3165. (b) Semmelhack, M. F.; Herndon, J. W. ; Liu, J. K.
Organometallics 1983, 2, 1885. (c) Rosenblum, M. J. Organomet. Chem.
1986, 300, 191. (d) Welker, M. E. Chem. ReV. 1992, 92, 97. (e) Wojcicki,
A.; Schuchart, C. E. Coord. Chem. ReV. 1990, 105, 35. (f) Lee, G.-H.; Peng,
S.-M.; Yang, G.-M.; Lush, S. F.; Liu, R.-S. Organometallics 1989, 8, 1106.
(g) For a review of Pauson-Khand reaction, see: Schore, N. E. Org. React.
1991, 40, 1. (h) Liebeskind, L. S.; Chidambaram, R. J. Am. Chem. Soc.
1987, 109, 5025. (i) Aumann, R.; Weidenhaupt, H. J. Chem. Ber. 1987,
120, 23. (j) Alper, H.; Brandes, D. A. Organometallics 1991, 10, 2457. (k)
O’Connor, J. M.; Pu, L.; Uhrhammer, R.; Johnson, J. A.; Rheingold, A. L.
J. Am. Chem. Soc. 1989, 111, 1889. (l) Hayakawa, Y.; Yokoyama, K.;
Noyori, R. J. Am. Chem. Soc. 1978, 100, 1791. (m) Yamashita, A.
Tetrahedron Lett. 1986, 27, 5915. (n) Xu, Y.-C.; Challener, C. A. ; Dragisch,
V.; Brandvold, T. A.; Peterson, G. A.; Wulff, W, D.; Williard, P. G. J. Am.
Chem. Soc. 1989, 111, 7269. (o) Brandvold, T. A.; Wulff, W. D.; Rheingold,
A. L. J. Am. Chem. Soc. 1990, 112, 1645. (p) Stein, F.; Duetsch, M.;
Lackmann, R.; Noltemeyer, M.; de Meijere, A. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1658.
Motherwell and Nakamura independently described the first
examples of intramolecular cycloaddition using MCPs in the
presence of palladium and nickel catalysts.6 Intramolecular
cycloaddition is entropically favored over intermolecular cy-
cloaddition and occurs with complete regiochemical control.7
(5) (a) Binger, P. Schuchardt, U. Angew. Chem., Int. Ed. Engl. 1977,
16, 249. (b) Binger, P. Schuchardt, U. Chem. Ber. 1980, 113, 3334. (c)
Binger. P.; Lu¨, Q.-H.; Wedemann, P. Angew. Chem., Int. Ed. Engl. 1985,
24, 316.
(2) For reviews, see: (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1986,
25, 1. (b) Trost, B. M. Pure & Appl. Chem., 1988, 60, 1615.
(6) (a) Lewis, R. T.; Motherwell, W. B.; Shipman, M. J. Chem. Soc.,
Chem. Commun. 1988, 948. (b) Bapuji, S. A.; Motherwell, W. B.; Shipman,
M. Tetrahedron Lett. 1989, 30, 7107. (c) Motherwell, W. B.; Shipman, M.
Tetrahedron Lett. 1991, 32, 1103. (d) Lewis, R. T.; Motherwell, W. B.;
Shipman, M.; Slawin, A. M. Z.; Williams, D. J. Tetrahedron 1995, 51,
3289. (e) Corlay, H.; Lewis, R. T.; Motherwell, W. B.; Shipman, M.
Tetrahedron 1995, 51, 3303. (f) Yamago, S.; Nakamura, E. J. Chem. Soc.,
Chem. Commun. 1988, 1112. (g) Yamago, S.; Nakamura, E. Tetrahedron
1989, 45, 3081. (h) Corlay, H.; Motherwell, W. B.; Pennell, A. M. K.;
Shipman, M.; Slawin, A. M. Z.; Williams, D. J. Tetrahedron 1996, 52,
4883.
(3) For reviews, see: (a) Binger, P.; Bu¨ch, H. M. Top. Curr. Chem. 1987,
135, 77. (b) Ohta, T.; Takaya, H. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, p 1185. (c)
Dzhemilev, U. M.; Khusnutdinov, R. I.; Tolstikov, G. A. J. Organomet.
Chem. 1991, 409, 15. (d) Binger, P.; Fox, D. In Methods Of Organic
Chemistry (Houben Weyl), Vol. E 21C, Part D, 1.6.1.2.3, p 2997.
(4) (a) Noyori, R.; Odagi, T.; Takaya, H. J. Am. Chem. Soc. 1970, 92,
5780. (b) Noyori, R.; Hayashi, N.; Katoˆ, M. J. Am. Chem. Soc. 1971, 93,
4948. (c) Noyori, R.; Kumagai, Y; Umeda, I, Takaya, H. J. Am. Chem.
Soc. 1972, 94, 4018. (d) Noyori, R.; Ishigami, T; Hayashi, N.; Takaya, H.
J. Am. Chem. Soc. 1973, 95, 1674. (e) Noyori, R.; Yamakawa, M.
Tetrahedron Lett. 1978, 19, 4823.
(7) For a full account of the intramolecular cycloadditions with bifunc-
tional conjunctive reagents, see: Trost, B. M.; Grese, T. A.; Chan, D. M.
T. J. Am. Chem. Soc. 1991, 113, 7350.
S0002-7863(96)01180-8 CCC: $12.00 © 1996 American Chemical Society

9598 J. Am. Chem. Soc., Vol. 118, No. 40, 1996
Lautens and Ren
Table 1. Preparation of Precursors for [3 + 2] Cycloaddition
Despite significant effort on the synthetic, mechanistic, and
theoretical aspects of the transition metal mediated MCP
cycloaddition many details of the process are still uncertain.
For example, prior to our work the stereochemical outcome of
the stereocenter on the cyclopropane ring C* during the
cycloaddition reaction was not known, eq 1.
In a preliminary report,8 we showed that the palladium
catalyzed intramolecular [3 + 2] cycloadditions of methyl-
enecyclopropanes is stereospecific and occurs with overall
retention of stereochemistry at the cyclopropane carbon, eq 2.
We now describe in detail our studies on the scope and
limitations of this methodology.
a C6H11 refers to cyclohexyl and C7H15 refers to n-heptyl. b TBDM-
SCl, DMF, imidazole, room temperature. c PCC, NaOAc, CH2Cl2, room
temperature. d HMPA was added as co-solvent.
Cycloaddition Precursor Preparation
The viability of the cycloaddition study depended on ready
access to diastereomerically pure MCPs.9 The diastereoselective
samarium promoted diiodomethane cyclopropanation of R-al-
lenic alcohols provided easy access to a variety of diastereo-
merically pure substituted MCPs.10 Starting from diastereo-
merically pure methylenecyclopropane carbinols, the precursors
for the cycloaddition reaction were prepared in a straightforward
manner, Table 1. Deprotonation of the alcohol with KH in the
presence of 18-crown-6 followed by trapping the alkoxide with
propargyl bromide leads to propargyl ethers in high yield.
Lithiation of the terminal acetylene using n-butyllithium and
trapping the resulting acetylide with different electrophiles
provided a variety of precursors for the cycloaddition study.
Comparison of Ni0 and Pd0 Catalysts. We reported that
Ni(COD)2 catalyzed the intermolecular [3 + 2] cycloaddition
between a diastereomerically pure methylenecyclopropane
carbinol methyl ether and phenyl vinyl sulfone with synthetically
useful levels of regio- and stereochemical control.8 When the
same partners were subjected to various Pd0 catalysis, no
reaction was observed. Similarly, attempts to react the MCP
with dimethylactylenedicarboxylate as the C-2 unit or the bis
TBDMS-ether of 1,4-butynediol led to polymerization of the
Table 2. Stereospecificity of the Cycloaddition
a P/Pd ) 2/1; typically 2-10 mol % of Pd2(dba)3 was used. See
experimental for details. b C6H11 refers to cyclohexyl and C7H15 refers
to n-heptyl. c Reflux for 4 h. d 10 mol % of Pd(PPh3)4 was used at reflux
in toluene for 2 h.
alkyne. We had also attempted intramolecular [3 + 2] cy-
cloadditions with Ni(COD)2 as the catalyst using a variety of
different substrates but in all cases observed the formation of
complex mixtures whose structures were not easily identified.
Therefore, Pd0 was the catalyst used throughout our investiga-
tions.
(8) Lautens, M.; Ren, Y.; Delanghe, P. H. M. J. Am. Chem. Soc. 1994,
116, 8821.
(9) For some examples of preparing methylenecyclopropanes, see: (a)
Jonczyk A.; Kmiotek-Skarzynska I. J. Org. Chem. 1989, 54, 2756. (b)
Jonczyk A.; Kmiotek-Skarzynska I.; Zdrojewski, T. J. Chem. Soc., Perkin
Trans. I 1994, 1605. (c) Ramaswamy, S.; Prasad, K.; Repic, O. J. Org.
Chem. 1992, 57, 6344. (d) Staley, S. W.; Norden, T. D. J. Am. Chem. Soc.
1984, 106, 3699. (e) Stolle, A.; Ollivier, J.; Piras, P. P.; Salau¨n, J., de
Meijere, A. J. Am. Chem. Soc. 1992, 114, 4051. (f) Heiner, T.; Michalski,
S.; Gerke, K.; Kuchta, G.; Buback, M.; de Meijere, A. Synlett 1995, 355.
(g) Ollivier, J.; Piras, P. P.; Stolle, A.; Aufranc, P.; de Meijere, A.; Salau¨n,
J. Tetrahedron Lett. 1992, 33, 3307. (h) Satoh, T.; Kawase, Y.; Yamakawa,
K. Tetrahedron Lett. 1990, 31, 3609. (i) Satoh, T.; Kawase, Y.; Yamakawa,
K. Bull. Chem, Soc. Jpn. 1991, 64, 1129. (j) Fischer, H.; Bidell, W.;
Hofmann, J. J. Chem. Soc., Chem. Commun. 1990, 858. (k) Padwa, A.;
Wannamaker, M. W. Tetrahedron 1991, 47, 6139. (l) Petasis, N. A.; Bzowej,
E. I. Tetrahedron Lett. 1993, 34, 943. (m) Achmatowicz, B.; Kabat, M.
M.; Krajewski, J.; Wicha, J. Tetrahedron 1992, 48, 10201. (n) Baldwin, J.
E; Adlington, R. M.; Bebbington, D.; Russel, A. T. Tetrahedron 1994, 50,
12015. (o) Ko¨ster, R.; Arora, S.; Binger, P. Liebigs Ann. Chem. 1973, 1219.
(p) Ko¨ster, R.; Arora, S.; Binger, P. Angew. Chem., Int. Ed. Engl. 1969, 8,
205. (q) Ko¨ster, R.; Arora, S.; Binger, P. Synthesis 1971, 322. For other
methods, see references 6(d) and 6(e).
Stereospecificity. The Pd0 catalyzed intramolecular [3 + 2]
cycloaddition between a diastereomerically pure MCP tethered
to an alkyne was shown to be a stereospecific reaction.8 Thus,
when 3a was reacted with 2 mol % of Pd2(dba)3 and 8 mol %
P(OiPr)3, intramolecular cycloaddition took place in 75% yield
and gave 11a as a single diastereomer as determined by high
field 400 MHz NMR (entry 1, Table 2). The diastereomeric
starting material 4 afforded 12 in 72% yield using 5 mol % of
Pd2(dba)3 and 20 mol % P(OiPr)3 (entry 3, Table 2). The NMR
spectra of diastereomers 11a and 12 showed significant differ-
ences. For instance, the 1H NMR (400 MHz) of 11a has vinylic
protons at 4.93 and 4.84 ppm, whereas in 12 the corresponding
two signals are found at 5.10 and 4.93 ppm, respectively. This
pattern is preserved for all the diastereomeric cycloadducts
investigated, regardless of the substitution pattern. The reactions
of 5 and 6a proceeded in an identical fashion and were also
stereospecific. Cycloaddition of the alcohol 3b gave 11b in
(10) (a) Lautens, M.; Delanghe, P. H. M. J. Org. Chem. 1993, 58, 5037.
(b) Lautens, M.; Delanghe, P. H. M. J. Am. Chem. Soc. 1994, 116, 8526.
(c) Lautens, M.; Ren, Y. J. Org. Chem. 1996, 61, 2210.

[3 + 2] Cycloadditions of Methylenecyclopropanes
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9599
Table 3. Effect of Substituent on the Cyclopropane Carbon
85% yield illustrating that the substituent on the acetylene does
not influence the stereospecificity.
Determination of Relative Stereochemistry. Due to over-
lapping key resonances, NMR techniques (NOE, 2D NMR)
failed to provide conclusive information on the relative stere-
ochemistry of the cycloadducts. Instead, we obtained unequivo-
cal proof by X-ray crystallography. Reduction of 11a with
DIBAL-H (-78 °C, THF) gave alcohol 11b which was
esterified (3,5-dinitrobenzoic acid, DCC, DMAP) to provide a
crystalline product, 11h (eq 3). Examination of the relative
stereochemistry between the carbon bearing the cyclohexyl ring
and that at the bridge revealed that the cycloaddition was not
only stereospecific but also occurred with overall retention of
stereochemistry.
a C6H11 refers to cyclohexyl. b P/Pd ) 2/1; typically 2-12 mol %
of Pd0 was used. See experimental for details.
Table 4. Effect of Substituent on the Acetylene
Substitution Effects. The two discoveries presented above
suggested an investigation of the generality of the reaction be
undertaken. Significant variation in reactivity has been observed
as a function of the location and nature of the substituent as
outlined below. Nevertheless, a wide variety of substitution
patterns are tolerated leading to a diverse range of methyl-
enecyclopentenes.
a P/Pd ) 2/1; typically 2-10 mol % of Pd2(dba)3 was used. See
experimental for details. b C6H11 refers to cyclohexyl. c 11 mol % of
Pd(PPh3)4 was used at reflux in toluene for 1.5 h. d A similar result
was observed when Pd(PPh3)4 was used as the catalyst.
cycloadduct in 54% yield which implied that the oxygen on
the tether played a role in influencing the reaction pathway.6e
(d) Substitution on the Alkyne. The substituent on the
acetylenic carbon had a significant influence on the success of
the cycloaddition. Alkynes bearing an electron withdrawing
group including an ester or ketone moiety underwent smooth
cycloaddition to give the cycloadduct in good yield. Substrates
bearing weaker electron withdrawing groups such as a hy-
droxymethyl or a protected hydroxymethyl group gave excellent
yields of the cycloadduct. The successful cycloaddition of
compound 3c (entry 3, Table 4) indicates that the hydroxy
oxygen does not play a role in delivering the palladium.6c
Surprisingly, in a substrate with a methyl substituent, 3g (entry
5, Table 4), only a very small amount of the desired cycloadduct
was formed with large amounts of unreacted starting material.
This result is in sharp contrast to the intermolecular cycload-
dition of simple unsubstituted methylenecyclopropanes where
nonactivated alkenes also undergo cycloaddition.3a
The cycloaddition of a substrate containing an alkyne bearing
a silicon was studied since the product would contain a vinyl
silane which upon protodesilylation would generate an adduct
equivalent to a cycloaddition with a terminal alkyne, a reaction
that failed to occur under these conditions. Alternatively,
transformation of the vinylsilane to a ketone would lead to
products that are equivalent to a formal reaction of a ketene
with a MCP.
Ni0/phosphite catalyzed intermolecular [3 + 2] cycloaddition
between MCP and alkynylsilanes is a well established reaction.5c
However, when Motherwell studied the intramolecular reaction,
all attempts to cyclize a silyl substituted acetylene were
unsuccessful.6e
We found the reaction was very sluggish with 3f but did occur
using 40-50 mol % Pd2(dba)3 or Pd(PPh3)4, (entry 1, Table
5). However, the TBDMS derivative 6b (entry 2, Table 5) and
PhMe2Si derivative 6c (entry 4, Table 5) failed to yield any
cycloadduct under Pd2(dba)3 catalysis. Only when 4 Å molec-
(a) Substitution on Carbinol Carbon. Substitution at R1
and R2 appears to have little effect on the stereoselectivity or
reactivity of the reaction which was demonstrated by the
successful cycloaddition of 7 (entry 6, Table 2).
(b) Substitution on the Exocyclic Methylene Group. A
substrate with a dialkylidene moiety worked as well as one
with a methylene group, and no scrambling of the carbon bear-
ing the dialkyl substituents was observed (entry 7, Table 2).
These observations mirror those of Motherwell who showed
that no migration occurred in a Pd0 catalyzed cycloaddition of
a MCP with a diphenylmethylene group although migration is
often observed in Pd0 catalyzed intermolecular cycloaddition
reactions.3a,6d
(c) Substitution on the Cyclopropane Carbon. Substitution
at the sp3 carbon on the methylenecyclopropane has a marked
effect on the success of the cycloaddition (Table 3). While the
reaction of 3a (R ) H, entry 1, Table 3) and 9 (R ) OCH3,
entry 2, Table 3) were straightforward, treatment of 10 (R )
Me, entry 3, Table 3) with either Pd2(dba)3 or Ni(COD)2 gave
a complex mixture of diene-containing products. Fortunately,
we found that Pd(PPh3)4 catalyzed the [3 + 2] cycloaddition of
10 and gave the desired cycloadduct in 43% yield accompanied
by some diene (entry 4, Table 3). It should be noted that
Motherwell reacted a related compound and diene formation
was also observed.6e However, a carbon analog gave the

9600 J. Am. Chem. Soc., Vol. 118, No. 40, 1996
Table 5. Effect of Silicon Substituent on the Acetylene
Lautens and Ren
Scheme 1
We see significant differences in reactivity as the substituent
on the alkyne is varied which supports the notion that coordina-
tion of this group is an important step in the reaction pathway.
Alkynes bearing electron-withdrawing groups are more reactive
than those with a silicon, Tables 4 and 5.
During the cleavage of the cyclopropyl carbon-carbon bond
trimethylenemethane-palladium complex of type x or metal-
lacycle y have been proposed as intermediates. Both intermedi-
ates may even be possible depending on the catalyst and/or
substrate.14
a C6H11 refers to cyclohexyl and C7H15 refers to n-heptyl. b P/Pd )
2/1; typically 40-80 mol % of Pd0 was used. See experimental for
details.
ular sieves were added (entry 3, Table 5) or when the catalyst
was changed to Pd(PPh3)4 (entry 5, Table 5), were the
cycloadducts obtained.11 Even under these improved conditions
a large amount of catalyst was required. It is not clear why
molecular sieves lead to improved yields with some substrates
beyond the obvious explanation of ensuring a dry reaction
environment.
Although Pd2(dba)3 is the most popular source of Pd0, the
failure of certain substrates to undergo the cycloaddition and
the difficulty of removing dba from the product prompted the
initial studies with Pd(PPh3)4 described above. Pd(PPh3)4 is
rarely used in the [3 + 2] MCP cycloaddition,3a,6 although it is
a popular catalyst in [3 + 2] TMM cycloadditions.2 Our studies
indicate Pd(PPh3)4 is a superior catalyst for many of the
substrates described in this work. For example substrate 3e
underwent cycloaddition in 92% yield in the presence of 11
mol % Pd(PPh3)4, which is an increase of 40% compared to
the corresponding Pd2(dba)3 reaction (entry 4, Table 4). Moder-
ate improvement was also observed for a substrate bearing a
carbomethoxy substituent (entry 5, Table 2). An added benefit
of using Pd(PPh3)4 was that purification was much easier. A
catalytic amount of Pd(PPh3)4 also catalyzed the cycloaddition
of 10 and gave significantly less diene than Pd2(dba)3 (entry 4,
Table 3).
Of the three catalytic systems studied, Pd(PPh3)4 exhibits the
highest reactivity, but this catalyst is the most air-sensitive.
Fortunately Pd2(dba)3 and Pd2(dba)3+sieves are satisfactory
catalytic systems for many substrates. It is important to note
that mixing Pd2(dba)3 with 4 equiv of PPh3 did not give identical
results to those obtained using Pd(PPh3)4. Furthermore the
choice of catalyst appears to be much more crucial for the
corresponding intramolecular [3 + 2] cycloaddition of MCP
with alkenes.12
Investigation of the Mechanism of the Cycloaddition. In
our preliminary report,8 we proposed a sequence of events to
explain the stereospecificity of the cycloaddition reaction
(Scheme 1). The first step is probably coordination of the
alkyne and the exocyclic methylene group to the pal-
ladium.3a,13-16,17k The metal then dissociates from the methylene
moiety and coordinates to the cyclopropane in an edge-on
orientation. Insertion into the distal cyclopropane bond gener-
ates a metallacyclobutane which undergoes carbometallation and
reductive elimination to yield the observed cycloadduct. Since
the overall reaction occurs with retention of configuration, an
important issue was to determine if the reaction follows a
retention-retention pathway or an inversion-inversion pathway
in the key bond-breaking and bond-making steps.
If the reaction goes through a TMM intermediate, a disro-
tatory-out ring-opening17 where the 2,3-σ bond undergoing
reaction bends away from the Pd0 would lead to TMM complex
25a (Scheme 2). The ensuing cycloaddition would then give
cycloadduct 26 with net inversion of stereochemistry at C*. Our
experimental results have unambiguously proven that cycload-
(13) Simple η2-coordination of metals with MCP has been observed for
1:1 complexes with Fe0, Rh1+, Ir1+, Pt2+, Pt0, and Ni0 in which the three-
membered ring remains intact. See: (a) Green, M.; Howard, J. A. K.;
Hughes, R. P.; Kellett, S. C.; Woodward, P. J. Chem. Soc., Dalton Trans.
1975, 2007. (b) Whitesides, T. H.; Slaven, R. W. J. Organomet. Chem.
1974, 67, 99. (c) Slaven, R. W.; Calabrese, J. C. Inorg. Chem. 1974, 13,
1895. (d) Isaeva, L. S.; Peganova, T. A.; Petrovskii, P. V.; Kravtsov, D. N.
J. Organomet. Chem. 1989, 376, 141. (e) Isaeva, L. S.; Peganova, T. A.;
Petrovskii, P. V. J. Organomet. Chem. 1983, 258, 367. η2-coordination of
the alkyne, see: (f) Samsel, E. G.; Norton, J. R. J. Am. Chem. Soc. 1984,
106, 5505. (g) Ryabov, A. D.; van Eldik, R.; Le Borgne, G.; Pfeffer, M.
Organometallics 1993, 12, 1386. (h) de Vaal, P.; Dedieu, A. J. Organomet.
Chem. 1994, 478, 121.
(14) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1983, 105, 2326.
(15) Binger found that ligands such as maleic anhydride, acrolein, and
acrylonitrile which bind very tightly to the catalyst can prevent any
interaction of the metal with MCP, and thus inhibit the cycloaddition. See
ref 3a.
(16) Binger found that intermolecular cycloaddition of MCP with simple
unstrained alkenes is complicated by cyclodimerization of MCP rather than
codimerization of MCP with alkenes due to the fact that MCP competes
successfully with unactivated alkenes in π-complexation to the metal. This
drawback can be overcome by simply using MCP substituted at the vinylic
position to decrease the degree of π-complexation to the metal. See ref 3a.
(17) TMM-metal complexes from metal-induced disrotatory ring open-
ing of alkylidenecyclopropanes are known. For the iron complex, see: (a)
Noyori, R.; Nishimura, T.; Takaya, H. J. Chem. Soc. D. 1969, 80. (b) Kagan,
J.; Liu, W.-L.; Cohen, S. M.; Schwartz, R. N. J. Organomet. Chem. 1974,
90, 67. (c) Carpenter, B. K.; Pinhas, A. R. J. Chem. Soc., Chem. Commun.
1980, 17. (d) Samuelson, A. G.; Carpenter, B. K. J. Chem. Soc., Chem.
Commun. 1981, 354. (e) Pinhas, A. R.; Samuelson, A. G.; Risemberg, R.;
Arnold, E. V.; Clardy, J.; Carpenter, B. K. J. Am. Chem. Soc. 1981, 103,
1668. For molybdenum complex, see: (f) Barnes, S. G.; Green, M. J. Chem,
Soc., Chem. Commun. 1980, 267. (g) Allen, S. R.; Barnes, S. G.; Green,
M.; Moran, G.; Trollope, L.; Murrall, N. W.; Welch, A. J.; Sharaiha, D.
M. J. Chem, Soc. D. 1984, 1157. For PdCl2 initiated disrotatory opening of
MCP in chloropalladation reactions, see: (h) Clemens, P. R.; Hughes, R.
P.; Martgerum, L. D. J. Am. Chem. Soc. 1981, 103, 2428. (i) Albright, T.
A.; Clemens, P. R.; Hughes, R. P.; Hunton, D. E.; Martgerum, L. D. J.
Am. Chem. Soc. 1982, 104, 5369. (j) Donaldson, W. A.; North, J. T.;
Gruetzmacher, J. A.; Finley, M. Tetrahedron 1990, 46, 2263. For a
theoretical calculation of Pd0 initiated [3 + 2] cycloaddition of methyl-
enecyclopropane with alkene, see: (k) Oishi, Y.; Sakamoto, E.; Fujimoto,
H. Inorg. Chem. 1996, 35, 231.
(11) (a) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(12) Lautens, M.; Ren, Y. J. Am. Chem. Soc., in press.

[3 + 2] Cycloadditions of Methylenecyclopropanes
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9601
Table 6. Deuterium Labeling Studies
Scheme 2
a P/Pd ) 2/1; typically 5-20 mol % of Pd2(dba)3 was used. See
experimental for details. b C7H15 refers to n-heptyl. c Ratio determined
by H and H NMR.
dition goes with overall retention of stereochemistry at C*
indicating that TMM intermediates are not involved in the
palladium catalyzed intramolecular cycloaddition with mono-
substituted methylenecyclopropanes.
We found that with MCPs bearing methyl substituents at the
angular position, insertion was followed by â-elimination to give
dienes with alkyne tether intact (entry 3, Table 3). Motherwell
also reported diene formation when methyl substituents were
present at the angular position6c which suggest the existence of
a distinct metallacyclobutane intermediate.
1
2
Scheme 3
Insertion into a methylenecyclopropane ring can be achieved
with a variety of different metals.18 It has been shown that
chloropalladation of MCP with a Pd2+ catalyst occurs with
retention of stereochemistry.19 Cross addition of platinum(II)
hydride over MCP has also been found to occur with retention
of configuration at the cyclopropane carbon.20
Ba¨ckvall’s theoretical study of the cyclopropane ring opening
by Pd0 and Pd2+ has shown that for Pd0 only the edge activation
has a low activation energy with a metallacyclobutane as the
resulting complex.21 The fate of the stereogenic carbon atom
in a carbon-palladium complex upon reaction with an alkyne
has been studied by Pfeffer who showed that retention of
configuration occurred with the carbopalladation.22 Since the
stereochemistry at C-2 is retained in the pathway leading to
the cycloadduct, a double retention pathway appears to be
operating in the MCP cycloaddition.
In order to probe the nature of the intermediate, we prepared
diastereomerically pure and/or deuterium labeled MCPs and
subjected them to the reaction conditions. Deuterated methyl-
enecyclopropane 28a was prepared using a samarium mediated
cyclopropanation of an allenic alcohol with CD2I2.23 Reaction
of 28a with Pd0 gave 29a and 30a with complete scrambling
of the label at the vinylic and allylic positions as determined
by 1H and 2H NMR (entry 1, Table 6). In our proposed
mechanism, either metallacyclobutane 20 or metallacyclohexane
21a can undergo interconversion between σ-allyl and π-allyl
species, which exchanges C-3 and C-4 prior to reductive
elimination to 22 (Scheme 1).
Two bulky substituents prefer to reside at C-4 of the exocyclic
double bond in the metallacyclobutane (20, Scheme 1) and
metallacyclohexane (21a, Scheme 1) rather than at C-3 in order
to avoid steric-congestion with the bulky palladium-ligand
complex.
When the reaction was run to 18% conversion, the recovered
starting material showed no scrambling of the label between
C-3 and C-4 but complete scrambling of label in the cycloadduct
(entry 2, Table 6). This is in contrast to studies by Noyori using
nickel catalysts where significant isomerization in the recovered
methylenecyclopropane was observed.2a,4e
From these results, information on the relative rates of the
various reaction processes in intramolecular palladium catalyzed
cycloadditions can be obtained. Since no scrambling is observed
in the recovered starting material, the insertion step must be
irreversible and rapidly followed by carbometallation. Since
complete scrambling is observed in the final product, the
scrambling event must be faster than the final reductive
elimination.
Reactions of the Cycloadducts. Selective 1,4-reduction of
the enoate generates two new stereocenters and a product
equivalent to the adduct from cycloaddition of an alkene. SmI2
reduction24 or an in situ generated copper hydride25 led to
decomposition, whereas the Stryker reagent26 smoothly reacted
with the enoate in high yield. The stereochemistry at angular
carbon was fully controlled, but almost no selectivity was seen
at the carbon bearing the ester (Scheme 3).
Interestingly, while scrambling of the carbon bearing the
deuterium label was complete, scrambling of alkyls was not
observed6d (entry 7, Table 2) which may be due to a steric effect.
Similarly a methyl cuprate also added to the enoate.27 The
intermediate ketenesilylacetal 33 was remarkably stable to an
aqueous workup and only decomposed to yield 34a and 34b
during column chromatography. A quaternary carbon center
(18) (a) Phillips, R. L.; Puddephatt, R. G. J. Chem. Soc. D. 1978, 1736.
(b) Larock, R. C.; Varaprath, S. J. Org. Chem. 1984, 49, 3432. (c) Balme,
G.; Fournet, G.; Gore, J. Tetrahedron Lett. 1986, 27, 3855. (d) Donaldson,
W. A.; Brodt, C. A. J. Organomet. Chem. 1987, 330, C33. (e) Fournet, G.;
Balme, G.; Gore, J. Tetrahedron 1988, 44, 5809. (f) Dallas, B. K.; Hughes,
R. P.; Schumann, K. J. Am. Chem. Soc. 1982, 104, 5380. (g) Hughes, R.
P.; Hunton, D. E.; Schumann, K. J. Organomet. Chem. 1980, 184, C67.
(h) Noyori, R.; Takaya, H. J. Chem. Soc., Chem. Commun. 1969, 77. Also
see: refs 13(b) and 17(a), (e), (g), (h), (i), and (j).
(19) Green, M.; Hughes, R. P. J. Chem. Soc. D. 1976, 1880.
(20) Attig, T. J. Organomet. Chem. 1978, 145, C13.
(21) Blomberg, M. R. A.; Siegbahn, P. E. M.; Ba¨ckvall, J.-E. J. Am.
Chem. Soc. 1987, 109, 4450 and references therein.
(22) Spencer J.; Pfeffer M. Tetrahedron: Asymmetry 1995, 6, 419.
(23) For the preparation of dideuteriodiiodomethane, see: Winstein, S.;
Friedrich, E. C.; Baker, R. and Lin, Y. Tetrahedron Suppl. 1966, 8, 621.
(24) Cabrera, A.; Alper, H. Tetrahedron Lett. 1992, 33, 5007.
(25) Semmelhack, M. F.; Stauffer, R. D.; Yamashita, A. J. Org. Chem.
1977, 42, 3180.
(26) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291. (b) Koenig, T. M.; Daeuble, J. F.; Brestensky, D. M.;
Stryker, J. M. Tetrahedron Lett. 1989, 30, 5677. (c) Daeuble, J. F.;
Brestensky, D. M.; Stryker, J. M.Tetrahedron Lett. 1990, 31, 2397. (d)
Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989, 111, 8818.
(27) (a) Linderman, R. J.; Godfrey, A.; Horne, K. Tetrahedron 1989,
45, 495. (b) Linderman, R. J.; McKenzie, J. R. J. Organomet. Chem. 1989,
361, 31.

9602 J. Am. Chem. Soc., Vol. 118, No. 40, 1996
Lautens and Ren
-78 °C for 1 h and then 2 h at room temperature. After an aqueous
workup, flash column chromatography (2% ethyl acetate in hexanes)
yielded the pure product.
was created with complete stereochemical control, and good
selectivity was also observed in the protonation step in contrast
to the results described previously (eq 4). The stereochemistry
of the major product 34a was determined by NOE which showed
that H1 and H2 were cis and H3 and H4 were on the same side
as the newly introduced methyl group.
General Procedure for the Cycloaddition using Pd0. Procedure
A: Pd2(dba)3/P(OiPr)3. A flame-dried round bottomed flask, equipped
with a condenser was charged with Pd2(dba)3 and P(OiPr)3 (P/Pd )
2/1 in mol ratio). Toluene (desulfurized and freshly distilled over
sodium) was introduced via a cannula followed by a solution of the
substrate in toluene. The mixture was heated to 110 °C and stirred
vigorously until the reaction was complete. Toluene was removed under
vacuum and the crude mixture was purified by column chromatography.
Elution of dibenzylideneacetone (dba) with toluene was followed by
further elution using a mixture of ethyl acetate in hexanes to give the
pure cycloadduct.
Procedure B: Pd2(dba)3/P(OiPr)3/MS 4 Å. Identical to procedure
A except 8-10 equiv (by weight vs Pd2(dba)3) of 4Å molecular sieves
were added to the reaction flask containing Pd2(dba)3 and P(OiPr)3.
Procedure C: Pd(PPh3)4. Identical to procedure A except Pd-
(PPh3)4 was added to the reaction flask instead of Pd2(dba)3 and
P(OiPr)3.
Selective epoxidation of the corresponding allylic alcohol 14d
was also possible using VO(acac)2/t-BuOOH (eq 5).28
cis-1-Cyclohexyl-6-methylene-3,5,6,6a-tetrahydro-1H-cyclopenta-
[c]furan-4-carboxylic Acid Methyl Ester (11a). The cycloaddition
was carried out as in general procedure A using 3a (30 mg, 0.11 mmol)
in toluene (25 mL) with Pd2(dba)3 (1.9 mg, 0.0021 mmol, 3.6 mol %
of Pd0) and P(OiPr)3 (2.0 µL, 0.0081 mmol, 7.4 mol %). The yellow-
brown reaction mixture was stirred at 110 °C for 1 h. The crude product
was purified by flash column chromatography (using 2% ethyl acetate
in hexanes as eluent) to afford 11a (22.6 mg, 75%) as a colorless oil.
IR (cm-1, neat) 2935, 2870, 1724, 1442; 1H NMR (400 MHz, CDCl3)
δ 4.93 (1H, m), 4.84 (1H, m), 4.56 (1H, ddd, J ) 15.7, 4.4, 1.8 Hz),
4.40 (1H, dddd, J ) 15.7, 4.4, 1.8, 1.8 Hz), 3.74 (1H, br d, J ) 9.2
Hz), 3.71 (3H, s), 3.65 (1H, ddd, J ) 19.2, 4.2, 2.5 Hz), 3.44-3.49
(2H, m), 1.87 (1H, dd, J ) 12.8, 1.8 Hz), 1.76 (2H, m), 1.69 (2H, t, J
) 12.1 Hz), 1.54 (1H, m), 1.09-1.28 (5H, m); 13C NMR (100 MHz,
CDCl3) δ 164.6, 164.1, 147.5, 122.7, 108.7, 84.7, 65.1, 57.8, 51.5, 44.4,
41.9, 30.2, 27.9, 26.6, 26.5, 26.2; HRMS calcd for C16H22O3 262.1569,
found 262.1567.
Summary
We have shown that palladium catalyzed intramolecular
cycloaddition of diastereomerically pure methylenecyclopro-
panes is stereospecific and occurs with retention of configuration
at the bond undergoing reaction. The reaction occurs in a
stepwise fashion, and metallacycles are likely intermediates. We
reacted deuterium labeled substrates and showed that insertion
into the methylenecyclopropanes is irreversible. Three different
types of palladium catalysts are found to facilitate the cycload-
dition. We have explored the scope of the reaction and found
that a wide range of substitution patterns in and around the
reactive centers are tolerated. The stereospecificity does not
seem to be affected by these changes. A few reactions of the
cycloadduct have also been briefly investigated.
cis-(1-Cyclohexyl-6-methylene-3,5,6,6a-tetrahydro-1H-cyclopen-
ta[c]furan-4-yl)methanol (11b). The cycloaddition was carried out
as in general procedure A using 3b (40 mg, 0.17 mmol) in toluene (40
mL) with Pd2(dba)3 (15.6 mg, 0.017 mmol, 20.0 mol % of Pd0) and
P(OiPr)3 (17 µL, 0.068 mmol, 40 mol %). The yellow-brown reaction
mixture was stirred at 110 °C for 4 h. The crude product was purified
by flash column chromatography (using 5% ethyl acetate in hexanes
as eluent) to afford 11b (34 mg, 85%) as a colorless oil. IR (cm-1
,
Experimental Section
1
neat) 3400, 2940, 2872, 1718, 1659, 1456, 1012, 890, 738; H NMR
(400 MHz, CDCl3) δ 4.90 (1H, dd, J ) 3.7, 2.6 Hz), 4.82 (1H, dd, J
) 4.1, 2.3 Hz), 4.36 (1H, d, J ) 12.1 Hz), 4.12-4.22 (3H, m), 3.55-
3.60 (1H, m), 3.51 (1H, br d, J ) 19.0 Hz), 3.38 (1H, dd, J ) 8.4, 5.1
Hz), 3.19 (1H, d, J ) 19.0 Hz), 1.88 (1H, br d, J ) 12.8 Hz), 1.77
(2H, br d, J ) 10.6 Hz), 1.69 (2H, br t, J ) 13.4 Hz), 1.46-1.56 (1H,
m), 1.06-1.30 (5H, m); 13C NMR (100 MHz, CDCl3) d 149.5, 143.4,
130.9, 107.7, 85.0, 63.1, 60.4, 56.3, 45.2, 42.3, 30.1, 28.2, 26.60, 26.59,
26.3; HRMS calcd for C15H22O2 234.3414, found 234.3417.
The following includes general experimental procedures, specific
details for representative reactions, and isolation and spectroscopic
information for the compounds prepared.
General Procedure for the Propargylation. Potassium hydride
(35 wt.% dispersion in mineral oil) was weighed in a flame-dried round
bottomed flask and washed three times with dry pentane. The pentane
residue was removed by blowing dry nitrogen through the flask for 5
min and the dry potassium hydride was weighed again. Dry THF was
then added, and the solution was cooled to 0 °C. A solution of the
methylenecyclopropane carbinol and a catalytic amount of 18-C-6 in
THF were added slowly at 0 °C. The reaction mixture was stirred at
0 °C for 60 min prior to addition of propargyl bromide (80 wt %
solution in toluene) at 0 °C. The reaction mixture was stirred at 0 °C
for 1 h and at room temperature for another 2 h. The reaction was
quenched by the addition of water. After a regular aqueous workup,
the organic layer was dried over anhydrous MgSO4. Purification by
flash column chromatography, eluting with 2% ethyl acetate in hexanes
provided the methylenecyclopropane carbinol propargyl ether.
General Procedure for the Carbomethoxylation. The propargyl
ether was dissolved in THF and stirred at -78 °C. n-BuLi (2.5 M
solution in hexane) was added slowly at -78 °C, and the resulting
brown solution was stirred at -78 °C for 60 min. Methyl chloroformate
was added at -78 °C, and the orange-brown solution was stirred at
Cycloadduct 11b was also prepared via the following procedure.
DIBAL-H (0.6 mL, 1 M solution in hexane, 0.6 mmol) was added
dropwise to a solution of 11a (40 mg, 0.15 mmol) in THF (1 mL) at
-78 °C. The mixture was stirred at -78 °C for 1 h until TLC showed
the reaction was complete. After an aqueous workup and drying of
the organic layer over anhydrous MgSO4, flash column chromatography
(30% EtOAc in hexane) gave 11b (35.5 mg, 99%) as a colorless oil.
Synthesis of Cycloadduct 11c. The cycloaddition was carried out
as in general procedure A using 3c (24 mg, 0.069 mmol) in toluene
(15 mL) with Pd2(dba)3 (4.4 mg, 0.0048 mmol, 14.0 mol % of Pd0)
and P(OiPr)3 (4.8 µL, 0.019 mmol, 28.0 mol %). The yellow-brown
reaction mixture was stirred at 110 °C for 12 h. The crude product
was purified by flash column chromatography (using 1% ethyl acetate
in hexanes as eluent) to afford 11c (24 mg, 100%) as a colorless oil.
1
IR (cm-1, neat) 2945, 2870, 1662, 1466, 1380, 1260, 1093, 840; H
NMR (400 MHz, CDCl3) δ 4.87 (1H, d, J ) 1.1 Hz), 4.80 (1H, d, J )
1.5 Hz), 4.40 (1H, d, J ) 12.5 Hz), 4.18 (1H, s), 4.17 (1H, s), 4.15
(1H, ddd, J ) 12.5, 4.0, 1.8 Hz), 3.50-3.57 (1H, m), 3.44 (1H, br d,
(28) (a) Sharpless K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973,
95, 6136. (b) Mihelich, E. D. Tetrahedron Lett. 1979, 20, 4729. (c) Rossiter,
B. E.; Verhoeven, T. R.; Sharpless K. B. Tetrahedron Lett. 1979, 20, 4733.

[3 + 2] Cycloadditions of Methylenecyclopropanes
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9603
J ) 19.1 Hz), 3.36 (1H, dd, J ) 8.4, 5.1 Hz), 3.10 (1H, d, J ) 19.1
Hz), 1.88 (1H, br d, J ) 11.7 Hz), 1.77 (2H, br d, J ) 11.0 Hz), 1.68
(2H, br t, J ) 13.9 Hz), 1.44-1.54 (1H, m), 1.04-1.30 (5H, m), 0.87
(9H, s); 13C NMR (100 MHz, CDCl3) δ 149.8, 141.7, 131.0, 107.3,
84.8, 63.6, 61.2, 56.3, 45.2, 42.3, 30.3, 28.2, 26.64, 26.62, 26.3, 25.9,
18.3, -5.39, -5.43; HRMS calcd for C21H36O2Si 348.2484, found
348.2468.
toluene (15 mL) with Pd2(dba)3 (8.3 mg, 0.0091 mmol, 23 mol % of
Pd0) and P(OiPr)3 (5.7 µL, 0.023 mmol, 29 mol %). The yellow-brown
reaction mixture was stirred at 110 °C for 1.5 h. The crude product
was purified by flash column chromatography (using 2% ethyl acetate
in hexanes as eluent) to afford 13 (15.6 mg, 71%) as a colorless oil.
1
IR (cm-1, neat) 2932, 2854, 1722, 1685, 1439, 1246, 1114; H NMR
(400 MHz, CDCl3) δ 4.95 (1H, dd, J ) 3.7, 2.2 Hz), 4.86 (1H, dd, J
) 4.4, 2.2 Hz), 4.55 (1H, ddd, J ) 16.0, 4.4, 2.0 Hz), 4.46 (1H, dddd,
J ) 16.0, 4.0, 1.8, 1.8 Hz), 3.72 (3H, s), 3.45-3.73 (4H, m), 1.71-
1.81 (1H, m), 1.59-1.69 (1H, m), 1.46-1.56 (1H, m), 1.36-1.46 (1H,
m), 1.20-1.36 (8H, m), 0.86 (3H, t, J ) 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 164.7, 164.1, 146.4, 122.7, 108.4, 80.7, 65.4, 60.9, 51.5, 44.3,
35.2, 31.8, 29.7, 29.2, 26.1, 22.6, 14.1; HRMS calcd for C17H26O3
278.1882, found 278.1880.
cis-1-(1-Cyclohexyl-6-methylene-3,5,6,6a-tetrahydro-1H-cyclopenta-
[c]furan-4-yl)ethanone (11e). The cycloaddition was carried out as
in general procedure C using 3e (47 mg, 0.19 mmol) in toluene (30
mL) with Pd(PPh3)4 (25 mg, 0.022 mmol, 11 mol % of Pd0). The
yellow solution was stirred at 110 °C for 1.5 h. After removing the
toluene, the crude product was purified by flash column chromatography
(using 1-2% ethyl acetate in hexanes as eluent) to afford 11e (43 mg,
92%) as a colorless oil. IR (cm-1, neat) 3411, 2926, 2856, 1735, 1668,
trans-1-Heptyl-6-methylene-3,5,6,6a-tetrahydro-1H-cyclopenta-
[c]furan-4-carboxylic Acid Methyl Ester (14a). The cycloaddition
was carried out as in general procedure A using 6a (42 mg, 0.015 mmol)
in toluene (20 mL) with Pd2(dba)3 (9.68 mg, 0.011 mmol, 14.0 mol %
of Pd0) and P(OiPr)3 (10.4 µL, 0.042 mmol, 28.0 mol %). The yellow-
brown reaction mixture was stirred at 110 °C for 1 h. After the workup,
the crude product was purified by flash column chromatography (using
2% ethyl acetate in hexanes as eluent) to afford 14a (29.5 mg, 70%)
as a colorless oil. IR (cm-1, neat) 2928, 2860, 1722, 1680, 1436, 1354,
1
1450, 1367, 1240, 1023; H NMR (400 MHz, CDCl3) δ 4.93 (1H, dt,
J ) 4.1, 1.4 Hz), 4.84 (1H, dt, J ) 3.7, 1.4 Hz), 4.57 (1H, ddd, J )
15.8, 4.8, 1.8 Hz), 4.48 (1H, dquint, J ) 15.8, 1.8 Hz), 3.80 (1H, dquint,
J ) 9.2, 2.2 Hz), 3.65 (1H, ddt, J ) 19.0, 6.6, 2.5 Hz), 3.45-3.54
(2H, m), 2.19 (3H, s), 1.87 (1H, br d, J ) 12.4 Hz), 1.62-1.83 (4H,
m), 1.50-1.60 (1H, m), 1.08-1.34 (5H, m); 13C NMR (100 MHz,
CDCl3) δ 194.8, 163.0, 147.1, 131.6, 108.5, 84.4, 65.4, 58.6, 44.6, 41.8,
30.2, 29.7, 28.9, 27.8, 26.5, 26.4, 26.2; HRMS calcd for C16H22O2
246.1620 , found 246.1621.
1
1332, 1248, 1114, 1014; H NMR (400 MHz, CDCl3) δ 5.07 (1H, d,
J ) 2.2 Hz), 4.83 (1H, d, J ) 2.2 Hz), 4.51 (1H, dd, J ) 16.1, 1.8
Hz), 4.38 (1H, ddd, J ) 16.1, 1.8, 1.8 Hz), 4.21 (1H, d, J ) 1.5 Hz),
4.20 (1H, d, J ) 1.1 Hz), 3.72 (3H, s), 3.69 (1H, ddd, J ) 20.5, 3.8,
2.7 Hz), 3.54 (1H, ddd, J ) 20.5, 2.2, 1.8 Hz), 1.33-1.50 (2H, m),
1.24 (9H, br s), 1.06 (1H, br s), 0.85 (3H, t, J ) 6.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 164.6, 163.1, 144.6, 123.1, 110.5, 77.6, 63.6,
60.7, 51.5, 44.6, 31.8, 29.5, 29.32, 29.27, 25.8, 22.7, 14.1; HRMS calcd
for C17H26O3 278.1882, found 278.1890.
cis-3-Cyclohexyl-4-methylene-6-trimethylsilanyl-3,3a,4,5-tetrahy-
dro-1H-cyclopenta[c]furan (11f). The cycloaddition was carried out
as in general procedure C using 3f (50 mg, 0.18 mmol) in toluene (30
mL) with Pd(PPh3)4 (150 mg, 0.13 mmol, 72 mol % of Pd0) added
portionwise over 12 h. The yellow solution was stirred at 110 °C for
24 h. After removing of the toluene, the crude product was purified
by flash column chromatography (using 10-30% toluene in hexanes
as eluent) to afford 11f (23 mg, 46%) as a colorless oil. IR (cm-1
,
1
neat) 2926, 2855, 1723, 1663, 1452, 1250, 1026, 838; H NMR (400
MHz, CDCl3) δ 4.84 (1H, s), 4.77 (1H, s), 4.22 (2H, br s), 3.56 (1H,
br d, J ) 8.8 Hz), 3.51 (1H, ddd, J ) 18.7, 3.6, 2.5 Hz), 3.39 (1H, dd,
J ) 8.8, 5.5 Hz), 3.22 (1H, dt, J ) 18.7, 1.5 Hz), 1.89 (1H, br d, J )
12.4 Hz), 1.60-1.82 (5H, m), 1.00-1.30 (5H, m), 0.067 (9H, s); 13C
NMR (100 MHz, CDCl3) δ 131.3, 127.8, 125.5, 106.2, 84.8, 64.7, 57.9,
49.2, 42.5, 30.1, 28.3, 26.64, 26.63, 26.3, -1.3 (3C); HRMS calcd for
C17H28OSi 276.1909, found 276.1912.
cis-1-Cyclohexyl-3,5,6,6a-tetrahydro-6-methylene-1H-cyclopenta-
[c]furan-4-methanol 3′,5′-Dinitrobenzote (11h). 3,5-Dinitrobenzoic
acid (43.5 mg, 0.21 mmol), 1,3-dicyclohexylcarbodiimide (DCC) (53
mg, 0.26 mmol), and 4-dimethylaminopyridine (DMAP) (4 mg, 0.033
mmol) were added to a solution of alcohol 11b (40 mg, 0.17 mmol) in
CH2Cl2 (2 mL). The yellow-brown solution was stirred at room
temperature for 1 h until TLC indicated the reaction was complete.
After an aqueous workup and drying of the organic layer over anhydrous
MgSO4, flash column chromatography (5% EtOAc in hexane) gave
11h (68 mg, 93%) as a white solid. White crystalline needles were
grown in a test tube from a 1:1 mixture of dichloromethane-pentane
in a sealed container in the presence of water at 4 °C.
trans-6-(tert-Butyldimethylsilanyl)-3-heptyl-4-methylene-3,3a,4,5-
tetrahydro-1H-cyclopenta[c]furan (14b). The cycloaddition was
carried out as in general procedure B using 6b (30 mg, 0.090 mmol)
in toluene (30 mL) with portionwise addition of Pd2(dba)3 (40 mg, 0.044
mmol, 98 mol % of Pd0), P(OiPr)3 (0.045 µL, 0.18 mmol), and MS 4Å
(200 mg). The yellow-brown reaction mixture was stirred at 110 °C
for 12 h. After removal of the toluene, the crude product was purified
by flash column chromatography (using 5-10% toluene in hexanes as
eluent) to afford 14b (11.8 mg, 40%) as a colorless oil. IR (cm-1
,
neat) 2932, 2861, 1655, 1467, 1250, 1019, 976, 890, 837, 773; 1H NMR
(400 MHz, CDCl3) δ 4.98 (1H, br d, J ) 2.2 Hz), 4.76 (1H, br d, J )
2.3 Hz), 4.18 (2H, br s), 4.12 (1H, dt, J ) 2.4, 8.1 Hz), 4.04 (1H, br
d, J ) 7.7 Hz), 3.59 (1H, ddt, J ) 20.1, 6.4, 2.7 Hz), 3.36 (1H, dt, J
) 20.2, 1.8 Hz), 0.95-1.46 (15H, m), 0.87 (9H, s), 0.038 (3H, s),
0.034 (3H, s); 13C NMR (100 MHz, CDCl3) δ 159.1, 148.4, 130.0,
107.9, 77.2, 63.6, 60.8, 51.3, 31.9, 29.75, 29.69, 29.3, 26.7 (3C), 25.8,
22.7, 17.8, 14.2, -5.4, -5.8; HRMS calcd for C21H38OSi 334.2692,
found 334.2680.
trans-6-(Dimethylphenylsilanyl)-3-heptyl-4-methylene-3,3a,4,5-
tetrahydro-1H-cyclopenta[c]furan (14c). The cycloaddition was
carried out as in general procedure C using 6c (48 mg, 0.14 mmol) in
toluene (30 mL) with Pd(PPh3)4 (130 mg, 0.11 mmol, 78 mol % of
Pd0) added portion wise over 12 h. The yellow solution was stirred at
110 °C for 24 h. After removal of the toluene, the crude product was
purified by flash column chromatography (using 10-20% toluene in
hexanes as eluent) to afford 14c (19 mg, 40%) as a colorless oil. IR
(cm-1, neat) 3073, 2961, 2929, 2854, 1661, 1640, 1463, 1426, 1249,
trans-1-Cyclohexyl-6-methylene-3,5,6,6a-tetrahydro-1H-cyclopen-
ta[c]furan-4-carboxylic Acid Methyl Ester (12). The cycloaddition
was carried out as in general procedure A using 4 (40 mg, 0.15 mmol)
in toluene (30 mL) with Pd2(dba)3 (7 mg, 0.0076 mmol, 10.0 mol %
of Pd0) and P(OiPr)3 (7.5 µL, 0.030 mmol, 20 mol %). The yellow-
brown reaction mixture was stirred at 110 °C for 1 h. The crude product
was purified by flash column chromatography (using 2% ethyl acetate
in hexanes as eluent) to afford 12 (28.6 mg, 72%) as a colorless oil.
1
1110, 1014, 886, 832, 816, 773, 698; H NMR (400 MHz, CDCl3) δ
1
IR (cm-1, neat) 2927, 2852, 1715, 1435, 1243, 1119; H NMR (400
7.45-7.48 (2H, m), 7.28-7.36 (3H, m), 4.97 (1H, br d, J ) 2.2 Hz),
4.78 (1H, dd, J ) 2.6, 1.8 Hz), 4.03-4.15 (3H, m), 3.98 (1H, br d, J
) 14.3 Hz), 0.96-1.44 (12H, m), 0.86 (3H, t, J ) 6.8 Hz), 0.35 (3H,
s), 0.34 (3H, s); 13C NMR (100 MHz, CDCl3) δ 159.5, 148.2, 137.7,
133.6 (2C), 129.8, 129.1, 127.8 (2C), 108.3, 77.6, 63.1, 61.0, 49.9,
31.9, 29.7 (2C), 29.3, 25.8, 22.7, 14.2, -2.4, -2.8; HRMS calcd for
C23H33OSi (M - H+) 353.2301, found 353.2288.
Synthesis of Cycloadduct 15. The cycloaddition was carried out
as in general procedure A using 7 (12.5 mg, 0.05 mmol) in toluene
(15 mL) with Pd2(dba)3 (2.8 mg, 0.0031 mmol, 12.0 mol % of Pd0)
and P(OiPr)3 (2.5 µL, 0.01 mmol, 20.1 mol %). The yellow-brown
reaction mixture was stirred at 110 °C for 2h. The crude product was
MHz, CDCl3) δ 5.10 (1H, dd, J ) 5.1, 2.5 Hz), 4.93 (1H, dd, J ) 5.1,
2.5 Hz), 4.60 (1H, ddd, J ) 15.7, 4.0, 1.8 Hz), 4.39 (1H, dddd, J )
15.7, 3.6, 2.2, 2.2 Hz), 4.25 (1H, br d, J ) 9.2 Hz), 4.06 (1H, dd, J )
9.2, 3.0 Hz), 3.73 (1H, br d, J ) 20.5 Hz), 3.72 (3H, s), 3.62 (1H, ddd,
J ) 20.5, 1.8, 1.8 Hz), 1.70 (1H, dd, J ) 12.4, 2.2 Hz), 1.46-1.66
(4H, m), 0.84-1.38 (6H, m); 13C NMR (100 MHz, CDCl3) δ 164.6,
163.7, 144.6, 121.5, 110.3, 81.6, 65.7, 59.7, 51.6, 44.5, 39.9, 31.0, 26.8,
26.5, 26.2, 26.0; HRMS calcd for C16H22O3 262.1569, found 262.1562.
cis-1-Heptyl-6-methylene-3,5,6,6a-tetrahydro-1H-cyclopenta-
[c]furan-4-carboxylic Acid Methyl Ester (13). The cycloaddition was
carried out as in general procedure A using 5 (22 mg, 0.079 mmol) in

9604 J. Am. Chem. Soc., Vol. 118, No. 40, 1996
Lautens and Ren
purified by flash column chromatography (using 1% ethyl acetate in
hexanes as eluent) to afford 15 (8.5 mg, 68%) as a colorless oil. IR
(cm-1, neat) 2933, 2862, 1716, 1682, 1439, 1241, 1111, 1006, 891,
Hz), 3.24 (1H, d, J ) 8.9 Hz), 3.16 (1H, d, J ) 18.9 Hz), 2.06 (1H, br
d, J ) 12.8 Hz), 1.69-1.84 (2H, m), 1.60-1.69 (1H, m), 1.40-1.58
(1H, m), 1.10-1.34 (3H, m), 1.16 (3H, s), 0.93-1.09 (2H, m), 0.80-
0.92 (1H, m); 13C NMR (100 MHz, CDCl3) δ 153.7, 148.7, 128.8,
108.0, 86.7, 61.6, 60.4, 60.0, 44.1, 39.6, 31.0, 30.6, 26.5, 26.2, 26.0,
18.5.
1
770; H NMR (500 MHz, CDCl3) δ 5.07 (1H, dd, J ) 4.9, 2.5 Hz),
4.93 (1H, dd, J ) 4.9, 2.5 Hz), 4.52 (1H, ddd, J ) 16.1, 4.4, 2.0 Hz),
4.43 (1H, ddt, J ) 16.1, 3.9, 2.0 Hz), 3.74 (3H, s), 3.70 (1H, br d, J
) 2.5 Hz), 3.68 (1H, ddd, J ) 20.0, 3.9, 2.9 Hz), 3.53 (1H, dt, 20.0,
2.0 Hz), 1.80 (1H, br d, J ) 12.2 Hz), 1.60-1.74 (3H, m), 1.48-1.59
(1H, m), 1.22-1.36 (3H, m), 1.10-1.20 (1H, m), 0.88 (1H, t, J ) 7.1
Hz); 13C NMR (100 MHz, CDCl3) δ 164.6, 164.2, 144.8, 123.0, 109.1,
81.3, 66.0, 63.3, 51.5, 44.5, 37.6, 28.1, 25.7, 22.9, 21.4; HRMS calcd
for C15H19O3 (M-H+) 247.1334, found 247.1330.
(R*,S*)-4-[1-(3-Methylenecyclopropyl-2,2-d2)-octyloxy]but-2-yno-
ic Acid Methyl Ester (28a). The carbomethoxylation was carried out
as in the general procedure. n-BuLi (2.5 M solution in hexane, 0.18
mL, 0.45 mmol) was added to the propargyl ether (90 mg, 0.40 mmol)
in THF (2 mL), followed by methyl chloroformate (0.062 mL, 0.81
mmol) to give 28a (92 mg, 81%) as a colorless oil. IR (cm-1, neat)
2955, 2925, 2857, 2242, 1720, 1433, 1381, 1255, 1090, 1057, 892,
cis-1-Cyclohexyl-6-(1-propylbutylidene)-3,5,6,6a-tetrahydro-1H-
cyclopenta[c]furan-4-carboxylic Acid Methyl Ester (16). The cy-
cloaddition was carried out as in general procedure A using 8 (30 mg,
0.087 mmol) in toluene (20 mL) with Pd2(dba)3 (5.50 mg, 0.0061 mmol,
14.0 mol % of Pd0) and P(OiPr)3 (6.0 µL, 0.024 mmol, 28.0 mol %).
The yellow-brown reaction mixture was stirred at 110 °C for 1.5 h.
The crude product was purified by flash column chromatography (using
2% ethyl acetate in hexanes as eluent) to afford 16 (17.4 mg, 58%) as
a colorless oil. IR (cm-1, neat) 2923, 2863, 1723, 1600, 1455, 1432,
1
751; H NMR (400 MHz, CDCl3) δ 5.47 (2H, m), 4.43 (1H, d, J )
16.7 Hz), 4.35 (1H, d, J ) 16.7 Hz), 3.77 (3H, s), 2.96 (1H, dt, J )
8.4, 6.2 Hz), 1.60-1.66 (2H, m), 1.44-1.54 (2H, m), 1.34-1.44 (1H,
2
m), 1.28 (8H, br s), 0.88 (3H, t, J ) 6.7 Hz); H NMR (61 MHz,
CHCl3) δ 1.26 (1D, s), 0.81 (1D, s); 13C NMR (100 MHz, CDCl3) δ
153.6, 133.5, 104.6, 84.7, 82.0, 77.1, 55.8, 52.7, 35.0, 31.8, 29.6, 29.3,
25.5, 22.7, 19.1, 14.1, 6.5 (m); HRMS calcd for C17H25D2O3 281.2086
(MH+), found 281.2082.
1
trans-1-Heptyl-6-methylene-3,5,6,6a-tetrahydro-5-d-1H-cyclopen-
ta[c]furan-5-d-4-carboxylic Acid Methyl Ester (29a) and trans-1-
Heptyl-6-(methylene-d2)-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-
4-carboxylic Acid Methyl Ester (30a). The cycloaddition was carried
out as in general procedure A using 28a (54 mg, 0.193 mmol) in toluene
(30 mL) with Pd2(dba)3 (8.80 mg, 0.0096 mmol, 10 mol % of Pd0) and
P(OiPr)3 (9.4 µL, 0.038 mmol, 20.0 mol %). The yellow-brown
reaction mixture was stirred at 110 °C for 7 h. The crude product was
purified by flash column chromatography (using 2% ethyl acetate in
hexanes as eluent) to afford a 1:1 mixture of 29a and 30a (39.1 mg,
72% combined yield) as a colorless oil. IR (cm-1, neat) 2955, 2927,
2860, 1722, 1683, 1458, 1437, 1352, 1328, 1277, 1245, 1203, 1164,
1243, 1121; H NMR (400 MHz, CDCl3) δ 4.60 (1H, dd, J ) 13.9,
1.5 Hz), 4.26 (1H, ddt, J ) 13.9, 4.4, 1.5 Hz), 3.89 (1H, br d, J ) 9.5
Hz), 3.73 (3H, s), 3.52 (2H, s), 3.39 (1H, dd, J ) 9.5, 1.5 Hz), 1.14-
2.00 (20H, m), 0.84-0.94 (5H, m); 13C NMR (100 MHz, CDCl3) δ
165.2, 162.9, 137.5, 129.0, 124.2, 84.6, 64.3, 55.2, 51.4, 41.4, 39.9,
35.4, 34.6, 31.7, 27.0, 26.5, 26.3, 24.6, 21.8, 20.8, 14.2, 14.1; HRMS
calcd for C22H34O3 346.2508, found 346.2491.
cis-1-Cyclohexyl-6a-methoxy-6-methylene-3,5,6,6a-tetrahydro-
1H-cyclopenta[c]furan-4-carboxylic Acid Methyl Ester (17). The
cycloaddition was carried out as in general procedure A using 9 (40
mg, 0.14 mmol) in toluene (30 mL) with Pd2(dba)3 (8.78 mg, 0.0096
mmol, 14.0 mol % of Pd0) and P(OiPr)3 (9.5 µL, 0.038 mmol, 28.0
mol %). The yellow-brown reaction mixture was stirred at 80 °C for
12 h. The crude product was purified by flash column chromatography
(using 2% ethyl acetate in hexanes as eluent) to afford 17 (30.0 mg,
1
1116, 1012, 901, 762, 710; H NMR (400 MHz, CDCl3) δ 5.08 (1H,
d, J ) 2.6 Hz), 4.84 (1H, d, J ) 1.8 Hz), 4.51 (2H, d, J ) 15.9 Hz),
4.38 (2H, d, J ) 15.9 Hz), 4.22 (2H, s), 4.20 (2H, s), 3.72 (6H, s),
3.69 (1H, ddd, J ) 20.3, 3.7, 2.5 Hz), 3.54 (1H, dt, J ) 20.3, 2.0 Hz),
1.33-1.50 (4H, m), 1.24 (18H, br s), 1.06 (2H, br s), 0.85 (6H, t, J )
6.8 Hz); 2H NMR (61 MHz, CHCl3) δ 5.10 (1D, s), 4.86 (1D, s), 3.68
(1D, s), 3.54 (1D, s); 13C NMR (100 MHz, CDCl3) δ 164.58, 164.56,
163.29, 163.16, 144.52, 144.39, 123.11, 123.00, 110.53, 110.48, 109.9
(m), 77.59, 63.54, 60.67, 60.61, 51.53, 44.50, 44.0 (m), 31.83, 29.52,
29.32, 29.24, 25.78, 22.66, 14.12; HRMS calcd for C17H24D2O3
280.2007, found 280.2001.
1
75%) as a colorless oil. IR (cm-1, neat) 2930, 2862, 1726, 1448; H
NMR (400 MHz, CDCl3) δ 5.39 (2H, m), 4.59 (1H, ddd, J ) 14.6,
2.2, 1.8 Hz), 4.39 (1H, ddd, J ) 14.6, 4.0, 2.9 Hz), 3.76 (3H, s), 3.55
(1H, ddd, J ) 20.5, 4.0, 2.2 Hz), 3.48 (1H, ddd, J ) 20.5, 2.6, 1.8
Hz), 3.34 (1H, d, J ) 7.7 Hz), 3.16 (3H, s), 2.07 (1H, br d, J ) 13.2
Hz), 1.82-1.96 (2H, m), 1.71 (2H, br d, J ) 13.2 Hz), 1.64 (1H, br d,
J ) 12.1 Hz), 0.98-1.31 (5H, m); 13C NMR (100 MHz, CDCl3) δ
164.5, 159.6, 143.3, 127.2, 115.8, 94.4, 86.7, 63.5, 51.9, 51.3, 42.9,
38.2, 30.5, 30.4, 26.5, 26.2, 26.1; HRMS calcd for C17H25O4 (MH+)
293.1753, found 293.1762.
Incomplete Cycloaddition of 28a. The cycloaddition was carried
out as in general procedure A using 28a (50 mg, 0.18 mmol) in toluene
(25 mL) with Pd2(dba)3 (4.9 mg, 0.0054 mmol, 6 mol % of Pd0) and
P(OiPr)3 (5.3 µL, 0.021 mmol, 12 mol %). The yellow-brown reaction
mixture was stirred at 110 °C for 50 min. The crude product was
purified by flash column chromatography (using 2% ethyl acetate in
hexanes as eluent) to afford starting material 28a (39 mg, 78%) and
cycloadducts 29a and 30a (8.8 mg, 18%). 2H NMR of the mixture of
29a and 30a indicated complete scrambling between C-1 and C-3,
cis-1-Cyclohexyl-6a-methyl-6-methylene-3,5,6,6a-tetrahydro-1H-
cyclopenta[c]furan-4-carboxylic Acid Methyl Ester (18). The cy-
cloaddition was carried out as in general procedure C using 10 (30
mg, 0.11 mmol) in toluene (30 mL) with Pd(PPh3)4 (15 mg, 0.013
mmol, 12 mol % of Pd0). The yellow solution was stirred at 110 °C
for 4 h. The crude product was purified by flash column chromatog-
raphy (using 0-2% EtOAc in toluene as eluent) to afford 18 (13 mg,
43%) as a colorless oil. IR (cm-1, neat) 2924, 2855, 1720, 1693, 1444,
2
whereas H NMR of 28a showed no scrambling of deuterium in the
recovered starting material.
1
1348, 1333, 1237, 1115, 1020, 887; H NMR (400 MHz, CDCl3) δ
(R*,S*)-1-Methylene-2-[1-(3-trimethylsilanylprop-2-ynyloxy)oc-
tyl]-3,3-d2-cyclopropane (28b). The deprotonation was carried out
as described in the general procedure for carbomethoxylation. Freshly
distilled TMSCl (0.1 mL, 0.79 mmol) was added to a solution of the
alkyne (65 mg, 0.29 mmol) and MeLi (1.4 M solution in ether, 0.22
mL, 0.31 mmol) at -78 °C. The resulting mixture was stirred at -78
°C for 1 h and room temperature for 2 h. Aqueous workup and column
chromatography gave compound 28b (80 mg, 93%). IR (cm-1, neat)
3071, 2958, 2928, 2856, 2173, 1462, 1378, 1346, 1251, 1084, 994,
4.92 (1H, dd, J ) 2.6, 1.1 Hz), 4.90 (1H, dd, J ) 2.2, 1.1 Hz), 4.51
(1H, ddd, J ) 16.5, 2.9, 1.8 Hz), 4.43 (1H, ddd, J ) 16.5, 4.2, 2.0
Hz), 3.73 (1H, br d, J ) 19.0 Hz), 3.71 (3H, s), 3.41 (1H, br d, J )
19.0 Hz), 3.33 (1H, d, J ) 3.3 Hz), 2.08 (1H, br d, J ) 14.6 Hz),
1.40-1.80 (2H, m), 1.22 (3H, s), 0.98-1.36 (3H, m), 0.80-0.90 (5H,
m); 13C NMR (100 MHz, CDCl3) δ 169.5, 165.0, 152.3, 120.8, 108.8,
86.5, 63.8, 61.8, 51.6, 43.2, 39.3, 31.0, 30.6, 26.5, 26.2, 26.0, 18.4;
HRMS calcd for C17H24O3 276.1725, found 276.1731.
1
cis-(1-Cyclohexyl-6a-methyl-6-methylene-3,5,6,6a-tetrahydro-1H-
cyclopenta[c]furan-4-yl)methanol (18a). 18 was then reduced to the
corresponding alcohols 18a by treating with Dabal-H in THF at -78
°C. For compounds 18a: IR (cm-1, neat) 3387, 2923, 2852, 1657,
1448, 1376, 1043, 1007, 887, 737; 1H NMR (400 MHz, CDCl3) δ 4.91
(1H, dd, J ) 2.7, 1.5 Hz), 4.88 (1H, dd, J ) 2.1, 1.5 Hz), 4.29 (1H,
dd, J ) 12.5, 1.0 Hz), 4.21 (1H, ddt, J ) 12.5, 6.1, 1.8 Hz), 4.18 (1H,
d, J ) 13.7 Hz), 4.13 (1H, d, J ) 13.7 Hz), 3.56 (1H, br d, J ) 18.9
888, 845, 761; H NMR (400 MHz, CDCl3) δ 5.47 (1H, d, J ) 0.7
Hz), 5.43 (1H, d, J ) 2.2 Hz), 4.29 (1H, d, J ) 15.7 Hz), 4.15 (1H, d,
J ) 15.7 Hz), 2.94 (1H, dt, J ) 8.8, 6.0 Hz), 1.56-1.64 (2H, m),
1.42-1.54 (2H, m), 1.30-1.40 (1H, m), 1.26 (8H, br s), 0.86 (3H, t,
2
J ) 6.7 Hz), 0.15 (9H, s); H NMR (61 MHz, CHCl3) δ 1.23 (1D, s),
0.80 (1D, s); 13C NMR (100 MHz, CDCl3) δ 133.7, 104.3, 102.5, 90.4,
81.3, 57.0, 35.0, 31.9, 29.7, 29.3, 25.7, 22.7, 19.4, 14.1, 6.2 (1C, br
qn), -0.1 (3C).

[3 + 2] Cycloadditions of Methylenecyclopropanes
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9605
Cycloaddition of 28b. The cycloaddition was carried out as in
general procedure A using 28b (60 mg, 0.20 mmol) in toluene (30
mL) with Pd2(dba)3 (19.3 mg, 0.021 mmol, 20.7 mol % of Pd0) and
P(OiPr)3 (20 µL, 0.081 mmol, 40 mol %). The brown-black solution
was stirred at 110 °C for 24 h. The crude product was purified by
flash column chromatography (using 1% ethyl acetate in hexanes as
eluent) to recover starting material 28b (49 mg, 82%). 2H NMR of
28b showed no scrambling of deuterium.
General Procedure for Reaction of the Cycloadducts with
Stryker’s Reagent. THF and H2O were degassed by sparging with
argon gas for 20 min. Stryker’s reagent in THF was added to a mixture
of the cycloadduct in THF and H2O, and the mixture was stirred at
room temperature for 2 h. The solvent was removed, and the residue
was purified by column chromatography.
[1r,3ar,4r(orâ),6ar]-(()-1-Heptyl-6-methylenehexahydrocyclo-
penta[c]furan-4-carboxylic Acid Methyl Ester (31). Hydride addition
was carried out as described in the general procedure, using cycloadduct
13 (23 mg, 0.083 mmol) in THF (4 mL) with H2O (20 µL) and Stryker’s
reagent (200 mg, 0.10 mmol) to yield 31 (22.7 mg, 98%) as an
inseparable 1.7:1 mixture of epimers.
[1r,3ar,4r(orâ),6ar]-(()-(1-Heptyl-6-methylenehexahydrocyclo-
penta[c]furan-4-yl)methanol (31a). 31 was then reduced to the
corresponding alcohols 31a by treating with Dabal-H in THF at -78
°C. For compounds 31a: 1H NMR (400 MHz, CDCl3) δ 4.89 (2H, br
s), 4.82 (1H, dd, J ) 2.2, 1.5 Hz), 4.79 (1H, dd, J ) 2.6, 1.5 Hz), 4.08
(1H, dd, J ) 8.8, 7.3 Hz), 3.93 (1H, dd, J ) 9.2, 7.7 Hz), 3.67 (1H,
dd, J ) 10.6, 6.2 Hz), 3.62 (1H, dd, J ) 10.6, 7.0 Hz), 3.44-3.56
(6H, m), 2.87 (1H, quintet, J ) 8.0 Hz), 2.70-2.76 (1H, m), 2.64-
2.70 (1H, m), 2.55-2.63 (2H, m), 2.16-2.39 (4H, m), 1.99 (1H, d, J
) 3.7 Hz), 1.16-1.64 (12H, m), 0.86 (3H, t, J ) 6.6 Hz); 13C NMR
(100 MHz, CDCl3) δ 153.1, 152.5, 107.4, 107.0, 86.7, 85.9, 72.8, 67.7,
65.8, 63.7, 55.6, 54.9, 47.9, 46.2, 44.9, 43.0, 35.9, 35.4, 35.1, 35.0,
31.8, 29.73, 29.70, 29.3, 26.46, 26.38, 22.7, 14.1.
was added MeLi (2.35 mL, 3.3 mmol). The mixture was warmed to
0 °C, stirred for 5 min and then recooled to -78 °C. A solution of
14a (30 mg, 0.11 mmol) in ether (3 mL) at -78 °C was added slowly
to the cuprate solution via a cannula followed by addition of TMSCl
(0.4 mL, 3.3 mmol) at -78 °C. The mixture was kept at -78 °C for
3 h and warmed up to -50 °C for 30 min. The reaction was quenched
by adding a solution of NH4Cl-NH4OH (2:1) at -78 °C. The reaction
was exposed to air and stirred until the color changed from yellow to
blue. Standard workup yielded 33 (1H NMR of crude mixture is
essentially pure 33). Column chromatography on silica gel using 2-4%
EtOAc in hexanes provided 34 (25 mg, 79%) as an inseparable mixture
of two isomers in a 7.6 : 1 ratio in favor of 34a. For compound 34a:
IR (cm-1, neat) 3076, 2957, 2926, 2854, 1737, 1660, 1459, 1434, 1362,
1254, 1233, 1197, 1166, 1058, 888; 1H NMR (400 MHz, C6D6) δ 4.94
(1H, d, J ) 1.4 Hz), 4.63 (1H, t, J ) 1.1 Hz), 4.16 (1H, d, J ) 9.9
Hz), 3.64-3.68 (1H, m), 3.32 (1H, dd, J ) 9.9, 1.1 Hz), 3.26 (3H, s),
2.91 (1H, br t, J ) 14.5 Hz), 2.47 (1H, ddd, J ) 13.2, 6.6, 1.1 Hz),
2.33 (1H, dd, J ) 14.6, 6.6 Hz), 2.25 (1H, br d, J ) 5.9 Hz), 1.55-
1.75 (2H, m), 1.14-1.54 (10H, m), 1.24 (3H, s), 0.89 (3H, t, J ) 6.8
Hz); 13C NMR (100 MHz, CDCl3) δ 173.4, 148.1, 109.2, 82.5, 76.4,
60.4, 53.8, 53.4, 51.6, 38.2, 31.8, 30.8, 29.7, 29.3, 27.0, 25.7, 22.7,
14.1; HRMS calcd for C18H31O3 (MH+) 295.2273, found 295.2279.
[1ar,3aâ,4r,6aS*]-(()-(4-Heptyl-3-methylenetetrahydro-1,5-di-
oxacyclopropa[c]pentalen-1a-yl)methanol (35). To allylic alcohol
14d (25 mg, 0.10 mmol) in anhydrous benzene (1 mL) was added VO-
(acac)2 (5 mg, 0.019 mmol) followed by t-BuOOH (0.015 mL, 0.15
mmol). The resulting brown solution was stirred at room temperature
for 1 h. Saturated Na2S2O3 solution was added to quench the reaction.
Normal workup and column chromatography (20-30% EtOAc in
hexanes) afforded epoxide 35 (16 mg, 60%). IR (cm-1, neat) 3432,
1
3077, 2936, 2862, 2246, 1656, 1468, 1415, 1381, 1019, 912, 737; H
NMR (400 MHz, CDCl3) δ 5.08 (1H, dd, J ) 3.6, 2.0 Hz), 4.96-4.98
(1H, m), 4.17 (1H, br t, J ) 9.6 Hz), 3.87-3.94 (3H, m), 3.81 (1H, br
d, J ) 12.8 Hz), 3.36 (1H, d, J ) 8.5 Hz), 2.79 (1H, d, J ) 18.3 Hz),
2.66 (1H, ddd, J ) 18.3, 4.8, 2.6 Hz), 1.81 (1H, br s), 1.10-1.52 (12
H, m), 0.85 (3H, t, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 145.5,
114.0, 80.0, 70.6, 60.9, 60.7, 52.7, 37.7, 31.8, 30.4, 29.4, 29.2, 26.1,
22.65, 22.63, 14.1; HRMS calcd for C16H26O3 266.1882, found
266.1876.
[1â,3ar,4r(orâ),6ar]-(()-1-Heptyl-6-methylenehexahydrocyclo-
penta[c]furan-4-carboxylic Acid Methyl Ester (32). Hydride addition
was carried out as described in the general procedure, using cycloadduct
14a (30 mg, 0.11 mmol) in THF (4 mL) with H2O (19 µL) and Stryker’s
reagent (200 mg, 0.10 mmol) to yield 32 (19 mg, 63%) as an inseparable
1.6:1 mixture of epimers.
[1â,3ar,4r(orâ),6ar]-(()-(1-Heptyl-6-methylenehexahydrocyclo-
penta[c]furan-4-yl)methanol (32a). 32 was then reduced to the
corresponding alcohols 32a by treating with Dabal-H in THF at -78
°C. For compounds 32a: 1H NMR (400 MHz, CDCl3) δ 4.98 (1H,
dd, J ) 2.5, 1.1 Hz), 4.96 (1H, d, J ) 1.1 Hz), 4.77 (1H, d, J ) 1.5
Hz), 4.71 (1H, t, J ) 1.1 Hz), 4.02 (1H, dd, J ) 9.9, 1.8 Hz), 3.79
(1H, d, J ) 6.6 Hz), 3.76 (1H, d, J ) 6.6 Hz), 3.69 (1H, t, J ) 7.7
Hz), 3.58-3.64 (2H, m), 3.54 (1H, d, J ) 7.4 Hz), 3.52 (1H, d, J )
7.3 Hz), 3.40 (2H, d, J ) 7.4 Hz), 3.00 (1H, t, J ) 7.7 Hz), 2.92 (1H,
t, J ) 7.3 Hz), 2.89 (1H, t, J ) 7.0 Hz), 2.60 (1H, t, J ) 7.1 Hz), 2.39
(1H, ddd, J ) 15.1, 7.7, 1.5 Hz), 2.23 (1H, d, J ) 6.2 Hz), 2.19 (1H,
d, J ) 6.6 Hz), 2.09 (1H, d, J ) 15.0 Hz), 2.03 (1H, dd, J ) 15.1, 7.7
Hz), 1.90 (1H, dt, J ) 1.5, 14.6 Hz), 1.58 (1H, s), 1.18-1.54 (12H,
m), 0.86 (3H, t, J ) 6.6 Hz).
Acknowledgment. The E. W. R Steacie Fund administered
by the Natural Science and Engineering Research Council
(NSERC) of Canada, the Merck Frost Center for Therapeutic
Research, Upjohn/Pharmacia (U.S.A.), and Eli Lilly (U.S.A.)
are thanked for financial support. Dr. P. H. M. Delanghe is
thanked for helpful discussions. T. Rovis is thanked for his
careful proofreading and helpful suggestions.
Supporting Information Available: Text describing the
details of experimental procedures and compound characteriza-
tion data that are not included in the Experimental Section (10
pages). See any current masthead page for ordering and Internet
access instructions.
[1â,3ar,4r,6ar]-(()-1-Heptyl-3a-methyl-6-methylenehexahydro-
cyclopenta[c]furan-4-carboxylic Acid Methyl Ester (34a). To a
solution of CuCN (148 mg, 1.65 mmol) in ether (2 mL) at -78 °C
JA9611809