Wolff/Cope Approach to the AB Ring of the Sesterterpenoid Variecolin

Article abstract of DOI:10.1021/acs.joc.7b02972

A stereoselective synthesis of the AB ring of the complex sesterterpenoid variecolin is presented. Our strategy features the development of a tandem Wolff/Cope rearrangement of α-diazo cyclobutyl ketones for the construction of fused, 8-membered carbocycles. Preliminary studies revealed a facile Wolff rearrangement but a difficult vinyl ketene cyclobutane Cope rearrangement. We have leveraged an efficient microwave-promoted tandem rearrangement to prepare the desired functionalized cyclooctadienones that we envision as potential key intermediates in the convergent synthesis of variecolin.

Full text of DOI:10.1021/acs.joc.7b02972

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Article
Wolff/Cope Approach to the AB Ring of the Sesterterpenoid Variecolin
Michael R Krout, Christopher Edwin Henry, Thomas Jensen,
Kun-Liang (Phil) Wu, Scott C Virgil, and Brian M. Stoltz
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 04 Jan 2018
Downloaded from http://pubs.acs.org on January 4, 2018
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Wolff/Cope Approach to the AB Ring of the Sesterterpenoid Variecolin
†
‡
§
||
Michael R. Krout, Christopher E. Henry, Thomas Jensen, Kun-Liang (Phil) Wu, Scott C
†
†
††,
Virgil, Brian M. Stoltz *
†Department of Chemistry, Bucknell University, Lewisburg, Pennsylvania 17837, United States
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‡Process Chemistry, Achaogen, Inc., South San Francisco, California 94080, United States
§Discovery Chemistry and DMPK, Neuroscience Drug Discovery, H. Lundbeck A/S, 2500
Valby, Denmarkꢀ
||Process Chemistry, Seattle Genetics, Bothell, Washington 98021, United States
††Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering,
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena,
California 91125, United States
stoltz@caltech.edu
Abstract Image
Abstract
A stereoselective synthesis of the AB ring of the complex sesterterpenoid variecolin is
presented. Our strategy features the development of a tandem Wolff/Cope rearrangement of α-
diazo cyclobutyl ketones for the construction of fused, eight-membered carbocycles. Preliminary
studies revealed a facile Wolff rearrangement but a difficult vinyl ketene cyclobutane Cope
rearrangement. We have leveraged an efficient microwave-promoted tandem rearrangement to
prepare the desired functionalized cyclooctadienones that we envision as potential key
intermediates in the convergent synthesis of variecolin.
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Introduction
The complex sesterterpenoid variecolin (1) was isolated in 1991 by Hensens and co-workers
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from the fungal fermentation extracts of Aspergillus variecolor. The fascinating polycyclic
structure of 1 was elucidated by NMR methods and later confirmed by X-ray crystallography,2
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with the natural antipode represented in Figure 1. Preliminary biological evaluation has
established an array of activities for variecolin. The original report identified 1 as a modest
angiotensin II receptor binding inhibitor with potential application in the treatment of
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hypertension. Subsequent studies demonstrated 1 to suppress the proliferation of induced mouse
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splenic lymphocytes. Variecolin has also been shown to compete with macrophage inflammatory
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protein (MIP)-1α for binding to CCR5, a key chemokine receptor involved in the uptake of HIV-
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1 into target cells. Other reports have identified general antifungal properties. Several variecolin
congeners have also been identified from other fungal species, with many exhibiting a similar
biological profile (Figure 1).2,3,4,5,6 The varied activity and intriguing molecular architecture of this
family of sesterterpenes serves to stimulate new strategies targeting their chemical synthesis. Our
interest in the pursuit of an effective synthetic strategy toward these bioactive natural products
focused on variecolin given that it is the most widely studied and biologically relevant member.
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Figure 1. Variecolin family of sesterterpenes.
Synthesis Design
The 25-carbon tetracyclic core of variecolin (1) consists of a central eight-membered ring and
possesses eight stereocenters, including two all-carbon quaternary stereocenters at C(11) and
C(14) of the BC and CD ring fusions, respectively. Synthetic control of the relative and absolute
stereochemistry of these trans-fused rings that form a stereopentad poses a notable design
challenge for critical bond-forming reactions. We therefore envisioned that the assembly of these
key features of variecolin in a convergent manner would provide opportunities to explore new
reactivity. When considering key elements toward our synthetic design, we were drawn to the
eight-membered B ring. Eight-membered rings are common structural motifs that occur in widely
diverse terrestrial plants, insects, marine organisms, and fungi. The theoretical and synthetic
intrigue of these medium-sized carbocyclic structures has stimulated the development of various
strategies for their preparation, many of which have been applied toward the synthesis of complex
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molecular targets. Inasmuch as we are restricted by the limitations of reaction scope in the state
of the art, the selective preparation of eight-membered carbocycles remains a noteworthy and
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continuing challenge to modern chemical methods. No total synthesis of variecolin or any family
members has been reported to date, however, significant progress toward this end has been
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achieved by the Piers and Molander labs. Related general strategic advancements have also been
reported.11,12,13
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The formulation of our synthetic approach toward variecolin (1) focused on the construction
of the central eight-membered ring, revealing a critical C ring disconnection that could simplify
the target into two functional AB (11) and D ring (12) fragments (Scheme 1). The scalable
synthesis of D ring fragment 13 has been advanced by our lab using an asymmetric alkylation/ring
contraction technology.14 Notably, this acylcyclopentene motif is amenable to selective
functionalization. A suitable AB ring fragment could comprise functionalized cyclooctadienone
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4 in order to facilitate selective bond forming reactions at the C(10) and C(11) positions. This
structural unit is comparable to fused bicyclic cycloheptadienones that have been constructed using
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a powerful tandem Wolff/Cope rearrangement developed in our lab. Extending this technology
to eight-membered carbocycles, we anticipated that AB ring synthon 14 could be accessed through
a Wolff/Cope rearrangement of highly functionalized α-diazo cyclobutyl ketone 15, which may in
turn be assembled via a cycloaddition of allylic alcohol 16 and an appropriate functionalized olefin
component. The design of tandem reaction sequences for the rapid generation of molecular
complexity is an area of constant investigation in our laboratory,16 and therefore a primary
objective of our synthetic endeavor toward variecolin (1) is the development of a tandem
Wolff/Cope rearrangement to forge fused eight-membered carbocyclic systems. Application of
this key transformation for the construction of the central B ring of 1 would expand the reaction
scope, and furthermore, would create a new tool for the general preparation of natural and non-
natural substances containing this eight-membered ring motif. Herein we report the asymmetric
synthesis of the AB ring of variecolin employing a tandem Wolff/Cope rearrangement to forge the
eight-membered carbocycle.
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Scheme 1. Retrosynthetic analysis of variecolin (1)
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Results and Discussion
A. Synthesis of a Wolff/Cope Model Substrate. The development of a tandem Wolff/Cope
rearrangement toward the fused bicyclic eight-membered AB ring fragment (14) required an
expedient, regio and stereoselective synthesis of a highly substituted cyclobutane substrate (e.g.,
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5). During the course of our efforts, we elected to employ an efficacious intramolecular
cyclobutadiene–olefin cycloaddition for the rapid construction of this moiety.17,18,19 Model studies
pursued toward this goal provided insight into the identification and physical properties of reaction
intermediates using a readily accessible cyclopentenol analogue.
Our investigations toward an AB ring model system began with the preparation of a suitable
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cyclopentenol that would engage cyclobutadiene via a tethered cycloaddition. Convenient access
to stereodefined 4-substituted cyclopentenols is possible using copper-catalyzed allylic
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substitution chemistry. Exposure of allylic monoacetate (±)-17 to a mixture of CuCN and p-
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tolylmagnesium bromide generated anti-cyclopentenol 18 in excellent yield (Scheme 2). We then
sought the alkylation of this alcohol with (cyclobutadiene)tricarbonyliron complexes that possess
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sufficient electrophilicity to react under mild conditions. This was achieved by the zinc(II)-
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catalyzed alkylation of cyclopentenol 18 with trichloroacetimidate 19 to prepare the requisite
intramolecular cycloaddition substrate 20 in 76% yield. Oxidative liberation of cyclobutadiene
promoted by ceric ammonium nitrate (CAN) and subsequent [4+2] cycloaddition rapidly
assembled cyclobutene 21 as a single diastereomer in 76% yield.
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Scheme 2. Tethered olefin-cyclobutadiene cycloaddition of alcohol (±)-18
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Advancement of cycloadduct 21 toward a Wolff/Cope substrate necessitated a regioselective
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olefin functionalization with our aim of generating a C(8) aldehyde and C(10) ester (i.e., 24). We
were intrigued by Schreiber’s method26,27 for the ozonolytic cleavage of olefins to terminally
differentiated products as it has been demonstrated as a powerful tool for the regioselective
cleavage of advanced synthetic intermediates in complex molecule synthesis.28 In the event,
ozonolysis of cycloadduct 21 in CH
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Cl /MeOH followed by an acylation and base induced
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elimination provided a mixture of several of compounds, including undesired acetal 22 in 13%
yield and an inseparable 9:1 mixture of acetal 23 and desired aldehyde 24 in 68% yield (Scheme
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quantities of desired olefin 25.
Scheme 3. Termini-differentiating ozonolysis of cyclobutene 21
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The production of acetals 22 and 23 from this unsymmetrical ozonolysis indicates diverging
reaction pathways. Cycloaddition of ozone and cyclobutene 21 likely generates primary ozonide
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ozonide to 27 (path a) positions the carbonyl oxide on the fully substituted carbon. Subsequent
addition of methanol to this intermediate and dehydration of 28 with Ac O/Et N generates acetal
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22. Conversely, primary ozonide cleavage in the opposite manner produces 29 (path b) with the
carbonyl oxide positioned on the less-substituted carbon. This intermediate further reacts by
another of two possible pathways: (1) addition of methanol from the reaction medium (path c) and
dehydration of 30 to generate acetal 23, or (2) methanol addition to the carbonyl oxide (path d)
and dehydration of 31 to furnish aldehyde 24. Although desired aldehyde 24 is a minor component
of this reaction, the selectivity for the cleavage of primary ozonide 26 via the desired path b is
favored in an approximate 5:1 ratio and is presumably the result of steric influences on the primary
ozonide moiety.30
Scheme 4. Diverging pathways for the termini-differentiating ozonolysis of cycloadduct 21
The identification of aldehyde 24 as a minor product from the unsymmetrical ozonolysis of
cyclobutene 21 hindered progress toward a model Wolff/Cope substrate. Fortuitously, we
recognized that acetal 23 and aldehyde 24 arise from the same fragmentation pathway (path b) and
thus possess the same C(8) aldehyde oxidation state. Encouraged by this result, we explored
potential equilibration conditions to determine the propensity for formation of aldehyde 24 from
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the isomeric aldehyde/acetal mixture (Table 1). We were gratified to find that solvation of pure
acetal 23 in methanol effected the equilibration in favor of aldehyde 24 and produced minor
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quantities of acetal diastereomer 32 (entries 1 and 2). A survey of various Lewis acids identified
the proficiency of divalent triflate salts in shifting the equilibrium to further favor 24 (entries 3–
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). Similarly, molecular sieves and combinations thereof with Lewis acids proved to be efficient
for the conversion to 24 (entries 7–10) to reach the apparent equilibrium of ca. 3:1 aldehyde 24 to
acetals 23 and 32. We elected to proceed in our synthesis using 4 Å MS due to operational
simplicity.
Table 1. Equilibration of acetal 23 to aldehyde 24
The equilibration of acetal 23 to desired aldehyde 24 considerably improved the overall
reaction sequence for the preparation of a Wolff/Cope -diazo cyclobutyl ketone substrate. An
optimized sequence involves the unsymmetrical ozonolysis of cyclobutene 21 followed by
equilibration with 4 Å MS in methanol to afford ca.1:3 ratio of acetals 23/32 and aldehyde 24
(
Scheme 5a). Wittig methylenation of this crude reaction mixture produced the desired olefin (25)
in 40% yield over three steps and the recovery of acetal diastereomers 23 and 32 in 14% yield. The
recovered acetal mixture enabled recycling of material to augment our quantity of olefin 25
(
Scheme 5b). The model Wolff/Cope substrate synthesis was completed by the high-yielding
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hydrolysis of ester 25 with KOTMS and conversion to -diazoketone 34 by way of an acid chloride
and diazomethane.
Scheme 5. a) Optimized synthesis of model α-diazo cyclobutyl ketone 34; b) Recycling of acetal
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3/32 to increase the production of olefin 25
B. Wolff-Cope Examination. The synthesis of -diazo cyclobutyl ketone 34 enabled the
examination of our key Wolff/Cope rearrangement toward the eight-membered B ring of
variecolin. A critical component to the success of our previously reported tandem Wolff/Cope
rearrangement was the identification of photochemical or silver-catalyzed sonochemical
conditions to allow direct access to a variety of [n–7] fused bicyclic systems in excellent yields.15
Thorough investigations of this transformation using substrate 34 under various photochemical or
silver(I)-catalyzed sonochemical conditions afforded only intractable mixtures and no evidence of
the desired cyclooctadienone 35. The lack of useful information acquired from these initial
experiments required us to examine the tandem process in a stepwise manner. Accordingly,
irradiation of -diazo cyclobutyl ketone 34 in methanol at 350 nm induced the photochemical
Wolff rearrangement to form homologated ester 37 as the sole product, confirming the
intermediacy of ketene 36 (Scheme 6). This critical result indicated that we were likely accessing
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a facile Wolff rearrangement, however, the ketene vinyl cyclobutane rearrangement does not
readily occur under the conditions surveyed.
Scheme 6. Preliminary Wolff/Cope rearrangement studies of α-diazo cyclobutyl ketone 34
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In order to rationalize the difficulty of the cis-ketene vinyl cyclobutane rearrangement of 36
we considered the analogous cis-divinyl cyclobutane rearrangement.32 A comparison of the
experimental activation energy for a strain-releasing Cope rearrangement of cis-divinyl
cyclobutane is approximately 4–5 kcal/mol higher than the barrier of the cyclopropane analogue,33
and is consistent with the modestly elevated reaction temperatures known to be required for cis-
divinyl cyclobutane rearrangements. This reactivity difference, when coupled with our
observations that the ketene vinyl cyclopropane rearrangement to afford substituted
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cycloheptadienones occurs under mild conditions, suggested that thermolysis of the intermediate
ketene should facilitate the rearrangement. In the event, a photochemical Wolff rearrangement
with subsequent thermolysis at 80 °C provided the desired cyclooctadienone 35 in 59% yield
(
Scheme 7). With the success of this tandem reaction, we recognized that the general instability of
a ketene intermediate and the time between photolysis/thermolysis could account for the moderate
yield of 35 and furthermore might hinder material throughput. Our search for alternative conditions
was bolstered by reports harnessing microwave irradiation to promote Wolff rearrangements,34
where we anticipated the surplus energy could facilitate a Cope rearrangement. Indeed, microwave
irradiation of α-diazo cyclobutyl ketone 34 for 20 minutes at 140 °C in toluene afforded
cyclooctadienone 35 in a remarkable 95% yield. The results of our model system explorations
thereby confirm the Wolff/Cope strategy for the synthesis of the AB fragment of variecolin (1),
and provide new tools for the construction of substituted eight-membered rings. Having
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established a viable route toward the AB ring system of variecolin through model system studies,
we then pursued an asymmetric synthesis of this desirable fragment.
Scheme 7. Optimal tandem Wolff/Cope rearrangement of α-diazo cyclobutyl ketone 34
1
1
1
1
1
1
1
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C. Asymmetric Synthesis of the AB ring of Variecolin. The application of our proven
intramolecular cycloaddition strategy for an asymmetric synthesis of the AB ring fragment (i.e.,
1
4) originated from a chiral cyclopentenol possessing syn stereochemistry. Allylic substitution of
3
5
monoacetate (+)-17 using CuCN and methylmagnesium chloride afforded a 95:5 mixture of
2
2
36
alcohols 38 and 39 in 91% yield (Scheme 8). Mitsunobu inversion of this alcohol mixture using
benzoic acid and subsequent methanolysis of the resulting ester produced allylic alcohol 16 in 81%
yield over two steps with the desired syn stereochemistry between C(3) and C(5). Lewis acid-
2
4
catalyzed coupling with trichloroacetimidate 19 gave the requisite intramolecular cycloaddition
substrate 40 in good yield.
Scheme 8. Asymmetric synthesis of intramolecular cycloaddition substrate 40
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Initial efforts to implement the CAN-promoted intramolecular cyclobutadiene–olefin
cycloaddition of 40 resulted in low yields and complex mixtures of products, presumably the result
of competing intermolecular dimerization reactions. Snapper has demonstrated that the rapid
oxidative decomplexation of (cyclobutadiene)tricarbonyliron complexes using CAN provides
sufficient access to cycloadducts of substrates predisposed for the intramolecular cycloaddition.37
This works well for anti-substrate 20, however, syn-substrate 40 possesses a C(3) methyl group
that sterically impedes cyclobutadiene access to the olefin. The alternative use of mild oxidants
such as trimethylamine-N-oxide enact a slow release of highly reactive cyclobutadiene to facilitate
access to cycloadducts of substrates with a lower propensity for the cycloaddition (e.g., 40).
Application of trimethylamine-N-oxide to facilitate the oxidative decomplexation of 40 in
refluxing acetone smoothly generated cycloadduct 41 (Scheme 9).29,38 Subsequent unsymmetrical
ozonolysis of 41, acetal equilibration promoted by 4 Å MS in refluxing methanol and Wittig
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methylenation afforded a 2.7:1 ratio of olefins 44 and 45, in addition to acetals 42 and 43. This
reaction sequence provided desired olefin 44 in 16% yield over four steps, together with 17% yield
3
9
of recyclable acetal 42. Acetal 43 was sufficiently crystalline to enable X-ray analysis, providing
further confirmation of the desired relative stereochemistry of this polycyclic fragment (Figure
4
0
2
). It is notable that the termini-differentiating ozonolysis of 41 provided ~ 3:1 ratio of products
4:45, whereas this differentiation strategy with cyclobutene substrate 21 yielded ~ 5:1 ratio of
4
products. The C(3) stereochemistry is the major structural difference between the two fused
polycyclic substrates, and it is plausible that subtle changes of the fused ring conformation are
impacting the primary ozonide fragmentation pathway (paths a and b, Scheme 4) in an unknown
way.
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Scheme 9. Cycloaddition, oxidative cleavage and olefination sequence toward an AB ring
Wolff/Cope substrate
1
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2
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Figure 2. X-ray crystal structure of acetal 43. The molecular structure is shown with 50%
probability ellipsoids.
We desired cyclooctadienone products in our synthesis of asymmetric AB ring fragment 14
where R = H, Me or alkyl. Model studies have demonstrated the tandem rearrangement where R
=
H (i.e., 34  35). However, alkyl substitution had not yet been explored for the Wolff/Cope
rearrangement and thus represented an unprecedented extension of this method. Advancing to the
target -diazoketones, hydrolysis of ester 44 to acid 46, conversion to the acid chloride and
treatment with either diazomethane (RCH
2
2
N where R = H) or diazoethane (R = Me) produced -
diazoketones 47 and 48, respectively (Scheme 10). The efficiency of diazomethane in the acylation
of the acid chloride of 46 was notable (91% yield), however, we were surprised by the capricious
4
1
and lower-yielding results obtained using diazoethane. Unfortunately, improvements in yield
4
2
could not be realized despite efforts toward further optimization. We were nonetheless delighted
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to find that the microwave-promoted tandem Wolff/Cope rearrangement of both substrates resulted
in the successful construction of their respective cyclooctadienones (49 and 50).
Scheme 10. AB ring α-diazo cyclobutyl ketone synthesis and Wolff/Cope rearrangement
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The low yield of -substituted cyclooctadienone 50 (R = Me) using microwave irradiation is
a result of the formation of numerous byproducts.43 Inspection of these various compounds
2
9
revealed that cyclopropane 51 is a major side product (ca. 1:1 ratio of 50:51) of this reaction,
ostensibly formed through a carbene intermediate. Two mechanisms have been advanced for the
Wolff rearrangement (Scheme 11), comprising a concerted group migration with nitrogen
expulsion to a ketene (53  56) or the stepwise loss of nitrogen to generate an  carbonyl carbene
4
2,44
intermediate (54  57).
The resulting carbene intermediate can then undergo the desired Wolff
rearrangement to ketene 56, or it can participate in other intra- or intermolecular reactions
characteristic of carbenes, such as cyclopropanations, hydride shifts and C–H insertions. Substrate
conformation has been demonstrated to be pivotal in the mechanistic outcome, with the s-Z
conformation typically resulting in products consistent with the concerted pathway.44,45 Moreover,
the large barrier of rotation around the C–C bond imposes a balance between electrostatic
2
attractions and steric repulsions that influence conformation. For example, substrates where R =
2
H exist mostly in the s-Z (53) conformation, whereas substrates where R = Me exist predominately
in the s-E conformation (54).44,45
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Scheme 11. Mechanistic pathways for a Wolff rearrangement
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1
1
1
1
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1
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2
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2
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A complicating factor in our analysis of the rearrangement of 48 is that the two mechanisms
often operate competitively with high substrate dependence. Given this insight and the interactions
that affect conformation, we reasoned that solvent polarity was a plausible parameter to explore.
We posited that non-polar solvents might enhance the electrostatic attraction in 52, favoring the s-
Z conformation and promoting the concerted rearrangement pathway to increase the production of
4
6
our targeted cyclooctadienone 50 (Table 2). We observed that the tandem rearrangement in
higher dielectric solvents such as acetonitrile or 1,2-dichloroethane favored cyclopropane
formation decidedly over the Wolff rearrangement (entries 1 and 2). The data suggests that polar
solvents could stabilize the charge-separated conformation (55), leading to greater population of
s-E and therefore increasing amounts of carbene-related products. Lower dielectric solvents, such
as THF, ethyl acetate, and toluene, modulated the selectivity and improved the formation of desired
product 50 (entries 3–6). Furthermore, the nonpolar solvents methylcyclohexane and heptane
reversed the reaction selectivity to favor the desired 50 as a major product in a 3:1 ratio (entries 7
and 8). Although a trend in solvent dielectric roughly reflects product selectivity in which lower
dielectric solvents seemingly favor the concerted Wolff rearrangement, the complex reaction
profile and other unidentified reaction products make it difficult to conclusively correlate solvent
polarity to the mechanistic pathway. Moreover, we do not know if the conformational
interconversion is fast relative to decomposition of 48. This is nonetheless an intriguing result that
has broader implications for future applications of the Wolff/Cope method.
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Table 2. Wolff/Cope solvent studies of substrate 48
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The application of solvent-optimized reaction conditions with heptane enabled the microwave-
promoted rearrangement of 48 to produce -methyl cyclooctadienone 50 in 42% isolated yield
(Equation 1). The success of this rearrangement is significant as it represents the first example of
the tandem Wolff/Cope rearrangement of a substrate possessing -alkyl functionality. Moreover,
the combined results from all α-diazo cyclobutyl ketone substrates in this study (i.e., 34, 47 and
4
8) highlight the utility of microwave irradiation to facilitate tandem rearrangements and expand
the collection of eight-membered rings available by this method.
Conclusion
We have described our efforts to develop a Wolff/Cope strategy for the asymmetric synthesis
of the AB ring of the complex sesterterpenoid variecolin. Our approach has employed an
intramolecular cyclobutadiene–olefin cycloaddition to control product regio and stereoselectivity,
as well as an advanced application of a termi-differentiating ozonolytic cleavage of a cyclobutene
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intermediate toward α-diazo cyclobutyl ketone substrates. These investigations have demonstrated
an efficient microwave-promoted tandem Wolff/Cope rearrangement to forge highly-substituted,
fused cyclooctadienone structures. Efforts are underway in our laboratory to leverage Wolff/Cope
products 49 and 50 in coupling reactions with suitable D ring fragments toward completion of
variecolin and will be reported in due course.
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Experimental Section
General Methods. Reactions, reagents and solvents. Unless otherwise stated, reactions were
performed in flame-dried glassware under an argon or nitrogen atmosphere using dry,
deoxygenated solvents. Solvents were dried by passage through an activated alumina column
under argon. Water (18 M) used as reaction medium was obtained from a Millipore MiliQ water
purification system. All starting materials were purchased from commercial sources and used as
received, unless otherwise stated. Liquids and solutions were transferred via syringe or positive-
pressure cannulation. Triethylamine was distilled from CaH
2
prior to use. Oxalyl chloride was
purified by distillation and stored in a Schlenk tube under nitrogen. Acetic acid was distilled from
4
7
CrO
dried and stored in a 115 °C oven. Diazomethane was freshly prepared from N-methyl-N-nitroso-
p-toluenesulfonamide (Diazald) as a solution in Et O using a Diazald kit. Diazoethane was freshly
prepared from N-ethyl-N-nitrosourea as a solution in Et O using a Diazald kit. Diazoalkane
3
. Solutions of p-TolMgBr, and MeMgCl were titrated prior to use. Molecular sieves were
2
4
8
2
solutions were dried over KOH pellets for ca. 30 min at or below 0 °C and cannula (Teflon)
transferred under nitrogen to a dry Erlenmeyer flask prior to use.
Instruments, purification and analysis. Reaction temperatures were controlled by an IKAmag
temperature modulator. Ozonolysis reactions were performed with an OzoneLab OL80 Desktop
ozone generator. Photochemical irradiation was performed in septum sealed quartz tubes with a
Luzchem Photochemical reactor or with a water-cooled Hanovia 450 W medium pressure
mercury-vapor immersion lamp. Microwave reactions were performed with a Biotage Initiator
Eight 400 W apparatus at 2.45 GHz and reaction temperatures were measured with an external
surface sensor. Thin-layer chromatography was performed using E. Merck silica gel 60 F254
precoated plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde,
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potassium permanganate, or ceric ammonium molybdate staining. SiliCycle SiliaFlash P60
Academic Silica Gel (particle size 40–63 μm; pore diameter 60 Å) was used for flash
chromatography. Analytical chiral HPLC was performed with an Agilent 1100 Series HPLC
utilizing a Chiralpak OD-H column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries,
Ltd. with 1 mL/min mobile phase and visualization at 254 nm. Analytical achiral GC was
performed on an Agilent 6850 GC with FID detector using an Agilent DB-WAX (30.0 m x
0
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6
.25 mm) column at 1.0 mL/min He carrier gas flow. Chiral GC was performed on an Agilent
850 GC with FID detector using a Chiraldex GTA column (30.0 m x 0.25 mm, purchased from
Bodman Industries) at 1.0 mL/min He carrier gas flow. Optical rotations were measured with a
1
13
Jasco P-1010 polarimeter at 589 nm using spectrophotometric grade solvents. H and C NMR
spectra were recorded on a Varian Mercury 300 (at 300 MHz and 75 MHz respectively), Varian
Inova 500 (at 500 MHz and 126 MHz, respectively) or Varian Inova 600 (at 600 MHz), and are
1
reported relative to residual protio-solvent for H (C
6
D
5
H at δ 7.16 ppm, CHCl at δ 7.26 ppm)
3
1
3
1
and solvent for C (C
6
D
6
at δ 128.06 ppm, CDCl
3
at δ 77.16 ppm). Data for H NMR spectra are
reported as follows: chemical shift ( ppm) (multiplicity, coupling constant (Hz), integration). IR
spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in
-1
wavenumbers (cm ). Melting points were acquired using a Buchi Melting Point B-545 instrument
and the values are uncorrected. High-resolution mass spectra were acquired using an Agilent 6200
Series TOF with an Agilent G1978A Multimode source in ESI, APCI, or MM (ESI/APCI)
ionization mode, in addition to the Caltech Mass Spectral Facility. Crystallographic data have been
deposited at the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, and copies can be obtained on
request, free of charge, by quoting the publication citation and the deposition number.
Trichloroacetimidate 19. To a round-bottom flask charged with hexanes-washed KH (41 mg,
1
.0 mmol, 0.057 equiv) and Et
2
O (43 mL) at 0 °C was added a solution of (hydroxymethyl
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cyclobutadiene)tricarbonyliron (SI3) (3.86 g, 17.4 mmol, 1.0 equiv) in Et
2
O (43 mL, 0.2 M total)
by cannula transfer. After 10 min, trichloroacetonitrile (8.7 mL, 87 mmol, 5.0 equiv) was added
dropwise by syringe to the light orange solution. The reaction turned dark brow over the course of
the addition. After 15 min, the ice bath was removed and upon reaching ambient temperature the
volatiles were removed in vacuo. The remaining dark brown oil was taken up in hexane (20 mL,
anhydrous) with vigorous shaking, filtered through a pad of Celite, and the reaction flask was
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washed with an additional portion of hexane (20 mL) and filtered. The combined filtrate was
concentrated in vacuo to afford 19 (6.38 g, 17.4 mmol, 100% yield) as a clear, pale red oil. This
oil was immediately used in the next step without further purification and it is not stable to
prolonged storage. R
f
= unstable to SiO
2
; 1H NMR (500 MHz, C
H), 3.49 (s, 2H), 3.30 (s, 1H); C{ H} NMR (126 MHz, C )  214.5, 162.6, 92.0, 76.8, 65.7,
6
D )  8.22 (br s, 1H), 4.25 (s,
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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1
2
6
6
D
6
-
1
4.9, 64.5; IR (Neat Film NaCl) 3344, 2049, 1971, 1666, 1449, 1368, 1304, 1288 cm ; HRMS
+
(FAB+) m/z: [M – CO] calc’d for C
9
H
6
Cl
3
FeNO 336.8763, found 336.8769.
3
Model cycloaddition substrate 20. To a round-bottom flask charged with Zn(OTf) (14.9 mg,
2
2
2
0.041 mmol, 0.05 equiv) and toluene (0.2 mL) at 0 °C was added aryl cyclopentenol 18 (151.3
mg, 0.868 mmol, 1.0 equiv) by syringe. To this suspension was added a solution of 19 (370 mg,
1
.01 mmol, 1.2 equiv) in toluene (0.2 mL) by cannula transfer, with further washing by additional
toluene (0.2 mL). A yellow precipitate was observed at the beginning of the addition, and this
turned into a thick slurry upon completion of the addition. The ice bath was allowed to expire over
1
.5 h and the reaction was stirred for an additional 6 h. The crude reaction mixture was transferred
directly onto a 5 g silica gel loading cartridge and purified by automated flash chromatography
using a 40 g silica column (1:0  9:1 hexanes/EtOAc) to afford 20 (250.8 mg, 0.663 mmol, 76%
1
yield) as a pale yellow oil. R
f
= 0.56 (4:1 hexanes/EtOAc); H NMR (300 MHz, C
6
D )  6.97
6
(
ABq, ΔδAB = 0.06, JAB = 7.8 Hz, 4H), 5.88–5.85 (m, 1H), 4.45–4.44 (m, 1H), 3.96–3.94 (m, 1H),
3
.55 (ABq, ΔδAB = 0.01, JAB = 9.2 Hz, 2H), 3.46 (s, 2H), 3.33 (s, 1H), 2.28 (ddd, J = 13.8, 6.9, 5.4
13
1
Hz, 1H), 2.14 (s, 3H), 1.86 (ddd, J = 13.7, 6.9, 5.4 Hz, 1H); C{ H} NMR (126 MHz, C
6
D
6
) 
2
2
15.0, 142.3, 140.1, 135.9, 131.6, 129.5, 127.4, 84.9, 82.5, 64.65, 64.64, 64.0, 62.3, 50.1, 41.2,
-1
1.0; IR (Neat Film NaCl) 2863, 2044, 1959, 1513, 1075, 1048, 613 cm ; HRMS (FAB+) m/z:
+
[
M] calc’d for C20
H
18
4
O Fe 378.0554, found 378.0551.
2
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Model cycloadduct 21. To a vigorously stirring solution of cycloaddition substrate 20 (683
mg, 1.806 mmol, 1.0 equiv) in acetone (1.81 mL, 1 mM) was added CAN (1.98 g, 3.61 mmol, 2.0
equiv) under ambient atmosphere. After 15 min, a second portion of CAN (1.98 g, 3.61 mmol, 2.0
equiv) was added. After an additional 5 min, consumption of 20 by TLC (4:1 hexanes/Et
2
O,
developed twice) was observed and the reaction was quenched by addition of sat aq NaHCO (50
3
mL). Stirring was ceased after 15 min, the solids were allowed to settle and the supernatant was
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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5
5
6
decanted into a flask (to prevent bumping) and concentrated in vacuo to ca. 50 mL. This slurry and
the remnants of the flask were transferred to a separatory funnel with minimal acetone, diluted
with brine (10 mL) and pentane (200 mL). The layers were separated, the organic phase was
washed with water (2 x 100 mL), and the combined aq layers were extracted with 1:1 hexanes/Et
200 mL). The combined organic layers were concentrated to ca. 25 mL, transferred to a sep funnel
and diluted with CH Cl (30 mL) and brine (25 mL). The layers were separated, the aq was
extracted with CH Cl (2 x 30 mL), the organics were dried over MgSO , filtered, and concentrated
to a dark orange oil. The crude material was purified by flash chromatography on SiO (2.5 x 21
cm, 15:1  9:1 hexanes/Et O, slow gradient) to afford 21 (326.2 mg, 1.37 mmol, 76% yield) as a
colorless oil that solidified in a –20 °C freezer. R
NMR (500 MHz, CDCl )  7.01 (ABq, ΔδAB = 0.03, JAB = 8.2 Hz, 4H), 6.35 (d, J = 2.1 Hz, 1H),
.31 (d, J = 2.3 Hz, 1H), 4.71–4.69 (m, 1H), 3.89 (ABq, ΔδAB = 0.04, JAB = 9.8 Hz, 2H), 3.27 (td,
J = 7.8, 3.4 Hz, 1H), 3.06 (app t, J = 6.1 Hz, 1H), 2.94 (s, 1H), 2.46 (ddd, J = 13.8, 7.0, 2.4 Hz,
2
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2
2
2
2
4
2
2
1
f
= 0.54 (4:1 hexanes/Et O, developed twice); H
2
3
6
1
3
1
1H), 2.35 (app t, J = 4.8 Hz, 1H), 2.32 (s, 3H), 2.03 (ddd, J = 13.8, 8.9, 4.9 Hz, 1H); C{ H} NMR
126 MHz, CDCl )  142.9, 140.3, 138.4, 135.6, 129.3, 127.2, 84.1, 71.2, 59.6, 54.9, 52.6, 50.3,
6.5, 44.6, 21.1; IR (Neat Film NaCl) 3025, 2949, 1514, 1074, 1041, 1025, 811, 744 cm ; HRMS
FAB+) m/z: [M + H – H 17O 237.1279, found 237.1271.
]+ calc’d for C17
(
3
-1
4
(
2
H
Diol 58. To a solution of cycloadduct 21 (18.0 mg, 75.5 mol, 1.0 equiv) in a 2:1 mixture of
Cl (1.0 mL) and MeOH (0.5 mL) was added a solution of Sudan Red 7b (25 L of a 0.05 wt
CH
2
2
%
in MeOH) and cooled to –78 °C. The resulting pink solution was sparged with a gentle stream
of oxygen for ca.1 min, then ozonolyzed until consumption of 21 by TLC (indicator typically
turned colorless just prior to completion). The solution was sparged with oxygen for another 1
min, and NaBH
reaction reached room temperature, CH
HCl (1 mL). The layers were separated, the aq extracted with CH
were dried over Na SO , filtered, and concentrated in vacuo. The crude material was purified by
flash chromatography on SiO
4
(28.8 mg, 0.76 mmol, 10 equiv) was added and the bath was removed. When the
Cl (2 mL) was added followed by quenching with 10%
Cl (3 x 2 mL), the organics
2
2
2
2
2
4
2
to afford 58 (18.2 mg, 66.3 mol, 88% yield) as a colorless oil. R
f
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=
0.31 (3:1 hexanes/EtOAc); H NMR (300 MHz, CDCl )  7.04 (ABq, ΔδAB = 0.08, JAB = 8.1
3
Hz, 4H), 4.60 (app t, J = 4.3 Hz, 1H), 4.23 (d, J = 11.5 Hz, 1H), 4.09 (d, J = 9.2 Hz, 1H), 3.87–
3.74 (comp m, 2H), 3.69 (d, J = 9.2 Hz, 1H), 3.55 (d, J = 11.5 Hz, 1H), 3.42 (ddd, J = 10.5, 7.0,
3
.7 Hz, 1H), 3.09 (br s, 2H), 2.82 (dd, J = 8.5, 5.3 Hz, 1H), 2.58 (dd, J = 14.0, 7.2 Hz, 1H), 2.36
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
dd, J = 11.0, 5.4 Hz, 1H), 2.31 (s, 3H), 1.99 (app dt, J = 8.7, 4.4 Hz, 1H), 1.73 (ddd, J = 14.0,
1
3
1
1
0.5, 3.5 Hz, 1H); C{ H} NMR (75 MHz, CDCl )  143.1, 135.7, 129.3, 127.0, 86.2, 80.6, 63.5,
3
63.4, 51.4, 50.8, 50.7, 49.1, 44.8, 42.2, 21.1; IR (Neat Film NaCl) 3332 (br), 2922, 1514, 1436,
-1
]+ calc’d for C17
1
2
100, 1037, 811 cm ; HRMS (FAB+) m/z: [M + H – H
2
H
21
3
O 273.1491, found
73.1485.
Optimized preparation of model olefin 25. The following procedure represents a telescoped
preparation of olefin 25. Individual optimization procedures can be found in the supporting
information. A solution of cyclobutene 21 (326.2 mg, 1.369 mmol, 1.0 equiv) in CH Cl /MeOH
(5:1, 27.4 mL, 0.05 M) containing NaHCO (34.5 mg, 0.411 mmol, 0.3 equiv) and Sudan Red 7b
150 L of a 0.05 wt % solution in MeOH) at –78 °C was sparged with a stream of oxygen for ca.
min and ozonolyzed until consumption by TLC analysis (typically as indicator turned colorless).
2
2
3
(
1
After sparging the solution with oxygen for an additional 3 min, the reaction was capped with a
drying tube and warmed to room temperature. The solution was filtered through a cotton plug,
washing with benzene (3 mL). The reaction was concentrated in vacuo to ca. 2 mL, and to this
flask was added a stir bar, septum, and the flask was evacuated/purged briefly (3x). The crude was
dissolved in CH
3.0 equiv) and Et
stirred at room temperature for 8 h, diluted with CH
then 10% NaOH (10 mL), dried over MgSO , filtered, and concentrated in vacuo to a pale yellow
oil. The crude oil was purified by flash chromatography on SiO (2.5 x 8 cm, 4:1  1:1
hexanes/Et O) to afford acetal 22 (61.5 g, 0.205 mmol, 15% yield) and a mixture of aldehyde 24
and acetals 23 and 32 (293.5 mg, 0.977 mmol, 71% yield).
2
Cl
N (286 L, 2.05 mmol, 1.5 equiv). The bath was removed and the reaction was
Cl (25 mL), washed with 2% HCl (10 mL),
2
(13.7 mL), cooled to 0 °C, and to this was added Ac
2
O (387 L, 4.11 mmol,
3
2
2
4
2
2
The mixture of 23, 24 and 32 (293.5 mg) was dissolved in MeOH (19.5 mL, 0.05 M) and to
this was added oven-dried 4 Å MS (489 mg, 0.5 g/mmol). After 24 h at room temperature the
reaction was diluted with EtOAc (20 mL), filtered through a plug of Celite, and concentrated to a
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turbid yellow oil. This was dissolved in CH
concentrated in vacuo to afford a pale yellow oil (312.1 mg).
To a solution of Ph P•CH Br (390 mg, 1.09 mmol, 1.05 equiv) in THF (3 mL) at 0 °C was
2
Cl
2
and passed through a small SiO plug and
2
3
3
added KOt-Bu (105 mg, 0.935 mmol, 0.9 equiv). The resulting bright yellow solution was stirred
for 1 h, and a solution of aldehyde 24 and acetals 23 and 32 (312.1 mg) in THF (2 mL, 0.2 M total)
was quantitatively transferred via cannulation. The bath was removed after 5 min and at 5 h the
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
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8
9
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2
3
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6
7
8
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1
2
3
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8
9
0
1
2
3
4
5
6
7
8
9
0
reaction was quenched with water (5 mL) and diluted with Et
the aq was extracted with Et O (2 x 10 mL), the combined organics were dried over Na
filtered, and concentrated in vacuo to a pale yellow oil. The crude material was purified by flash
chromatography on SiO (2.5 x 15 cm, 9:1  1:1 hexanes/Et O) to afford olefin 25 (162.2 mg,
.544 mmol, 40% yield over three steps) and ca. 7:3 mixture of acetals 23 and 32 (59.5 mg,
.198 mmol, 14% yield over three steps).
2
O (5 mL). The layers were separated,
2
2
SO ,
4
2
2
0
0
2
9
1
Model acetal 22. R
f
= 0.52 (1:2 hexanes/Et
2
O); H NMR (500 MHz, CDCl )  7.13 (d, J =
3
7.8 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 5.37 (s, 1H), 4.77 (dd, J = 5.2, 4.0 Hz, 1H), 4.14 (d, J = 9.7
Hz, 1H), 4.03 (d, J = 9.7 Hz, 1H), 3.57 (app t, J = 6.4z Hz, 1H), 3.50 (s, 3H), 3.49 (ddd, J = 10.8,
6
.8, 4.3, 1H), 2.57 (dd, J = 14.2, 7.0 Hz, 1H), 2.55–2.53 (comp m, 2H), 2.33 (s, 3H), 1.80 (ddd, J
1
3
1
=
14.4, 10.8, 3.6 Hz, 1H); C{ H} NMR (126 MHz, CDCl )  175.5, 141.3, 136.3, 129.5, 127.2,
3
109.0, 85.9, 73.0, 56.8, 55.5, 51.9, 51.3, 51.2, 44.5, 44.2, 21.1; IR (Neat Film NaCl) 2927, 1773,
-
1
+
1
515, 1353, 1182, 1143, 1118, 1018, 990, 930, 814 cm ; HRMS (FAB+) m/z: [M + H] calc’d for
C
18
H
21
O
4
301.1440, found 301.1448.
29
1
Model desired acetal 23. R
f
= 0.33 (1:2 hexanes/Et
2
O); H NMR (500 MHz, CDCl )  7.08
3
(ABq, ΔδAB = 0.04, JAB = 8.0 Hz, 4H), 5.40 (s, 1H), 4.71 (dd, J = 5.4, 3.1 Hz, 1H), 4.08 (d, J =
1
7
6
0.5 Hz, 1H), 3.78 (d, J = 10.5 Hz, 1H), 3.55 (dt, J = 11.6, 6.1 Hz, 1H), 3.48 (s, 3H), 3.31 (dd, J =
.4, 5.7 Hz, 1H), 2.89 (d, J = 2.4 Hz, 1H), 2.66 (ddd, J = 7.6, 5.2, 2.4 Hz, 1H), 2.53 (dd, J = 13.8,
13
1
.7 Hz, 1H), 2.31 (s, 3H), 1.76 (ddd, J = 13.8, 11.7, 3.1 Hz, 1H); C{ H} NMR (126 MHz, CDCl )
3
 177.7, 140.1, 136.1, 129.4, 127.1, 106.3, 85.7, 71.8, 56.8, 55.0, 51.1, 50.0, 47.9, 46.2, 43.9, 21.1;
IR (Neat Film NaCl) 2925, 2847, 1772, 1516, 1352, 1207, 1168, 1144, 1108, 1042, 943, 814, 729,
-1
+
7
05 cm ; HRMS (FAB+) m/z: [M + H] calc’d for C18
H
21
O 301.1440, found 301.1444.
4
Model aldehyde 24. Aldehyde 24 was difficult to isolate as a pure compound, as it usually
1
contained varying quantities of acetal 23. It has the following spectral properties: H NMR (300
MHz, CDCl
3
)  9.76 (s, 1H), 7.07 (ABq, ΔδAB = 0.05, JAB = 8.3 Hz, 4H), 4.69 (dd, J = 4.6, 3.9 Hz,
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H), 4.10 (d, J = 9.6 Hz, 1H), 3.91 (d, J = 9.7 Hz, 1H), 3.70 (s, 3H), 3.59 (dd, J = 8.3, 5.3 Hz, 1H),
3.45 (ddd, J = 10.7, 7.1, 3.7 Hz, 1H), 3.06–2.97 (comp m, 2H), 2.63 (dd, J = 14.2, 7.2 Hz, 1H),
.31 (s, 3H), 1.81 (ddd, J = 14.1, 10.7, 3.4 Hz, 1H).
Model olefin 25. R = 0.62 (2:1 hexanes/EtOAc); H NMR (500 MHz, CDCl
2
1
f
3
)  7.07 (ABq,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ΔδAB = 0.04, JAB = 8.0 Hz, 4H), 5.94 (dd, J = 17.5, 10.8 Hz, 1H), 5.18 (dd, J = 10.8, 1.1 Hz, 1H),
5.14 (dd, J = 17.5, 1.1 Hz, 1H), 4.65–4.63 (m, 1H), 4.03 (d, J = 9.2 Hz, 1H), 3.62 (s, 3H), 3.57 (d,
J = 9.2 Hz, 1H), 3.40 (ddd, J = 10.6, 7.1, 3.6 Hz, 1H), 3.26 (dd, J = 8.5, 5.2 Hz, 1H), 3.03 (ddd, J
=
8.7, 5.2, 3.6 Hz, 1H), 2.98 (d, J = 5.5 Hz, 1H), 2.64 (dd, J = 14.1, 7.3 Hz, 1H), 2.31 (s, 3H), 1.78
13
1
(
ddd, J = 14.0, 10.6, 3.4 Hz, 1H); C{ H} NMR (126 MHz, CDCl
3
)  173.3, 142.6, 135.6, 134.7,
129.2, 127.1, 116.3, 86.5, 78.9, 55.2, 53.0, 51.6, 51.2, 51.1, 45.0, 40.8, 21.1; IR (Neat Film NaCl)
-1
+
2
952, 2922, 1733, 1515, 1435, 1210, 1158, 1055, 1037, 919, 812 cm ; HRMS (EI+) m/z: [M]
calc’d for C19
H
22
O
3
298.1569, found 298.1580.
29
1
Model desired acetal 32. R
f
= 0.19 (1:2 hexanes/Et
2
O); H NMR (500 MHz, CDCl
3
)  7.08
(ABq, ΔδAB = 0.04, JAB = 8.0 Hz, 4H), 5.30 (s, 1H), 4.68 (dd, J = 5.6, 3.3 Hz, 1H), 4.07 (d, J = 9.5
Hz, 1H), 3.72 (dd, 7.2, 6.2 Hz, 1H), 3.69 (d, J = 9.5 Hz, 1H), 3.63 (s, 3H), 3.50 (dt, J = 11.4, 5.8
Hz, 1H), 2.85 (d, J = 2.7 Hz, 1H), 2.66 (ddd, J = 7.6, 4.9, 2.7 Hz, 1H), 2.54 (dd, J = 13.9, 6.8 Hz,
13
1
1
H), 2.31 (s, 3H), 1.79 (ddd, J = 13.9, 11.4, 3.3 Hz, 1H); C{ H} NMR (126 MHz, CDCl
3
) 
175.8, 140.8, 136.1, 129.4, 127.1, 104.0, 86.0, 72.7, 58.7, 54.5, 50.23, 50.20, 47.7, 44.8, 44.0, 21.1;
-1
IR (Neat Film NaCl) 2922, 1770, 1515, 1450, 1386, 1209, 1170, 1106, 1041, 995, 942, 813 cm ;
+
HRMS (MM: ESI/APCI) m/z: [M + H] calc’d for C18
H
21
4
O 301.1434, found 301.1432.
Model dimethyl acetal 59. To a solution of acetal 23 (1.0 equiv) in MeOH (25 mM) was added
either La(OTf)
3
or Sm(OTf)
3
(0.20 equiv). The reaction was stirred until complete conversion by
1
TLC, diluted with Et
2
O, filtered through a plug of Celite, and concentrated in vacuo. The crude H
1
NMR showed 59 as the exclusive product. R
CDCl
.87 (ABq, ΔδAB = 0.01, JAB = 9.2 Hz, 2H), 3.67 (s, 3H), 3.51 (s, 3H), 3.39 (s, 3H), 3.36 (ddd, J =
f
= 0.36 (1:2 hexanes/Et
2
O); H NMR (600 MHz,
3
)  7.06 (ABq, ΔδAB = 0.04, JAB = 7.9 Hz, 4H), 4.69 (s, 1H), 4.58 (dd, J = 4.8, 3.8 Hz, 1H),
3
10.7, 7.4, 3.8 Hz, 1H), 3.23 (dd, J = 8.6, 5.3 Hz, 1H), 2.93 (ddd, J = 8.8, 5.4, 3.6 Hz, 1H), 2.82 (d,
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1
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1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
J = 5.7 Hz, 1H), 2.60 (dd, J = 14.1, 7.4 Hz, 1H), 2.30 (s, 3H), 1.75 (ddd, J = 14.1, 10.4, 3.6 Hz,
1
3
1
1
H); C{ H} NMR (126 MHz, CDCl
3
)  174.1, 142.7, 135.6, 129.2, 127.1, 105.0, 85.8, 75.0,
58.3, 56.6, 54.5, 52.1, 51.7, 51.4, 49.4, 45.0, 42.4, 21.1; IR (Neat Film NaCl) 2952, 1727, 1515,
-
1
]+ calc’d for
1
435, 1362, 1210, 1069, 1042, 977, 813 cm ; HRMS (FAB+) m/z: [M + H – H
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C
20
H
25
O
5
345.1702, found 345.1701.
Model acid 33. To a solution of olefin 25 (162.2 mg, 0.544 mmol, 1.0 equiv) in THF (10.9
mL, 0.05 M) at 0 °C was added KOTMS (698 mg, 5.44 mmol, 10 equiv) in one portion. The
cooling bath was removed and the reaction was stirred until consumption by TLC analysis
(typically 5–6 h). The reaction was then cooled to 0 °C and slowly quenched with 1 N HCl (10
mL), diluted with EtOAc (20 mL) and brine (5 mL). The layers were separated, the aq was
extracted with EtOAc (3 x 20 mL), the combined organics were dried over Na
2
SO
4
, filtered, and
concentrated to a pale yellow semisolid. The crude material was purified by flash chromatography
on SiO
2
(1:1 hexanes/EtOAc) to give 33 (148.7 mg, 0.523 mmol, 96% yield) as a white solid. R =
f
1
0
4
1
.23 (2:1 hexanes/EtOAc); H NMR (500 MHz, CDCl
3
)  7.06 (ABq, ΔδAB = 0.04, JAB = 8.0 Hz,
H), 6.00 (dd, J = 17.5, 10.8 Hz, 1H), 5.21 (dd, J = 10.8, 1.1 Hz, 1H), 5.17 (dd, J = 17.6, 1.2 Hz,
H), 4.64 (dd, J = 4.8, 3.6 Hz, 1H), 4.04 (d, J = 9.3 Hz, 1H), 3.57 (d, J = 9.3 Hz, 1H), 3.40 (ddd,
J = 10.5, 7.2, 3.5 Hz, 1H), 3.26 (dd, J = 8.2, 5.2 Hz, 1H), 3.00–2.95 (comp m, 2H), 2.64 (d, J =
13
1
1
4.2, 7.3 Hz, 1H), 2.31 (s, 3H), 1.78 (ddd, J = 14.0, 10.6, 3.4 Hz, 1H); C{ H} NMR (126 MHz,
CDCl )  177.7, 142.6, 135.7, 134.4, 139.3, 127.7, 116.6, 86.6, 79.0, 54.9, 53.2, 51.14, 51.10, 44.9,
0.8, 21.1; IR (Neat Film NaCl) 2923, 1729, 1700, 1515, 1418, 1223, 1053, 992, 918, 812 cm ;
3
-1
4
+
HRMS (FAB+) m/z: [M + H] calc’d for C18
H
21
O 285.1491, found 285.1495.
3
Model α-diazo cyclobutyl ketone 34. To a solution of acid 33 (14.7 mg, 51.7 mol, 1.0 equiv)
in CH Cl (2 mL, 0.025 M) at 0 °C was added a solution of oxalyl chloride (107 L of a 1.45 M
solution in CH Cl , 155 mol, 3.0 equiv), followed by 1 drop of DMF. The reaction was stirred
2
2
2
2
for 1 h, at which point the stir bar was removed and the volatiles were removed on a rotovap purged
with argon. The septum and stir bar were replaced and the crude material was further dried under
high vacuum for 10 min. The resulting crude semisolid was partially dissolved in CH
2
Cl (1 mL)
2
and transferred quantitatively via Teflon cannula to a vigorously stirring solution of excess
diazomethane (5–8 mL) at 0 °C. After 30 min the cooling bath was removed, and after a further
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hour the diazomethane was pulled off via water aspirator. The pale yellow solution was filtered
through a small SiO plug (Et O) and concentrated in vacuo. The crude material was purified by
flash chromatography on SiO
2
2
2
(9:1  3:1 hexanes/EtOAc) to afford 34 (13.2 mg, 42.8 mol, 83%
1
yield) as a bright yellow oil that solidified in a –20 °C freezer. R
NMR (500 MHz, CDCl
H), 5.17 (d, J = 10.8 Hz, 1H), 5.11–5.06 (br m, 2H), 4.64 (app t, J = 4.0 Hz, 1H), 3.97 (br d, J =
9.1 Hz, 1H), 3.66 (br d, J = 8.6 Hz, 1H), 3.36 (ddd, J = 10.6, 7.7, 3.5 Hz, 1H), 3.19 (br s, 1H), 3.11
f
= 0.31 (2:1 hexanes/EtOAc); H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
)  7.05 (ABq, ΔδAB = 0.04, JAB = 7.9 Hz, 4H), 6.01 (dd, 17.5, 10.8 Hz,
1
(
br s, 1H), 2.92 (br s, 1H), 2.64 (dd, J = 14.1, 7.3 Hz, 1H), 2.30 (s, 3H), 1.78 (ddd, J = 13.7, 10.5,
13
1
3
.0 Hz, 1H); C{ H} NMR (126 MHz, CDCl
3
)  193.6, 142.5, 135.7, 134.9, 129.3, 127.1, 116.0,
8
6.5, 78.6, 60.8, 55.3, 53.6, 51.4, 44.9, 40.5, 30.4, 21.1; IR (Neat Film NaCl) 2955, 2921, 2100,
-1
+
1633, 1514, 1370, 1352, 1048, 812 cm ; HRMS (FAB+) m/z: [M + H] calc’d for C19
09.1603, found 309.1619.
H
21
O
2
N
2
3
Model homologated ester 37. A solution of -diazo cyclobutyl ketone 34 (3.2 mg, 104 mol)
in MeOH (5.2 mL, 2 mM) in a dried quartz tube was irradiated in a Luzchem rayonette ( = 350
nm) for 1.5 h. The solution was concentrated in vacuo and revealed homologated ester 37 as the
1
sole product by crude H NMR. An analytical sample was obtained from purification by
preparative TLC on SiO
colorless oil. R
2
(2:1 hexanes/EtOAc) to give 37 (2.4 mg, 7.7 mol, 74% yield) as a
1
f
= 0.43 (2:1 hexanes/EtOAc); H NMR (500 MHz, CDCl
3
)  7.04 (ABq, ΔδAB
=
0.04, JAB = 5 Hz, 4H), 5.89 (dd, J = 16.9, 10.2 Hz, 1H), 5.22 (d, J = 10.7 Hz, 1H), 5.13 (d, J = 17.5
Hz, 1H), 4.64 (app t, J = 3.9 Hz, 1H), 3.97 (d, J = 8.7 Hz, 1H), 3.51 (s, 3H), 3.50 (d, J = 8.7 Hz,
1
H), 3.46–3.42 (m, 1H), 3.23 (dd, J = 7.9, 5.8 Hz, 1H), 2.61 (dd, J = 14.1, 7.3 Hz, 1H), 2.54–2.36
(comp m, 3H), 2.30 (s, 3H), 2.11 (app dt, J = 7.7, 3.8 Hz, 1H), 1.78 (ddd, J = 12.7, 10.4, 2.1 Hz,
1
3
1
1H); C{ H} NMR (126 MHz, CDCl
3
)  173.1, 143.6, 135.5, 135.3, 129.2, 127.1, 116.4, 86.7,
7
1
9.2, 52.4, 51.9, 51.6, 50.1, 47.0, 46.9, 45.0, 37.2, 21.1; IR (Neat Film NaCl) 2951, 2922, 1736,
-1
+
514, 1435, 1207, 1163, 1041, 916, 808 cm ; HRMS (EI+) m/z: [M] calc’d for C20
H
24
O
3
312.1726, found 312.1725.
Wolff/Cope rearrangement to cyclooctadienone 35. Photochemical/Thermal: A solution of
-diazo cyclobutyl ketone 34 (3.5 mg, 11.4 mol) in benzene (5.7 mL, 2 mM) in a dried quartz

tube was irradiated in a Luzchem photochemical reactor ( = 310 nm) for 10 min, and then the
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2
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2
2
2
2
2
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3
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lamp was turned off and the quartz tube was placed in an 80 °C oil bath for 2 h. The reaction was
concentrated in vacuo and purified by preparative TLC on SiO (1:1 hexanes/Et O, developed
2
2
twice) to give model cyclooctadienone 35 (1.9 mg, 6.8 mol, 59% yield) as a colorless oil.
Microwave (thermal): A solution of -diazo cyclobutyl ketone 34 (2.3 mg, 7.5 mol) in
toluene (1.5 mL, 5 mM) was prepared in a non-dried microwave vial containing a stir bar under
ambient atmosphere. The vial was sealed and irradiated in a Biotage Initiator microwave reactor
at 400 W until the temperature reached 140 °C, and the temperature was maintained for 20 min.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The vial was cooled to room temperature, the seal was removed, and the contents were
1
concentrated in vacuo. Reaction conversion was monitored by H NMR analysis (C
6
D ). The crude
6
material was purified by preparative TLC on SiO (2:1 hexanes/EtOAc) to give 35 (2.0 mg, 7.1
2
mol, 95% yield) as a colorless oil that solidified in a –20 °C freezer. R = 0.32 (3:1
f
1
hexanes/EtOAc); H NMR (CDCl
3
, 500 MHz)  7.15 (ABq, ΔδAB = 0.02, JAB = 8.3 Hz, 4H), 5.80–
5
.73 (comp m, 2H), 5.63–5.59 (m, 1H), 4.76 (app t, J = 5.2 Hz, 1H), 4.49 (dd, J = 13.1, 1.5 Hz,
H), 4.40 (dd, J = 13.2, 1.0 Hz, 1H), 3.66 (td, J = 6.8, 4.0 Hz, 1H), 3.41 (dd, J = 14.7, 8.1 Hz, 1H),
1
3.23 (app t, J = 11.3 Hz, 1H), 3.13–3.05 (comp m, 2H), 2.34 (s, 3H), 2.30 (dd, J = 13.8, 5.9 Hz,
13
1
1
1
H), 1.93 (ddd, J = 13.8, 12.1, 4.6 Hz, 1H); C{ H} NMR (126 MHz, CDCl
3
)  203.3, 146.8,
1
39.7, 138.4, 136.9, 129.7, 129.2, 127.9, 144.2, 85.3, 72.2, 53.9, 50.6, 48.1, 45.4, 41.4, 21.2; H
NMR (500 MHz, C
6
D )  6.99 (d, J = 7.7 Hz, 2H), 6.86 (d, J = 6.9 Hz, 2H), 5.77 (dt, J = 13.5, 1.3
6
Hz, 1H), 5.56 (d, J = 13.6 Hz, 1H), 5.11–5.08 (m, 1H), 4.35 (app t, J = 5.1 Hz, 1H), 4.24 (d, J =
1
2

3.1 Hz, 1H), 4.11 (d, J = 13.2 Hz, 1H), 3.04–2.89 (comp m, 4H), 2.70 (app t, J = 11.3 Hz, 1H),
1
3
1
.20 (dd, J = 13.6, 5.9 Hz, 1H), 2.15 (s, 3H), 1.53–1.46 (m, 1H); C{ H} NMR (126 MHz, C
6
6
D )
201.9, 147.2, 139.2, 138.6, 136.8, 130.1, 130.0, 128.7, 114.4, 85.5, 72.5, 53.8, 51.2, 48.3, 45.9,
41.9, 21.3; IR (Neat Film NaCl) 3015, 2922, 1693, 1661, 1516, 1435, 1318, 1208, 1062, 1030, 817
-1
–
cm ; HRMS (MM: ESI/APCI) m/z: [M – H] calc’d for C19
H
19
2
O 279.1391, found 279.1384.
Anti-cyclopentenol 38. A 2 L, 3-neck flask was charged with CuCN (2.01 g, 112.2 mmol. 0.2
equiv) and THF (280 mL), and the suspension was cooled to ca. –20 °C (internal) using a cryocool.
To this was added a solution of MeMgCl (109 mL, 337 mmol of a 3.1 M solution in THF) and the
internal temperature warmed to –14 °C. After 30 min at –20 °C, a solution of monoacetate (+)-
3
5
1
7 (15.95 g, 112.2 mmol, 1.0 equiv) in THF (40 mL) was slowly transferred (quantitative) via
cannulation at such a rate that the internal temperature does not rise above –10 °C (required ca. 1
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h). After 30 min the reaction was slowly quenched with sat. aq NH Cl (100 mL), 50% sat. brine
4
(100 mL), the cooling bath was removed and the viscous suspension was stirred vigorously for
several hours. Additional water (200 mL) and 3% HCl (100 mL) was added and the layers were
separated. The aq layer was extracted with Et
2
O (3 x 200 mL), the combined organics were dried
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
over MgSO , filtered, and concentrated carefully (water bath = 5 °C, down to 30 torr) to a pale
4
yellow oil. The crude material was purified by short path distillation (bp = 88–92 °C, 40 torr) to
afford a 95:5 mixture of 38 and 39 (8.847 g, 90.2 mmol, 80% yield). The early distillation fractions
and Et
SiO (2.5 x 27 cm, 6:1  1:1 pentane/Et
9.996 g, 101.9 mmol, 91% yield). R (38) = 0.35 (1:1 hexanes/EtOAc); R
2
O washings from the apparatus were combined and purified by flash chromatography on
O) to provide another 1.049 g of 38 and 39 (combined
(39) = 0.29 (1:1
2
2
f
f
hexanes/EtOAc); bp = 88–92 °C (40 torr). An analytical sample of 38 was obtained from the
1
column conditions above. H NMR (500 MHz, CDCl
3
)  5.89 (dd, J = 5.5, 1.9 Hz, 1H), 5.79 (dt,
J = 4.8, 2.3 Hz, 1H), 4.87 (dt, J = 4.8, 2.3 Hz, 1H), 2.95 (dqdt, J = 9.5, 7.2, 4.9, 2.3 Hz, 1H), 1.96
(ddd, J = 14.0, 7.5, 2.6 Hz, 1H), 1.71 (ddd, J = 14.0, 7.1, 5.2 Hz, 1H), 1.48 (br s, 1H), 1.03 (d, J =
13
1
7
.1 Hz, 3H); C{ H} NMR (126 MHz, CDCl )  142.0, 132.1, 77.6, 42.7, 38.5, 21.0; IR (Neat
3
-1
+
Film NaCl) 3338 (br), 2956, 2870, 1354, 1088, 1017, 982, 742 cm ; HRMS (EI+) m/z: [M] calc’d
21
for C
6
H10O 98.07317, found 98.07171; []
D
–272.2 (c 0.39, CHCl , 99% ee). GC conditions: 45
3
°C isothermal, GTA column, t
R
(min): major = 37.7, minor = 36.7.
Syn-cyclopentenol 16. To a suspension of Ph P (13.41 g, 51.12 mmol, 1.2 equiv) and benzoic
3
acid (6.243 g, 51.12 mmol, 1.2 equiv) in toluene (237 mL) at –75 °C (internal) was added DIAD
(10.1 mL, 51.12 mmol, 1.2 equiv) dropwise, neat over 15 min. The resulting yellow suspension
was stirred vigorously for 30 min, at which point a solution of 38 and 39 (4.1806 g, 42.60 mmol,
1
.0 equiv) in toluene (47 mL, 0.15 M total) was transferred via cannula quantitatively over 30 min
observed maximum temperature increase to –70 °C). When ca. 1/3 of this solution was added, the
reaction mixture turned homogeneous. After complete addition of 38 and 39, the reaction was
stirred for an additional 30 min (white precipitate had formed) and quenched with sat. aq NaHCO
(
3
(100 mL) and water (100 mL) and the contents were warmed to room temperature. The layers were
separated, the aq was extracted with Et
2
O (2 x 50 mL), and the combined organics were shaken
P. The layers were separated, the aq was
with 3% aq H
2
O
2
until TLC showed disappearance of Ph
3
extracted with Et
2
O (1 x 50 mL), and the combined organics were dried over MgSO , filtered, and
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2
2
2
2
2
2
2
2
2
3
3
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3
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concentrated to a pale yellow solid. The crude material was purified by flash chromatography on
SiO (7 x 7.5 cm, 1:0  24:1 hexanes/Et O, dry loaded onto SiO ) to give the expected syn-
benzoate (60, 7.792 g, 38.53 mmol, 90% yield) as a pale yellow oil. R = 0.57 (3:1 hexanes/EtOAc);
1H NMR (500 MHz, CDCl
)  8.05-8.03 (m, 2H), 7.56–7.53 (m, 1H), 7.44–7.41 (m, 2H), 6.03 (dd,
J = 4.4, 2.0 Hz, 1H), 5.90–5.86 (comp m, 2H), 2.80–2.73 (m, 1H), 2.65 (dt, J = 14.0, 7.8 Hz, 1H),
2
2
2
f
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
1
.51 (dq, J = 12.5, 3.7 Hz, 1H), 1.16 (d, J = 7.0 Hz, 3H); C{ H} NMR (126 MHz, CDCl
3
) 
166.6, 142.9, 132.9, 130.8, 129.7, 128.6, 128.4, 80.9, 38.9, 38.7, 21.7; IR (Neat Film NaCl) 2961,
-1
+
1
716, 1451, 1340, 1315, 1272, 1110, 711 cm ; HRMS (EI+) m/z: [M] calc’d for C13
H
14
O
2
2
5.7
2
02.0994, found 202.1019; []
D
+123.8 (c 1.175, CHCl , 98–99% ee).
3
To a solution of syn-benzoate 60 (6.255g, 30.93 mmol, 1.0 equiv) in MeOH (62 mL, 0.5 M)
was added K CO (8.549 g, 61.85 mmol, 2.0 equiv) in one portion. After completion as judged by
TLC analysis (3 h, 3:1 hexanes/EtOAc), the reaction was concentrated carefully in vacuo to a
slurry (ca. 5–10 mL). The white slurry was diluted with brine (25 mL) and extracted with Et O (4
x 25 mL, follow by TLC), the organics were dried over MgSO , filtered, and concentrated carefully
2
3
2
4
in vacuo. The crude material was purified by flash chromatography on SiO (5 x 12 cm, 6:1  1:1
2
1
pentane/Et
2
O) and concentrated down to 100 torr until H NMR analysis revealed the absence of
solvent to afford 16 (2.728 g, 27.79 mmol, 90% yield) as a colorless oil. R = 0.25 (3:1
f
1
hexanes/EtOAc); H NMR (500 MHz, CDCl
3
)  5.82 (dt, J = 5.5, 1.5 Hz, 1H), 5.73 (dt, J = 5.5,
2.0 Hz, 1H), 4.79 (br s, 1H), 2.66–2.59 (m, 1H), 2.52 (dt, J = 13.4, 7.6 Hz, 1H), 1.79 (br s, 1H),
1
3
1
1
1
1
.17 (dt, 13.4, 5.4 Hz, 1H), 1.09 (d, J = 7.0 Hz, 3H); C{ H} NMR (126 MHz, CDCl
3
)  140.4,
32.8, 77.8, 42.6, 39.0, 22.0; IR (Neat Film NaCl) 3338 (br), 3048, 2959, 2870, 1456, 1356, 1322,
-1
+
27
115, 1051, 755 cm ; HRMS (EI+) m/z: [M] calc’d for C
6
H
10O 98.07317, found 98.07135; []
D
–23.0 (c 0.475, CHCl
21.2, minor = 20.7.
3
, 98.2% ee). GC conditions: 50 °C isothermal, GTA column, t
R
(min): major
=
Cycloaddition substrate 40. To a round-bottom flask containing Zn(OTf) (271 mg, 0.745
2
mmol, 0.05 equiv) and toluene (3.7 mL) at 0 °C was added cyclopentenol 16 (1.45 g, 14.8 mmol,
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.0 equiv) by syringe. To this suspension was added a solution of cyclobutadiene
trichloroacetimidate 19 (6.38 g, 17.4 mmol, 1.2 equiv) in toluene (2.0 mL) by cannula transfer,
with further washing by toluene (1.7 mL). A yellow precipitate was observed at the beginning of
the addition, and this turned into a viscous slurry upon completion of the addition. The ice bath
was allowed to expire over 1.5 h and the reaction was stirred for an additional 0.5 h at ambient
temperature. The crude reaction mixture was transferred directly onto a 25 g silica gel loading
cartridge and purified by automated flash chromatography using a 125 g silica column (1:0  19:1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
hexanes/EtOAc) to afford 40 (3.65 g, 12.2 mmol, 82% yield) as a pale yellow oil. R = 0.73 (4:1
f
1
hexanes/EtOAc); H NMR (500 MHz, C
6
D )  5.72 (app dt, J = 5.6, 1.9 Hz, 1H), 5.66 (app dt, J
6
= 5.6, 1.6 Hz, 1H), 4.27–4.24 (m, 1H), 3.53 (ABq, ΔδAB = 0.01, JAB = 9.1 Hz, 2H), 3.48 (s, 2H),
.32 (s, 1H), 2.43–2.39 (m, 1H), 2.15 (app dt, J = 13.3, 7.6 Hz, 1H), 1.26 (ddd, J = 17.0, 11.2, 6.9
3
1
3
1
Hz, 1H), 0.98 (d, J = 7.0 Hz, 3H); C{ H} NMR (126 MHz, C
6
D
6
)  215.0, 140.5, 130.5, 85.2,
8
2.6, 64.64, 64.58, 64.0, 62.2, 39.1, 38.9, 21.6; IR (Neat Film NaCl) 2961, 2871, 2046, 1965, 1359,
-
1
+
1076, 1055, 757 cm ; HRMS (FAB+) m/z: [M] calc’d for C14
H
14FeO 302.0242, found 302.0244;
4
2
5
[]
D
+22.7 (c 0.86, hexane, 98% ee).
29
Cycloadduct 41. A solution of cycloaddition substrate 40 (2.3582 g, 7.806 mmol, 1.0 equiv)
dissolved in acetone (780 mL, 10 mM) in a 1 L round-bottom flask fitted with a reflux condenser
was warmed in a 70 °C oil bath. When the solution approached reflux, the condenser was
momentarily removed and Me
portion. The solution was allowed to reflux and within 10 min the reaction vessel was filled with
a rust colored precipitate. After 4 h a second portion of Me NO•2H O (4.35 g, 45.9 mmol, 5.8
3
NO•2H
2
O (8.77 g, 78.9 mmol, 10 equiv) was added in a single
3
2
equiv) was added. The solution was heated at reflux for an additional 17 h after which the reaction
was judged to be complete by TLC analysis (4:1 hexanes/EtOAc). The solution was cooled to
room temperature and poured directly onto a SiO
column was washed with 0  10% Et O in pentane, and all fractions containing cyclobutene 41
were combined and concentrated carefully to a volume of ca. 30 mL by atmospheric pressure
distillation. This solution was purified by flash chromatography on SiO (packed with pentane,
eluted with 20:1 pentane/Et O). The fractions containing 41 were combined and concentrated to a
2
column (25 x 5 cm) packed in pentane. The
2
2
2
volume of ca. 10 mL by atmospheric pressure distillation. This pale yellow cyclobutene solution
in pentane was used directly in the following reaction. An analytical sample of cyclobutene 41
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