Selective C-C and C-H Bond Activation/Cleavage of Pinene Derivatives: Synthesis of Enantiopure Cyclohexenone Scaffolds and Mechanistic Insights

Article abstract of DOI:10.1021/jacs.5b02254

The continued development of transition-metal-mediated C-C bond activation/cleavage methods would provide even more opportunities to implement novel synthetic strategies. We have explored the Rh(I)-catalyzed C-C activation of cyclobutanols resident in hydroxylated derivatives of pinene, which proceed in a complementary manner to the C-C bond cleavage that we have observed with many traditional electrophilic reagents. Mechanistic and computational studies have provided insight into the role of C-H bond activation in the stereochemical outcome of the Rh-catalyzed C-C bond activation process. Using this new approach, functionalized cyclohexenones that form the cores of natural products, including the spiroindicumides and phomactin A, have been accessed.

Full text of DOI:10.1021/jacs.5b02254

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Article
Selective C–C and C–H Bond Activation/Cleavage
of Pinene Derivatives: Synthesis of Enantiopure
Cyclohexenone Scaffolds and Mechanistic Insights
Ahmad Masarwa, Manuel Weber, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 19 Apr 2015
Downloaded from http://pubs.acs.org on April 20, 2015
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Selective C–C and C–H Bond Activation/Cleavage of Pinene Derivatives:
Synthesis of Enantiopure Cyclohexenone Scaffolds and Mechanistic Insights**
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Ahmad Masarwa, Manuel Weber and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, CA 94720 (USA), E-mail:
rsarpong@berkeley.edu
Keywords: C–C / C–H Activation/Cleavage • Rhodium Catalysis • Rearrangements • Pinene Derivatives • Natural Products
Abstract
The continued development of transition metal-mediated C–C bond activation/cleavage methods would provide
even more opportunities to implement novel synthetic strategies. We have explored the Rh(I)-catalyzed C–C
activation of cyclobutanols resident in hydroxylated derivatives of pinene, which proceed in a complementary
manner to the C–C bond cleavage which we have observed with many traditional electrophilic reagents.
Mechanistic and computational studies have provided insight into the role of C–H activation in the
stereochemical outcome of the Rh-catalyzed C–C bond activation process. Using this new approach,
functionalized cyclohexenones that form the cores of natural products including the spiroindicumides and
phomactin A have been accessed.
Introduction
Carbon-hydrogen (C–H) and carbon-carbon (C–C) bonds are ubiquitous in organic molecules. As such,
advances that accomplish the selective activation and functionalization of C–H and C–C bonds have the
potential to revolutionize the synthesis of complex organic molecules. While methods for C–H
activation/functionalization1 have grown exponentially over the last decade, comparatively few methods for C–
C bond activation have emerged.2 General and effective methods for C–C activation are likely to change the
practice of complex molecule chemical synthesis just as C–H activation/functionalization logic is beginning to
influence the synthesis of complex molecules.3 In particular, methods to selectively activate a desired C(sp3)–
C(sp3) bond using transition metal complexes remains difficult to achieve.2 In order to make C–C bond
activation processes broadly applicable in complex molecule synthesis, their scope and limitations need to be
identified. This can be effectively achieved by exploring these methods in functional group rich, complex
settings such as those encountered in natural product scaffolds. In this Article, we report our studies in this
direction, which has focused on C–C bond activation/cleavage reactions of cyclobutanols, accessed in two steps
from carvone, to yield functionalized cyclohexenone derivatives (e.g., 2 and 3, Figure 1) that comprise the cores
of several natural products. We also provide mechanistic insights into these Rh(I)-catalyzed transformations.
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As a part of a general program to synthesize natural products including suaveolindol (4, Figure 1), phomactin A
(5), spiroindicumides A and B (6 and 7), and others (8–11), we recognized that the core scaffold of these
compounds could arise from sustainable, readily available, and inexpensive carvone. A key challenge in
achieving a unified strategy to these compounds (in particular 4–7) would rely on identifying a divergent
reaction on each enantiomer of carvone that would lead to the programmed installation of the C4 all-carbon
quaternary stereocenter present in 2, ent-2, 3 and ent-3 (see box in Figure 1).
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Figure 1. Unified, carvone-based, strategy to natural product core scaffolds.
Results and Discussion
We commenced our studies with the conversion of (+)-carvone (1) to a diastereomeric mixture of epoxides (12;
1:1 d.r.) upon treatment with m-CPBA. Subjecting the diastereomers of 12 to in-situ generated
bis(cyclopentadienyl) titanium chloride (Cp2TiCl) yields readily-separable cyclobutanol-containing bicycles
13a and 13b (ratio of 3:2), following the precedent of Bermejo and coworkers.4 We have obtained unambiguous
support for the structures of 13a and 13b using X-ray crystallographic analysis (see CYLviews in Scheme 1).5
This is a readily scalable route and multigram quantities of 13a/b can be accessed in a single pass.
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Scheme 1. Synthesis of cyclobutanol diastereomers 13a and 13b.
We envisioned that diastereomers 13 would serve as substrates in C–C bond activation and cleavage processes
to yield substituted cyclohexenones such as 2 and 3 as well as the cores of 8–11. As illustrated in Figure 2,
complementary fragmentation scenarios could be imagined (e.g., for 13a). While opening of the cyclobutane
ring was anticipated on the basis of strain release considerations,6 it was unclear which C–C bond would be
cleaved (C1–C2 vs. C1–C4). It was our expectation that through the appropriate choice of activating agent
(transition metal complex or traditional electrophiles/oxidants), selectivity for the cleavage of either C–C bond
could be achieved.
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Figure 2. Proposed tactics for selective C-C bond cleavage in pinene derivatives, exemplified for 13a.
Despite the existing wealth of information on the skeletal rearrangement/fragmentation of pinene and associated
derivatives,7 the rearrangement chemistry of hydroxylated variants such as 13a and 13b have not been
investigated. Thus, we initiated our studies on the C–C bond activation/cleavage of 13a/b using well-established
reagents for the fragmentation/ rearrangement of pinene (e.g., m-CPBA). Treatment of 13a with m-CPBA
(Scheme 2A) leads to a diastereoselective epoxidation of the pinene derivative, which is then transformed to 15
(confirmed by X-ray crystallographic analysis) in 78% yield via 14. Similarly, 13b (Scheme 2B) rearranges to
17 and 18 (both confirmed by X-ray analysis) upon treatment with m-CPBA in 93% combined yield.
Compound 17 (which maps on to the core of the natural product 8)8 arises from migration of the most
substituted proximal C1–C4 bond (grey arrow in 16), whereas bridging tricycle 18 (the core of the natural
product 9)9 results from opening of the epoxide intermediate (blue arrow in 16) by the pendant primary hydroxy
group.
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Scheme 2: m-CPBA-Promoted selective C1–C4 bond cleavage/ rearrangement of 13a and 13b. B: When CDCl3 was used as the
reaction solvent, a 1:9 ratio of 17:18 was observed, whereas in CH2Cl2 a 1:3 mixture was formed.
In addition, when 13a was subjected to a BrØnsted acid (PPTS) (Scheme 3A), the intermediate tertiary
carbocation (19) rearranges to 20 as a result of the cleavage/migration of the more substituted C1–C4 bond. In
the same fashion, 13b was transformed to naturally occurring 1010 and 21 (Scheme 3B), where the incipient
carbocation is intramolecularly intercepted by the primary hydroxy group.11
Scheme 3: Products formed during the PPTS-initiated C–C bond cleavage/rearrangement of 13a and 13b. Products 21 and 10 were
formed in a 1:0.2 ratio alongside with a C1-C2 cleavage/rearrangement product.11
Treatment of 13b with N-bromosuccinimide yields 25 (Scheme 4A), where a bridging ether linkage has formed
via the intermediacy of 23 and 24, whereas exposure of diastereomer 13a to the same conditions gives a lactone
28 via 26 and 27 (Scheme 4B).12
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Scheme 4. NBS-promoted selective C1–C4 bond cleavage/rearrangement of 13.
All the rearrangements of the pinene derivatives described thus far have involved the cleavage of the more
substituted C1–C4 bond. In molecules such as 13, the C1–C4 bond is the weaker, longer bond (compare X-ray
bond length in 13a: C1–C2 = 1.551 Å, C1–C4 = 1.567 Å; 13b: C1–C2 = 1.535 Å, C1–C4 = 1.589). In addition,
the cleavage of the C1-C4 bond favors the antiperiplanar relationship with either the epoxide (in 14 and 16;
Scheme 2A and 2B) or the bromonium moiety (in 23; Scheme 4A and 4B). These observations are consittent
with previous observations for pinene derivatives.7c In order to access natural product cores such as 2 and 3, the
less substituted, proximal, C1–C2 bond has to be cleaved. To achieve this goal, we sought to employ transition
metal complexes. It is well established that transition metal complexes can be sterically and electronically tuned
(by the choice of metal or ligand) to exhibit a preference for the carbon (1°, 2° or 3°) on which the metal would
reside on an incipient organometallic intermediate (e.g., primary C(sp3)-[M] species vs. a tertiary C(sp3)-[M]).
This outcome can either be thermodynamic (if the process is reversible) or kinetic (i.e., reflected in the
transition state energies).2,13 Over the last decade, significant advances have been made in the use of transition
metal complexes to facilitate the opening of strained cyclic compounds.13 Of the complexes that have been
reported to effect these transformations, Rh complexes have emerged as the most generally applicable.14
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We initiated our Rh-catalyzed ring opening investigations using conditions developed by Murakami15 and by
Cramer16 with 13a/b as the substrates (Scheme 5). Cyclohexenones 2 and 3 as well as 29 and 31 and phenol
side product 30 were obtained following complete consumption of the starting material under the stated
conditions. All of the observed products result from selective C1–C2 bond cleavage (C1–C4 ring opening
products have not been observed). Following optimization, conditions to selectively access 2, 29, 3 as well as
3017 were identified.18 For diastereomer 13a, the addition of S-BINAP as a ligand to the standard conditions was
beneficial19 and resulted in the formation of 29 as the exclusive diastereomer20 (with respect to the C5
stereocenter, Scheme 5). The formation of 2 as the major product could be achieved only when [Rh(COD)OH]2
was used as the catalyst at low temperature (see entry 3).21 At the lower temperature (i.e., 40 °C) phenol 30 was
only observed in trace amounts, since the retro-aldol step that is required for its formation (see below) may
59 require a higher temperature to proceed. A longer reaction time (Scheme 5, entry 3: 48 h vs. entry 1: 1.5 h)
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allowed us to isomerize 29 to the thermodynamically favored conjugated enone 2 (compare also Scheme 5
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bottom: isomerization of 31 to 3). However, with diastereomer 13b as the substrate, the standard conditions
with a catalytic amount of [Rh(COD)OH]2 in the absence of S-BINAP proved superior, giving 3 in high yield.22
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Scheme 5. Selective Rh-catalyzed C1–C2 bond cleavage/rearrangement of 13.
Mechanistically, products 2 and 3 could arise from a simple protonolysis of the alkyl-Rh intermediate 2-Rh
(Scheme 6B). However, a rationale for the formation of 29, 31, and 30 required further insight into the
mechanism of the C–C bond cleavage process. To this end, exposure of 13a-Ac (Scheme 6C), bearing an acetyl
group on the primary hydroxyl, to the reaction conditions led to clean conversion, suggesting that
deprotonation of the primary hydroxyl in 13a is not a requirement for the Rh-catalyzed cyclobutanol opening.
In contrast, bis-acetyl substrate 13a-Ac2 did not react, which supports the importance of deprotonation
involving the tertiary hydroxy group of 13a to the cyclobutane opening step.23 We have also conducted
deuteration studies to gain more insight into the fate of the initially formed organo-Rh intermediate (i.e., 2-Rh).
Using diastereomer 13a-D2 (Scheme 6A) in the presence of D2O, with [Rh(COD)OH]2 as catalyst and S-BINAP
as a ligand, we observed 98% D incorporation in 29-D at C5 and none at C2, indicating that the newly
introduced hydrogen at C2 is likely delivered intramolecularly. This newly introduced proton at C2 could either
result from a 1,3-Rh shift24 (Scheme 6B, Path A) or through a series of isomerization reactions (occurring by -
H elimination and re-addition of [Rh-H];25 Scheme 6B, Path B). In Path A (i.e., after alkoxy-Rh 13a-Rh
undergoes selective C1–C2 bond activation to give alkyl-Rh complex 2-Rh), an ensuing 1,3-Rh shift would
yield -allyl-Rh intermediate 29a-Rh via 2’-Rh. Metal enolate 29a-Rh, may be protonated or deuterated to give
29a-E as a single diastereomer. This diastereoselectivity could arise from the fact that the primary OH/OD
group triggers the protonation/deuteration, since a mixture of diastereomers (29a-E) is observed for the
protonation of 29a-Rh where R = Ac. However, this position (i.e., C5) is fairly acidic and epimerization was
observed when the reaction was allowed to proceed over longer periods, and during silica gel chromatographic
purification. However, in the crude reaction mixture, only a single diastereomer was observed i.e., 29a-E
(where E, R = H, D). Alternatively, in Path B, alkyl-Rh intermediate 2-Rh or the allylic Rh species (2’-Rh) may
undergo -H-elimination followed by isomerization to give 32/33, which converts to 30 by retro-aldol reaction.
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O
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(98% D; >95:5 d.r.)
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OR
Selective
C1-C2 activation
[Rh]
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-H Elim.
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[Rh]
[Rh]
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-CH2O
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Isomerization
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OH
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30
R = H
C.
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Cs2CO3 (1.5 equiv),
t-butyl acrylate (5 equiv)
Me
OR"
OR
Me
Me
Me
Me
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Me
Me
C6D6, 70 °C, 1 d
O
OAc
OH
(92% yield)
13a
13a-Ac
13a-Ac
13a
(R' = H; R" = Ac)
2 (R', R" = Ac)
(R', R'' = H)
33-Ac
(70% yield)
30
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from
from
Me
[Rh(COD)OH]2 (10 mol %)
S-BINAP (20 mol %)
t-butyl acrylate (5 equiv)
5
Me
OH
Me
O
C6D6, 65 °C, 1.5 h
70% (>90% by NMR)
29-H
from
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Scheme 6. A: Deuteration studies; B: Mechanistic hypothesis of the Rh(I)-mediated transformations; C: Reactions with t-butyl
acrylate as an additive. (add. = addition, elim.=elimination, epim.=epimerization)
In an attempt to intercept the presumed [Rh-H] species that may be generated from 2-Rh, we added t-butyl
acrylate as a [Rh-H]-acceptor (Scheme 6C). In the presence of t-butyl acrylate (5 equiv), 13a is converted to
phenol 30 under the stated conditions. However, 13a-Ac, bearing an acetyl group, is selectively converted to
33-Ac under the same conditions, supporting the intermediacy of dienone 3326 (where R = H, Scheme 6B) in the
formation of phenol 30.27 Changing the ligand from COD to S-BINAP resulted in a substantial increase in the
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selectivity of the product formation (compare entries 1 to 2 in Scheme 5). An even more significant difference
was observed when t-butyl acrylate was added to the reaction mixture; with COD as ligand, phenol 30 was
obtained as the sole product (see Scheme 6C). On the other hand, using S-BINAP as the ligand (under otherwise
identical conditions, Scheme 6C), 29-H was formed as the major product, without any trace of 30 observed. It
therefore appears that when using S-BINAP as the ligand, a direct 1,3-Rh shift (Path A, Scheme 6B) is
dominant over Path B. However, the mechanism of the 1,3-Rh migration16 remained to be fully elucidated.
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On the basis of our combined observations, a 1,3-Rh migration would most likely occur through C–H activation
involving 2-Rh.28 In the expected C–H activation process, the Rh migrates from a thermodynamically less
favored alkyl C(sp3) to a more favored allylic C(sp3) position, (see 2-Rh2’-Rh/29a-Rh, Scheme 6). The
likelihood of such an allylic C(sp3)–H activation step is in agreement with the recent elegant observations of
Lam and coworkers. 29 In their studies, the unexpected migration of Rh from a thermodynamically more favored
vinyl C(sp2) to a less favored allylic C(sp3) position via C–H activation was observed.
To support the proposed C–H activation in the 1,3-Rh migration, we have undertaken computational analysis of
the overall process (A  F) as summarized in Figure 3.30
Figure 3. Energy profile of the CC-/CH-activation and reductive elimination steps for the transformation of 13a-Rh  2’-Rh.
Numbers represent relative energies reported in kcal mol-1 at the DFT/M06-L/6-311+G(d,p)/LanL2DZ-F level in benzene and include
zero-point energy correction. Numbers in brackets are gas-phase energies from IRC calculation and do not include zero-point energy
correction.
We found that the C–C bond activations (A  TS1  B) with either COD (blue lines) or S-BINAP (red lines)
as ligands, show reasonable activation barriers of 3.9 and 7.7 kcal mol-1, respectively. However, the most
important difference was found in the stereospecific 1,3-Rh migration step by an oxidative C–H insertion and
ensuing reductive elimination process (C  F via transition states TS2 and TS3). A total energy demand of
27.4 kcal mol-1 was found when S-BINAP was modeled as the ligand, and 29.4 kcal mol-1 for COD. In general,
these barriers indicate the feasibility of such a 1,3-Rh-migration through C–H activation. Although the barrier
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for the C–H activation (C  D) is lower when COD is modeled as the ligand (G0 = 2.0 kcal -1), the reductive
elimination (E  F) was calculated to be lower by 3.7 kcal mol-1 for the S-BINAP ligand. The lower overall
barrier of the Rh-shift process for the S-BINAP system (G0 = 2.0 kcal -1) may indicate that with this ligand, a
C–H activation scenario is kinetically more favored than in the case with COD as the ligand.
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Experimentally, such a C(sp3)–H bond activation is supported by several observations. First, tricycle 21
(Scheme 7A) is converted to 3 upon exposure to a catalytic amount of the Rh-precatalyst and R-BINAP.
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Scheme 7. A: Selective Rh-catalyzed C-C/C-H activation for 21 and stereospecific synthesis of 36. B: Energy profile of the
stereospecific 1,4-[Rh] shift G  J. Numbers represent relative energies reported in kcal mol-1 at the DFT/M06-L/6-
311+G(d,p)/LanL2DZ-F level in benzene and include zero-point energy correction. Numbers in brackets are gas-phase energies from
IRC calculation and do not include zero-point energy correction.
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We believe this transformation proceeds via 34, which following a net 1,4-Rh migration by C–H activation
affords 35 that undergoes -alkoxy elimination to give 3. Of note, when 21 is subjected to the standard
conditions (i.e., in the absence of R-BINAP, see Scheme 7A), the addition of t-butyl acrylate as a hydride
acceptor leads to the exclusive formation of 36,31 while in the presence of R-BINAP (blue highlighting in
Scheme 7A), 3 is formed as the major product. These observations suggest that with BINAP as ligand, a
stereospecific Rh-shift is dominant, whereas with COD as the ligand, -H elimination becomes significant,
leading to a complex reaction mixture, presumably proceeding through an isomerization process.
For the transformation of 21 to 3, the isomerization pathway25 is very unlikely, since the re-addition of [Rh-H],
bearing the bulky R-BINAP ligand, would have to occur from the sterically less accessible -face (i.e., concave
face) of 36 in order to give 3 where both vicinal Me-groups are syn disposed.
19 The unlikelihood of a Rh-H isomerization pathway is further supported by the observation that in the reaction of
cyclohexanone 36 with in-situ generated [Rh–H], 3 is not observed as a product.32 The activation barrier for a
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stereospecific 1,4-Rh migration28 proceeding by C(sp3)–H activation was computed at 19.6 kcal mol-1 (see
Scheme 7B) and the barrier for the subsequent reductive elimination was computed as 8.7 kcal mol-1, which are
in agreement with reported systems.30
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28
Conclusion
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30
31
In summary, a series of enantiopure cyclohexenone and cyclohexanone derivatives (e.g., 2, 3, 17, and 36) that
32 comprise the cores of several natural products (4, 5, 8, and 11, respectively) have been accessed from readily
33
34
available carvone. Key to these transformations is a selective C–C bond activation/cleavage. Traditional
electrophilic reagents as well as Rh(I) complexes were employed in order to achieve complementary C–C bond
cleavages. Our mechanistic investigations into the Rh-catalyzed C–C activation indicate that a subsequent Rh
migration most likely proceeds by C–H activation. To the best of our knowledge, this work represents the first
observations of a 1,3- and 1,4- C(sp3) to C(sp3) Rh migration occurring through C–H bond activation.33
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Supporting Information Available
Experimental and computational details, analytical and supplemental data for the prepared compounds can be
found in the electronic supporting information. . This information is available free of charge via the internet at
http://pubs.acs.org.
Acknowledgments
The authors thank the Rothschild Foundation and VATAT (The Israeli Council for Higher Education) for
postdoctoral fellowships to A.M. and the DAAD (German Academic Exchange Service) for a postdoctoral
fellowship to M.W. We thank Dr. A. DiPasquale for solving the crystal structures, supported by NIH Shared
Instrument Grant (S10-RR027172) as well as NSF CHE-0840505 for funding computational resources at UCB
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and Dr. Kathleen Durkin for assistance. Funding was in part provided by the NSF under CCI center for selective
C-H functionalization (CHE-1205646)
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References and Notes
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[1]
For reviews see: a) Ackermann, L. Acc. Chem. Res. 2014, 46, 281; b) Engle, K. M.; Mei, T.-S.; Wasa,
M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788; c) Ackermann, L.; Modern Arylation Methods, Wiley-
VCH, Weinheim, 2009; d) Bergman, R.G. Science 1984, 223, 902.
[2]
a) Murakami, M.; Ito, Y. in Topics in Organometallic Chemistry. Vol. 3, Springer, Berlin 1999, pp 97;
b) Jun, C. H. Chem. Soc. Rev. 2004, 33, 610; c) Rybtchinski, B.; Milstein, D. Angew. Chem. Int. Ed.
1999, 38, 870; d) Marek, I.; Masarwa, A.; Delaye, P.-O.; Leibeling, M. Angew. Chem. Int. Ed. 2015,
−C Bond activation" Vol 346, Springer, Berlin
54, 414; e) Dong, G. (Ed.), Top. Curr. Chem. “C
2014;
f) Ruhland, K. Eur. J. Org. Chem. 2012, 2683; g) Aïssa, C. Synthesis 2011, 3389; h) Murakami, M.;
Matsuda, T. Chem. Commun. 2011, 47, 1100; i) Park, Y.J.; Park, J.-W.; Junn, C.-H. Acc. Chem. Res.
2008, 41, 222; j) Murakami, M.; Makino, M.; Ashida, S.; Matsuda, T. Bull. Chem. Soc. Jpn. 2006, 79,
1315; k) Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715; l) Jun, C.-H. Chem. Soc. Rev.
2004, 33, 610; m) Perthuisot, C.; Edelbach, B. L.; Zubris, D. L.; Simhai, N.; Iverson, C. N.; Müller, C.;
Satoh, T.; Jones, W. D. J. Mol. Catal. A 2002, 189, 157.
[3]
[4]
For a recent example, see: Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed. 2012,
51, 8960.
Bermejo, F. A.; Mateos, A. F.; Escribano, A. M.; Lago, R. M.; Burón, L. M.; López, M. R.; González,
R. R. Tetrahedron 2006, 62, 8933–8942.
38 [5]
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40
X-Ray structures were visualized with CYLview, 1.0b; Legault, C. Y., Université de Sherbrooke, 2009
(http://www.cylview.org). Most of the hydrogen atoms are removed for clarity.
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[6]
Cyclobutanes have an inherent ringstrain of 28 kcal/mol, see ref 13a.
43
[7]
a) Erman, M.B.; Kane, B. J. Chem. Biodivers. 2008, 5, 910; b) Mann, J.; Davidson, R. S.; Hobbs, J. B.;
Banthorpe, D. V.; Harborne, J. B. Natural Products, Addison Wesley Longman Ltd. Harlow, UK,
1994, pp 309; c) Bhattacharyya, P. K; Prema, B. R.; Kulkarni, B. D.; Pradhan, S. K. Nature 1960, 187,
689.
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49
[8]
50
Gan, L.-S.; Zhan, Z.-J.; Yang, S.-P.; Yu; J.-M. J. Asian Nat. Prod. Res. 2006, 8, 589.
51
[9]
52
a) Shibata, S.; Nakahara, M. Chem. Pharm. Bull. 1963, 11, 372; b) Aimi, N.; Inaba, M.; Watanabe, M.;
Shibata, S. Tetrahedron 1969, 25, 1825; c) Yoshikawa, M.; Harada, E.; Kawaguchi, A.; Yamahara, J.;
Murakami, N.; Kitagawa, I. Chem. Pharm. Bull. 1993, 41, 630; d) Martín-Rodríguez, M.; Galán-
Fernández, R.; Marcos-Escribano, A.; Bermejo, F. A. J. Org. Chem. 2009, 74, 1798.
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57
[10]
This is the first non-biotransformation based preparation of 10; for an earlier preparation see:
Miyazawa, M.; Miyamoto, Y. J. Mol. Catal. B. 2004, 27, 83.
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[11]
See the supporting information for additional details and rearrangements where also a cleavage of the
C1-C2 bond was observed.
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[12]
[13]
Treating 13a with Br2 instead of NBS also forms lactone 28 in similar yield.
a) Seiser, T.; Saget, T.; Tran, D.N.; Cramer, N. Angew. Chem. Int. Ed. 2011, 50, 7740; b) Masarwa, A.;
Marek, I. Chem. Eur. J. 2010, 16, 9712.
12 [14]
a) Murakami, M. Chem. Rec., 2010, 10, 326; b) Cramer, N.; Seiser, T. Synlett 2011, 449.
For a recent example, see: Yada, A.; Fujita, S.; Murakami, M. J. Am. Chem. Soc. 2014, 136, 7217.
Seiser, T.; Cramer, N. J. Am. Chem. Soc. 2010, 132, 5340.
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[15]
[16]
[17]
[18]
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See Scheme 6B for the selective synthesis of 30.
The relative configurations of 2 and 3 were elucidated by NOESY experiments and 13C-NMR
calculations, see supporting information.
[19]
Using R-BINAP resulted in a “mismatch”, impeding the ring opening reaction and giving a complex
reaction mixture.
[20]
[21]
The relative configuration of 29 was elucidated by NOESY NMR, see supporting information.
Product 2 can also be obtained by a) treating 29 with a base (i.e. Cs2CO3, see supporting information)
or b) under the [Rh(COD)OH]2 conditions and a longer reaction time.
[22]
[23]
[24]
[25]
[26]
For the most efficient access to 3, see Scheme 7 top.
The same results were obtained for the other diastereomer.
For a 1,3-Rh shift by a proto-demetallation process see reference 16.
Matsuda, T.; Shigeno, M.; Murakami, M. J. Am. Chem. Soc, 2007, 129, 12086.
Importantly, dienone 33-Ac could offer opportunities for oxygenation at C3 to access the
spiroindicumides.
[27]
[28]
Diastereomers 13b and 13b-Ac gave similar results, see supporting information for details.
For examples of 1,4- and 1,5-Rh shifts from C(sp3) to C(sp2) by C-H activation, see: a) Seiser, T.;
Roth, O. A.; Cramer, N. Angew. Chem. Int. Ed. 2009, 48, 6320; b) Ishida, N.; Shimamoto, Y.; Yano,
T.; Murakami, M. J. Am. Chem. Soc., 2013, 135, 19103.
[29]
[30]
Burns, D. J.; Lam, H. W. Angew. Chem., Int. Ed. 2014, 53, 9931.
This setup was recently used in many DFT investigations for Rh-catalyzed reactions, see: Yu, H.;
Wang, C.; Yang, Y.; Dang, Z.-M. Chem. Eur. J. 2014, 20, 3839 and references therein. See the
supporting information for further computational details.
[31]
For a racemic access/isolation to such natural product (cores), see: a) Nagaraju, C.; Prasad, K. R.
Angew. Chem. Int. Ed. 2014, 53, 10997; b) Shiao, H.-Y.; Hsieh, H.-P.; Liao, C.-C. Org. Lett. 2008, 10,
449; c) Milborrow, B. V. Phytochemistry 1975, 14, 1045; d) Powell, R. G.; Weisleder, D.; Smith, C. R.
J. Org. Chem. 1986, 51, 1074.
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[32]
Although we observe slow conversion of 36 (ca. 45% after 1 day, ca. 70% after 3 days), only
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unidentified side products were formed. See the supporting information for details.
[33]
CCDC 1051272 (10), CCDC 1051273 (13a), CCDC 1051274 (13b), CCDC 1051275 (15), CCDC
1051276 (17), CCDC 1051277 (18), CCDC 1051278 (28) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.
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