Computationally guided stereocontrol of the combined C-H functionalization/cope rearrangement

Article abstract of DOI:10.1002/anie.201103568

Diastereoselectivity in control: The synthetic utility of the C-H functionalization/Cope rearrangement reaction has been greatly expanded by the design of substrates that will react through a boat transition state instead of a chair transition state. The products are formed with the opposite diastereoselectivity as previously obtained (see scheme, ABSA= acetamidobenzenesulfonylazide).

Full text of DOI:10.1002/anie.201103568

Communications
DOI: 10.1002/anie.201103568
À
C H Functionalization
À
Computationally Guided Stereocontrol of the Combined C H
Functionalization/Cope Rearrangement**
Yajing Lian, Kenneth I. Hardcastle, and Huw M. L. Davies*
À
Developing practical methods for C H functionalization has
attracted considerable attention from the synthetic commun-
ity.[1] One of the major challenges in this field is to achieve
transformations that are not only site selective, but also
stereoselective.[2] One highly stereoselective intermolecular
the transition states for other products were energetically
accessible. In particular, the s-cis chair transition state was
only 2 kcalmolÀ1 more stable than the s-cis boat transition
state. Inspired by the computational studies, the current study
is directed towards switching the diastereoselectivity of the
CHCR reaction by forcing the reaction to proceed through
the s-cis boat transition state B instead of the s-cis chair
transition state A (Figure 1).
À
À
C H functionalization method is the combined C H func-
tionalization/Cope rearrangement (CHCR) between allylic
C H bonds and vinylcarbenoid compounds. This trans-
[3]
À
formation can generate two new stereocenters. When chiral
dirhodium catalysts such as [Rh2{(S)-dosp}4][4] (see Scheme 2)
are used, the products are formed essentially as single
diastereomers and in the majority of cases with > 97% ee.
This method has been developed into a powerful protocol for
the synthesis of natural products and pharmaceutical tar-
gets.[3] In all of the studies reported to date, the stereochem-
istry is consistent with a reaction occurring on the s-cis
conformation of the vinylcarbenoid and proceeding through a
chair transition state, as illustrated in [Eq. (1)].
Figure 1. The chair and boat transition states for the CHCR reaction.
TMS=trimethylsilyl.
To limit the number of potential transition states available
for the CHCR reaction, the study described herein was
conducted with b-siloxyvinyldiazoacetates. The carbenoid
derived from (E)-vinyldiazoacetates has little preference for
the s-trans over the s-cis configuration,[5] whereas the internal
substituent in the vinylcarbenoid derived from the b-silox-
yvinyldiazoacetate strongly prefers the s-cis configuration.[5]
In the s-trans configuration, the siloxy group would point
towards the “wall” of the catalyst (Scheme 1).
Previous studies have shown that [Rh2{(S)-ptad}4]
(Scheme 2) is the optimum chiral catalyst for asymmetric
reactions with siloxyvinyldiazoacetate 1.[7] To test a baseline
substrate, the [Rh2{(S)-ptad}4]-catalyzed reaction of diazo-
acetate 1 with the siloxycyclohexene 2a was examined
[Eq. (2); TFT= trifluorotoluene, TBDPS = tert-butyldiphe-
nylsilyl]. Characterizable material was obtained by hydrolysis
Recently, we completed a detailed computational study of
the CHCR reaction.[5] The reaction was shown to be an
asynchronous process, involving an initial hydride transfer
event followed by carbon–carbon bond formation. Even
though all the previously reported examples of CHCR
reactions are highly diastereoselective, the calculations
showed that different product outcomes are possible, depend-
ing on whether the s-cis or s-trans configurations of the
vinylcarbenoid species[6] are involved and whether the
reaction proceeds through a chair or a boat transition state.
Furthermore, the calculations on a model system showed that
[*] Y. Lian, Dr. K. I. Hardcastle, Prof. Dr. H. M. L. Davies
Department of Chemistry, Emory University
1515 Dickey Drive, Atlanta, GA 30322 (USA)
E-mail: hmdavie@emory.edu
Homepage: http://www.chemistry.emory.edu/
[**] This material is based on work supported by the National Science
Foundation under the Center for Chemical Innovation in Stereose-
À
lective C H Functionalization (CHE-0943980) and by the National
Institutes of Health (GM080337).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103568.
Scheme 1. The s-cis and s-trans configurations of the rhodium carbe-
noid derived from 1.
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CHCR reaction generating a mixture of diastereomeric
products.
Scheme 2. Structures of [Rh2{(S)-dosp}4] and [Rh2{(S)-ptad}4].
Further evaluation of the proposed transition states D and
E related to the formation of 5 suggested that the cyclopentyl
ring could be incorporated into the boat transition state E
(Figure 3). Furthermore, it became evident that a 2-substitu-
ent on the cyclopentenyl ring would cause the chair transition
state D to be destabilized. If this proved to be the case, then
the opposite diastereomeric series of products would become
accessible.
of the silyl enol ether of the crude product followed by
conversion of the b-keto ester into the b-keto-a-diazoacetate
3a in 74% yield for the three-step sequence.[8] The b-keto-a-
diazoacetate 3a was formed as a single diastereomer with
89% ee. The reaction with the bulky siloxycyclohexene 2b
selectively afforded the diazoacetate 3b with even higher
enantioselectivity (97% ee). The relative and absolute con-
figuration of product 3b was determined unambiguously by
X-ray crystallography.[9]
Figure 3. Transition state models for reaction of 1 with cyclopentenes.
The observed stereochemistry is consistent with the
previously published examples of the CHCR reaction and
would occur in a reaction proceeding through a chair
transition state.[3e] An examination of the two possible
transition states reveals that in the boat transition state C
the remainder of the cyclohexyl ring would point towards the
“wall” of the catalyst, and therefore, it would be reasonable to
propose that this arrangement would be unfavorable
(Figure 2).
The [Rh2{(S)-ptad}4]-catalyzed decomposition of siloxy-
diazoacetate 1 in the presence of 1,2-disubstituted cyclo-
pentenyl derivatives afforded the b-keto-a-diazoacetates 6–
11 (Scheme 3). In all cases, a single CHCR product was
produced with excellent diastereoselectivity (d.r. > 30:1) and
enantioselectivity (> 97% ee). In the case of the unsym-
metrical cyclopentene substrates, the resulting products, 6, 7,
À
and 9, are derived from site-selective C H functionalization
initiated at the methylene group allylic to the siloxy group.
The relative and absolute configuration of 7 was unambigu-
ously assigned by X-ray crystallography. The configurations
of products 9 and 10 were also unambiguously confirmed by
X-ray crystallographic analysis of products derived from them
(see the Supporting Information). In each case, the relative
configuration was consistent with a reaction proceeding
through a boat transition state, and is opposite to the products
3a and 3b derived from the cyclohexene derivatives 2a and
2b. The structures of 6, 8, and 11 were tentatively assigned by
assuming they are formed through a similar boat transition
state.
Normally, the CHCR reaction is influenced by the
presence of other stereogenic centers in the substrate and
high levels of enantiomeric differentiation have been repor-
ted.[3a–d] Consequently, we explored if a desymmetrization
would be feasible in a CHCR reaction. The reaction with
cyclopentene 12 successfully generated product 13 as a single
diastereomer with extremely high enantioselectivity [Eq. (4)].
This represents the first example of desymmetrization in the
Figure 2. The s-cis/boat transition state model for the reaction of 1
with 2.
We envisioned that a possible way to limit the steric
influence of the ring would be to use a smaller ring size.
Indeed, when the reaction was repeated with the siloxycyclo-
pentene 4, two diastereomers of the CHCR product 5 were
produced in a 4:1 ratio [Eq. (3)]. This is the first example of a
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Communications
containing {Rh2{(S)-ptad}4] (16.5 mg, 0.01 equiv) and substrate
(1.0 mmol, 1.0 equiv) in dried trifluorotoluene (6 mL) under argon.
The solution was warmed to room temperature over 2 h. The mixture
was concentrated under reduced pressure and then stirred with 5 g
silica gel in hexanes (15 mL) for 30 mins. The mixture was filtrated
and washed with several portions of Et2O. The organic solution was
concentrated under vacuum and the residue was purified by flash
chromatography on silica gel (5–30% diethyl ether in pentane) to
provide a colorless oil, which was dissolved in 5 mL dried CH3CN
containing p-ABSA (240 mg, 1.0 mmol, 1.0 equiv) and Et3N
(0.30 mL, 2.0 mmol, 2.0 equiv). The mixture was stirred for an
additional 3 h and then concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (5–30%
diethyl ether in pentane) to provide b-keto diazoacetates.
Received: May 24, 2011
Published online: August 30, 2011
À
Keywords: carbenoids · C H functionalization ·
Cope rearrangement · diastereoselectivity · rhodium
.
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Scheme 3. The CHCR reactions with cyclopentenyl derivatives.
TBS=tert-butyldimethylsilyl, TBDPS=tert-butyldiphenylsilyl.
CHCR reaction. The relative configuration of 13 inside the
ring was assigned by NOE studies and was consistent with the
outcome predicted by a boat transition state model (see the
Supporting Information), while the stereochemistry in the
chain was tentatively assigned assuming a boat transition
state.
À
[2] For recent examples of stereoselective C H functionalization, see
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In conclusion, the synthetic utility of the CHCR reaction
has been greatly expanded by the design of substrates that will
react through a boat transition state instead of a chair
transition state. This has led to the formation of the reversed
diastereomeric series of products in a highly stereoselective
manner. This study demonstrates the value of computational
studies, not only to rationalize a new synthetic process, but
also to identify opportunities to develop new reactions. The
results showcase the synthetic potential of using carbenoid
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À
chemistry to achieve highly enantioselective C H function-
alization reactions.
Experimental SectionÀ
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Typical procedure for the C H functionalization: A solution of (Z)-
methyl 2-diazo-3-((trimethylsilyl)oxy)pent-3-enoate (1) (365 mg,
1.6 mmol, 1.6 equiv) in dried trifluorotoluene (6 mL) was added by
syringe pump over 3 h at À208C to an oven-dried 25 mL flask
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[7] a) E. Nadeau, D. L. Ventura, J. A. Brekan, H. M. L. Davies, J.
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[9] CCDC 815184 (ent-3b from [Rh2{(R)-ptad)4]-catalyzed reaction),
815183 (7), 815179 (9a derived from 9), and 815180 (10b derived
from 10) 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.a-
c.uk/datarequest/cif.
[8] p-ABSA: p-Acetamidobenzenesulfonylazide (CAS 2158–14–7).
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