Ring-contraction strategy for the practical, scalable, catalytic asymmetric synthesis of versatile γ-quaternary acylcyclopentenes

Article abstract of DOI:10.1002/anie.201007814

Contraction action! A simple protocol for the catalytic asymmetric synthesis of highly functionalized γ-quaternary acylcyclopentenes (see schematic) in up to 91 % overall yield and 92 % ee has been developed. The reaction sequence employs a palladium-catalyzed enantioselective alkylation reaction and exploits the unusual stability of β-hydroxy cycloheptanones to achieve a general and robust method for performing two-carbon ring contractions. Copyright

Full text of DOI:10.1002/anie.201007814

Communications
DOI: 10.1002/anie.201007814
Ring Contraction
Ring-Contraction Strategy for the Practical, Scalable, Catalytic
Asymmetric Synthesis of Versatile g-Quaternary Acylcyclopentenes**
Allen Y. Hong, Michael R. Krout, Thomas Jensen, Nathan B. Bennett, Andrew M. Harned, and
Brian M. Stoltz*
Dedicated to Dr. Ahamindra Jain
Highly substituted cyclopentanes are a common structural
motif integrated into thousands of natural products.[1]
Selected examples of bioactive compounds containing this
basic structural unit include the hamigerans (2),[2a] steroids
(3),[2b] pleuromutilin antibiotics (4),[2c] cyathane diterpenoids
(5),[2d] cyclic botryococcenes (6),[2e] and anti-HBV schisanwil-
sonenes (7a–c)[2f] (Figure 1). Synthetic methods for the
asymmetric preparation of cyclopentanoid cores with multi-
ple functional group handles are highly desirable because
they allow for the strategic synthesis of these and other
natural products.[3] Toward this goal, we envisioned that
functionalized chiral units such as acylcyclopentene 1 could
serve as valuable synthetic intermediates (Figure 1). Here, we
describe a general and enantioselective preparation of
versatile chiral acylcyclopentenes[4,5] that combines a catalytic
asymmetric alkylation reaction[6] and a facile two-carbon ring
contraction.
Our work in this area began with observation of the
unusual reactivity of seven-membered ring vinylogous esters
compared to their six-membered ring counterparts. Although
Figure 1. Representative natural products possessing cyclopentanoid
core structures with quaternary stereocenters.
[*] A. Y. Hong, Dr. M. R. Krout, Dr. T. Jensen, N. B. Bennett,
LiAlH4 reduction of vinylogous ester 8 gave expected enone
9[7] as the major product after acidic workup (Scheme 1A),
subjecting the analogous seven-membered ring vinylogous
ester (10a) to identical reaction conditions led to cyclo-
heptenone 11a as only a minor product (Scheme 1B).
Interestingly, the major product was identified as stable b-
Prof. A. M. Harned, Prof. B. M. Stoltz
Warren and Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering, Division of Chemistry and Chemical Engi-
neering, California Institute of Technology, 1200 E. California Blvd,
MC 101-20, Pasadena, CA 91125 (USA)
Fax: (+1)626-395-8436
E-mail: stoltz@caltech.edu
[**] This publication is based on work supported by Award No. KUS-11-
006-02, made by King Abdullah University of Science and Technol-
ogy (KAUST). The authors wish to thank NIH-NIGMS
(R01M080269-01), Amgen, Abbott, Boehringer Ingelheim, and
Caltech for financial support. M.R.K. acknowledges Eli Lilly for a
predoctoral fellowship. T.J. acknowledges the Danish Council for
Independent Research/Natural Sciences for a postdoctoral fellow-
ship. Materia, Inc. is gratefully acknowledged for the donation of
catalysts. Lawrence Henling and Dr. Michael Day are gratefully
acknowledged for X-ray crystallographic structure determination.
The Bruker KAPPA APEXII X-ray diffractometer used in this study
was purchased via an NSF CRIF:MU award to Caltech (CHE-
0639094). Prof. Sarah Reisman, Dr. Scott Virgil, Dr. Christopher
Henry, and Nathaniel Sherden are acknowledged for helpful
discussions. Dr. David VanderVelde and Dr. Scott Ross are
acknowledged for NMR assistance. The Varian 400 MR instrument
used in this study was purchased via an NIH award to Caltech (NIH
RR027690). Dr. Mona Shahgholi and Naseem Torian are acknowl-
edged for high-resolution mass spectrometry assistance.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007814.
Scheme 1. Anomalous reactivity of seven-membered ring vinylogous
esters and discovery of a ring-contraction reaction.
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Angew. Chem. Int. Ed. 2011, 50, 2756 –2760

hydroxyketone 12a.[8] The lack of appreciable b-elimination
even under acidic conditions suggests that subtle, but
fundamental differences in ring conformational preferences
between six- and seven-membered rings may lead to the
strikingly different product distributions.[9]
Table 2: Scope of the Pd-catalyzed enantioselective alkylation of cyclic
vinylogous esters.[a]
To further examine the inherent reactivity of b-hydroxy-
ketone 12a, we exposed the compound to a variety of basic
reaction conditions. Treatment of b-hydroxyketone 12a with
LiOtBu in tBuOH afforded acylcyclopentene 1a in 53% yield
without any evidence of direct b-hydroxy elimination to
enone 11a (Scheme 1). Overall, the reaction constitutes a
two-carbon ring contraction that likely proceeds through a
Entry
Substrate
14
R
Product
10
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
14a
14b
14c
14d
14e
CH3
CH2CH3
CH2Ph
CH2C CH
CH2CH2CH CH2
10a
10b
10c
10d
10e
91
89
98
88
95
88
92
86
89
87
retro-aldol
fragmentation/aldol
cyclization
pathway.
Although some examples of the preparation of acylcyclopen-
tenes from seven-membered rings[10] are known, general ring-
contraction methods have not been demonstrated with g-
quaternary stereocenters and catalytic asymmetric routes are
unprecedented.
ꢀ
=
6
14 f
10 f
90
90
Enticed by this initial finding, we investigated the effect of
different bases on product formation (Table 1). Alcohol
additives in combination with LiOH in THF improved the
7
8
14g
14h
10g
10h
99
96
86
87
CH2CH2CN
Table 1: Ring-contraction optimization.[a]
9
14i
14j
14k
10i
10j
10k
97
98
90
85
83
80
10
11
Entry
Base
Additive
Solvent
T [8C]
Yield [%][b]
1
2
3
4
LiOtBu
LiOH
LiOH
LiOH
none
tBuOH
THF
THF
40
60
60
60
71 (53)[c]
78
tBuOH
HFIP[d]
87
[a] Conditions: b-ketoester (1.0 equiv), [Pd2(pmdba)3] (2.5 mol%), (S)-
tBu-PHOX (6.25 mol%) in PhCH3 (0.1m) at 308C; pmdba=4,4’-
methoxydibenzylideneacetone. [b] Yield of isolated products. [c] Deter-
mined by HPLC or SFC analysis using a chiral column. LDA=lithium
diisopropylamide, Ts=4-toluenesulfonyl.
CF3CH2OH
THF
96 (84)[c]
[a] Conditions: b-hydroxyketone (1.0 equiv), base (1.5 equiv), additive
(1.5 equiv) in solvent (0.1m) at indicated temperature for 9–24 h. [b] GC
yield using an internal standard. [c] Yield of isolated products in
parentheses. [d] HFIP=1,1,1,3,3,3-hexafluoro-2-propanol. THF=tetra-
hydrofuran.
10a in 91% yield and 88% ee (Table 2, entry 1).[17,18]
Substituents such as ethyl, benzyl, propargyl, homoallyl, and
2,4-pentadienyl groups were well tolerated in the reaction,
giving similarly high yields and enantioselectivity (Table 2,
entries 2–6). A number of heteroatom-containing substrates
were explored to test if more diverse functionality could be
incorporated into our target acylcyclopentenes (Table 2,
entries 7–11). b-Ketoesters bearing a 2-chloroallyl substitu-
tent readily underwent the enantioselective alkylation reac-
tion (Table 2, entry 7). Gratifyingly, compounds that possess
Lewis basic moieties readily furnished the desired products
without complications (Table 2, entries 8 and 9). Even indoles
and free aldehydes could be incorporated into the cyclo-
heptenone products (Table 2, entries 10 and 11).
The chiral vinylogous esters (e.g., 10) prepared above
allowed us to examine the scope of the ring-contraction
reaction (Table 3). Substrate reduction with LiAlH4 and base-
promoted rearrangement of vinylogous esters bearing g-alkyl
substituents provided access to the corresponding acylcyclo-
pentenes in excellent yields over the two-step protocol
yield for the reaction (Table 1, entries 2–4), with
CF3CH2OH[11] enabling the production of 1a in 96%
yield.[12] It is interesting to note that enone 11a was not
observed under any of the surveyed conditions. Among the
conditions that promote the desired ring contraction, the
combination of LiOH and CF3CH2OH in THF offered a mild,
efficient, and selective method for further studies (Table 1,
entry 4).
With an optimized procedure for the ring contraction, we
turned our attention to the asymmetric synthesis of various
quaternary a-substituted vinylogous esters (e.g., 10,
Table 2).[13,14] A number of racemic b-ketoester substrates
(e.g., 14) for catalytic enantioselective alkylation could be
obtained by acylation of parent vinylogous ester 13 with allyl
cyanoformate[15] and trapping with a range of electrophiles
under basic conditions.[16] Application of our standard enan-
tioselective decarboxylative alkylation reaction condi-
tions[6,13] to substrate 14a produced chiral vinylogous ester
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Communications
Table 3: Ring-contraction substrate scope.
formed well in the ring-contraction chemistry. With the
combination of asymmetric alkylation and ring contraction,
we achieved a route to substituted acylcyclopentenes with a
wide range of functionality at the g-quaternary stereocenter.
To demonstrate the practicality and scalability of the
method, the a-methyl b-ketoester 14a was converted to the
corresponding acylcyclopentene 1a in 69% yield over three
steps on 15 g scale (Scheme 2A).[16] Notably, the multigram
Entry Substrate R1
R2
Product Overall
10
1
Yield
[%][e]
1[a,d]
2[a,d]
3[a,d]
4[a,d]
5[a,d]
10a
10b
10c
10d
10e
CH3
CH2CH3
CH2Ph
CH2CH CH2 1a
84
90
86
95
87
=
=
CH2CH CH2 1b
=
CH2CH CH2 1c
ꢀ
=
CH2C CH
CH2CH CH2 1d
=
=
CH2CH2CH CH2 CH2CH CH2 1e
6[a,d]
10 f
CH2CH CH2 1 f
91
=
7[a,d]
8[a,d]
10g
10h
CH2CH CH2 1g
92
85
=
=
CH2CH2CN
CH2CH CH2 1h
9[b,d]
10i
CH2CH CH2 1i
80
=
10[a,d] 10j
CH2CH CH2 1j
87
=
11[c,d,f] 10l
CH2OTBDPS
(CH2)3OTBDPS
CH2CH CH2 1l
91
85
=
12[c,d,g] 10m
CH2CH CH2 1m
=
13[a,d,h]
81
87
14[a,d,g]
[a] Reduction conditions A: vinylogous ester (1.0 equiv), LiAlH4
(0.55 equiv) in Et2O (0.2m) at 08C, then 10% aqueous HCl quench.
[b] Reduction conditions B: 1) vinylogous ester (1.0 equiv), DIBAL
(1.2 equiv) in PHCH3 (0.03m) at À788C; 2) oxalic acid·2H2O in
MeOH (0.02m). [c] Reduction conditions C: vinylogous ester
(1.0 equiv), CeCl3·7H2O (1.0 equiv), NaBH4 (3.0 equiv) in MeOH
(0.02m) at 08C, then 10% aqueous HCl in Et2O at 08C. [d] Ring-
contraction conditions: b-hydroxyketone (1.0 equiv), CF3CH2OH
(1.5 equiv), LiOH (1.5 equiv) in THF (0.1m) at 608C. [e] Yield of isolated
products over 2–3 steps. [f] See the Supporting Information for
experimental procedures for substrate synthesis. [g] Prepared from
14k. See the Supporting Information. [h] Prepared from 14a. See the
Supporting Information. DIBAL=diisobutylaluminum hydride, TBDPS=
tert-butyldiphenylsilyl.
Scheme 2. Multigram ring contraction, enrichment of ee values by
recrystallization, and organometallic modified ring-contraction
sequence. Color code for ORTEP plot of structure 16 in (B): green I,
blue N, red O, gray C. TFE=2,2,2-trifluoroethanol.
protocol proceeds with reduced catalyst loading and at higher
reaction concentrations for the asymmetric alkylation step.
Additionally, the enantiopurity of the acylcyclopentene 1a
can be increased to 98% ee by recrystallization of semi-
carbazone 15 (Scheme 2B).[16] Hydrolysis of semicarbazone
15 with aqueous HCl enabled facile recovery of 1a. Further
derivatization afforded X-ray quality crystals of 16 for
verification of absolute configuration.[20] To enable access to
b-substituted acylcyclopentenes, addition of nBuMgBr to 10a
resulted in formation of tertiary b-hydroxyketone 17 (Sche-
me 2C).[16] Application of modified ring-contraction condi-
tions allowed access to acylcyclopentene 18.
(Table 3, entries 1–6). The chloroallyl-, nitrile-, and indole-
containing substrates could be transformed with similarly
high yields using the same conditions (Table 3, entries 7, 8,
and 10). Alternatively, DIBAL allowed smooth conversion of
vinylogous ester 10i containing an N-basic pyridine (Table 3,
entry 9). Milder reductions under Luche conditions enabled
facile conversion of silyl ether substrates (Table 3, entries 11
and 12).[19] Furthermore, trans-propenyl substituted (Table 3,
entry 13) and spirocyclic substrates (Table 3, entry 14) per-
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Angew. Chem. Int. Ed. 2011, 50, 2756 –2760

With a versatile, enantioselective synthesis of g-quater-
nary acylcyclopentenes 1 in hand, we sought to demonstrate
the further synthetic utility of these compounds. By combin-
ing site-selective manipulations in short reaction sequences
(1–4 steps), any of five reactive handles present in acylcyclo-
pentene 1 can be functionalized (Scheme 3, sites A–E).
[1] For a review of general methods for cyclopentane synthesis by
ring contraction, see: L. F. Silva, Jr., Tetrahedron 2002, 58, 9137 –
9161.
[2] a) K. D. Wellington, R. C. Cambie, P. S. Rutledge, P. R. Berg-
quist, J. Nat. Prod. 2000, 63, 79 – 85; b) J. S. Mills, J. Chem. Soc.
1956, 2196 – 2202; c) F. Kavanagh, A. Hervey, W. J. Robbins,
Proc. Natl. Acad. Sci. USA 1951, 37, 570 – 574; d) J. Peng, K.
Walsh, V. Weedman, J. D. Bergthold, J. Lynch, K. L. Lieu, I. A.
Braude, M. Kelly, M. T. Hamann, Tetrahedron 2002, 58, 7809 –
7819; e) A. Behrens, P. Schaeffer, S. Bernasconi, P. Albrecht,
Org. Lett. 2000, 2, 1271 – 1274; f) W.-H. Ma, H. Huang, P. Zhou,
D.-F. Chen, J. Nat. Prod. 2009, 72, 676 – 678.
[3] For a review discussing our strategy of using natural product
structures to drive the development of enantioselective catalysis,
see: J. T. Mohr, M. R. Krout, B. M. Stoltz, Nature 2008, 455, 323 –
332.
[4] For an example of the preparation of substituted acylcyclopen-
tenes from five-membered rings, see: B. M. Trost, G. M.
Schroeder, Chem. Eur. J. 2005, 11, 174 – 184.
[5] For selected examples of the preparation of substituted acylcy-
clopentenes from six-membered rings, see: a) S. R. Wilson, R. B.
Turner, J. Org. Chem. 1973, 38, 2870 – 2873; b) E. G. Gibbons, J.
Am. Chem. Soc. 1982, 104, 1767 – 1769; c) L. A. Paquette, K.
Dahnke, J. Doyon, W. He, K. Wyant, D. Friedrich, J. Org. Chem.
1991, 56, 6199 – 6205.
[6] a) D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126,
15044 – 15045; b) J. T. Mohr, D. C. Behenna, A. M. Harned,
B. M. Stoltz, Angew. Chem. 2005, 117, 7084 – 7087; Angew.
Chem. Int. Ed. 2005, 44, 6924 – 6927; c) J. T. Mohr, B. M. Stoltz,
Chem. Asian J. 2007, 2, 1476 – 1491; d) M. Seto, J. L. Roizen,
B. M. Stoltz, Angew. Chem. 2008, 120, 6979 – 6982; Angew.
Chem. Int. Ed. 2008, 47, 6873 – 6876.
[7] G. Stork, R. L. Danheiser, J. Org. Chem. 1973, 38, 1775 – 1776.
[8] While a recent report shows a single example of a similar b-
hydroxyketone, we believe the unusual reactivity and synthetic
potential of these compounds has not been fully explored: H.
Rinderhagen, J. Mattay, Chem. Eur. J. 2004, 10, 851 – 874.
[9] Differences in ring conformational preferences can also be
Scheme 3. Versatility and synthetic utility of acylcyclopentenes.
1
observed in the H NMR spectra of 1,3-cyclohexadione (exclu-
sively ketoenol form) and 1,3-cycloheptadione (exclusively
diketo form), see: N. Do, R. E. McDermott, J. A. Ragan, Org.
Synth. 2008, 85, 138 – 146.
Through careful implementation of these transformations,
diverse monocarbocyclic (1j, 18–23), spirocyclic (24 and 25),
and fused polycyclic structures (26 and 27) can be obtained.[16]
In summary, we have developed a catalytic enantioselec-
tive synthesis for the preparation of densely functionalized
chiral acylcyclopentenes in excellent yields and enantioselec-
tivities. The protocol exploits a highly efficient Pd-catalyzed
asymmetric alkylation reaction and a newly developed, mild
two-carbon ring contraction. The important chiral building
blocks formed using this method can undergo a variety of
synthetic transformations and will serve as valuable inter-
mediates for the total synthesis of natural products. Efforts
directed toward these ends are currently underway and will be
reported in due course.
[10] For selected examples of the preparation of substituted acylcy-
clopentenes from seven-membered rings, see: a) J. J. Frankel, S.
Julia, C. Richard-Neuville, Bull. Soc. Chim. Fr. 1968, 4870 – 4875;
b) C.-H. Jun, C. W. Moon, S.-G. Lim, H. Lee, Org. Lett. 2002, 4,
1595 – 1597.
[11] For a discussion of the properties of fluorinated alcohols and
their use, see: J.-P. Begue, D. Bonnet-Delpon, B. Crousse, Synlett
2004, 18 – 29.
[12] a) A lithium alkoxide species is presumably generated in situ
based on pKa values, see: F. G. Bordwell, Acc. Chem. Res. 1988,
21, 456 – 463; b) The use of LiOCH2CF3 as base provided
comparable results (90% isolated yield), supporting the like-
lihood of its in situ formation under the reaction conditions.[16]
[13] For examples of the asymmetric alkylation of vinylogous esters
or thioesters from our laboratory, see: a) D. E. White, I. C.
Stewart, R. H. Grubbs, B. M. Stoltz, J. Am. Chem. Soc. 2008, 130,
810 – 811; b) S. R. Levine, M. R. Krout, B. M. Stoltz, Org. Lett.
2009, 11, 289 – 292; c) K. V. Petrova, J. T. Mohr, B. M. Stoltz,
Org. Lett. 2009, 11, 293 – 295.
Received: December 12, 2010
Published online: February 24, 2011
[14] For a related example of the asymmetric alkylation of vinylogous
thioesters, see: B. M. Trost, R. N. Bream, J. Xu, Angew. Chem.
2006, 118, 3181 – 3184; Angew. Chem. Int. Ed. 2006, 45, 3109 –
3112.
Keywords: aldol reaction · allylation · asymmetric catalysis ·
rearrangement reactions · ring contraction
.
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Communications
[15] a) L. N. Mander, S. P. Sethi, Tetrahedron Lett. 1983, 24, 5425 –
5428; b) D. M. X. Donnelly, J.-P. Finet, B. A. Rattigan, J. Chem.
Soc. Perkin Trans. 1 1993, 1729 – 1735.
[16] See Supporting Information for experimental procedures.
[17] a) K. Tani, D. C. Behenna, R. M. McFadden, B. M. Stoltz, Org.
Lett. 2007, 9, 2529 – 2531; b) M. R. Krout, J. T. Mohr, B. M.
Stoltz, Org. Synth. 2009, 82, 181 – 193.
[18] [Pd2(pmdba)3] is preferable to [Pd2(dba)3] in this reaction for
ease of separation of pmdba from the reaction products during
purification. dba = dibenzylideneacetone.
[19] Exposure of aldehyde 10k (Table 2, entry 11) to our standard
reduction/ring contraction conditions produced a mixture of
products as shown below:
[20] CCDC 686849 (16) contains 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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