Chiral N-heterocyclic carbenes in natural product synthesis: Application of Ru-catalyzed asymmetric ring-opening/cross-metathesis and Cu-catalyzed allylic alkylation to total synthesis of baconipyrone C

Article abstract of DOI:10.1002/anie.200700501

(Chemical Equation Presented) Chiral carbenes as major players: Two recently discovered chiral N-heterocyclic carbene (NHC) complexes play a crucial role in a concise enantioselective total synthesis of baconipyrone C (see scheme). An (NHC)Cu complex catalyzes a double asymmetric allylic alkylation (AAA), and an (NHC)Ru complex catalyzes an asymmetric ring-opening/cross- metathesis (AROM/CM) to establish the absolute configuration of the target. RCM = ring-closing metathesis.

Full text of DOI:10.1002/anie.200700501

Communications
DOI: 10.1002/anie.200700501
Natural Products
Chiral N-Heterocyclic Carbenes in Natural Product Synthesis: Appli-
cation of Ru-Catalyzed Asymmetric Ring-Opening/Cross-Metathesis
and Cu-Catalyzed Allylic Alkylation to Total Synthesis of
Baconipyrone C**
Dennis G. Gillingham and Amir H. Hoveyda*
Natural product synthesis and development of catalysts and
methods benefit from a critical relationship.[1] A new process
provides access to alternative, and often more efficient,
routes—it renders a previously untenable scheme feasible.
Total synthesis, an important testing ground for a new catalyst
and the transformation that it promotes, is particularly
valuable when it necessitates the discovery of a method that
might otherwise remain unknown. Herein, we report an
enantioselective synthesis of the unusual siphonariid metab-
olite baconipyrone C.[2] The total synthesis demonstrates the
utility of recently developed N-heterocyclic carbene (NHC)
complexes (Scheme 1); it provides the first application of Ru-
catalyzed asymmetric olefin metathesis.[3–4] Completion of the
synthesis necessitated the development of a new protocol for
catalytic asymmetric allylic alkylation (AAA) as well—the
first with an alkylaluminum reagent.[5,6]
The retrosynthesis for baconipyrone C is presented in
Scheme 2. We envisioned that pseudo-C2-symmetric diketone
I might be prepared via 1,6-diene II; this approach would
allow us to investigate whether chiral (NHC)Cu complexes
developed for AAA reactions[5,6] provide efficient access to
1,6-diene II via III. Segment IV would be synthesized by
reductive cleavage of pyran V, secured by asymmetric ring-
opening/cross-metathesis (AROM/CM) of VI.[3e] The chiral
catalyst-based approach in Scheme 2 thus differs fundamen-
tally from the well-established chiral auxiliary-based diaste-
reoselective aldol strategies[7] employed in the only other
recorded total synthesis of this target.[8]
The catalytic double AAA proposed for
conversion of III to II establishes, in a single
operation, the two stereogenic centers in I,
but would present a number of challenges as
well. One set of complications is inherent to
processes that are promoted by a single chiral
catalyst and that involve diastereo- and
enantioselective formation of proximal ste-
reogenic centers. The initially established
center can strongly influence, often in com-
petition with the chiral catalyst, the sense of
stereocontrol in the subsequent bond forma-
tion. Thus, as illustrated in Scheme 3, addi-
tion of the first Me unit to diene III would
generate two new stereogenic centers. The
first alkylation delivers VII (or the corre-
sponding syn isomer), wherein the central
carbon, unlike III or the desired final product
II, is a stereogenic center. Selective forma-
tion of II requires that the second alkylation
occur preferentially with the opposite sense
of relative stereochemistry (vs. III!VII);
Scheme 1. NHC-based complexes examined and utilized for the total synthesis of
baconipyrone C.
otherwise, meso-VIII AAA would be generated. That is, II
can only be obtained selectively if the chiral catalyst—not the
stereogenic centers in VII—dictates the course of the second
alkylation.
[*] D. G. Gillingham, Prof. A. H. Hoveyda
Department ofChemistry
Merkert Chemistry Center
Boston College
The substitution pattern of the olefins in III poses another
challenge. This class of olefins represents a difficult and
relatively unexplored set of substrates for catalytic AAA,[5]
the first examples of which were only recently reported.[9]
Existing disclosures do not, however, contain reactions that
involve acyclic substrates with a non-aromatic olefin sub-
stituent.
Chestnut Hill, MA 02467 (USA)
Fax: (+1)617-552-1442
E-mail: amir.hoveyda@bc.edu
[**] We are grateful to the NIH (GM-47480) and NSF (CHE-0213009) for
financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 2. Retrosynthetic analysis for baconipyrone C. AAA=asymmetric allylic alkylation; AROM/CM=asymmetric ring-opening/cross-meta-
thesis; PG=protecting proup; LG=leaving group.
of the anti diastereomer—desirable in the first part of
the double AAA but not the second, which, as a
result, must be controlled by the chiral catalyst. Next,
we probed alkylations in the presence of chiral NHC
complexes 1–3 (Scheme 1) and commercially avail-
able CuCl2·2H2O. Complexes 1[6a] and 3,[11] unlike 2,[3f]
(Table 1, entries 6–8) catalyze the desired process in
98% and 94% ee, respectively. Chiral NHC–sulfonate
3 is, however, more efficient than NHC–aryloxide 1.
The observation that NHC complex
3 with
Scheme 3. Catalyst versus substrate control in the catalytic double AAA.
CuCl2·2H2O promotes the reaction beyond 50%
conversion to afford 8 in high ee suggests that this
system can influence the AAA of the slower-reacting
To identify conditions for the catalytic double AAA, we
investigated related reactions of rac-7 (Table 1). Protocols
involving dialkylzinc reagents, highly effective for AAA of
disubstituted and even the sterically congested a-trisubsti-
tuted olefins,[3f,6a] miss the mark in this case (Table 1,
entries 1–4). We thus turned our attention to the more
Lewis acidic and nucleophilic Me3Al.[10] Reaction with CuCN
proved encouraging (entry 5): in contrast to alkylation with
Me2Zn (10% conv. in 24 h, 200 mol% CuCN; entry 1),
reaction with Me3Al proceeds to greater than 98% conver-
sion in 4 h with 15 mol% Cu salt, affording a 9:1 mixture of
8:9 (>20:1 SN2’:SN2). The observed diastereoselectivity
implies that substrate-controlled alkylation favors formation
enantiomer of 7 (S-7). As illustrated in Scheme 4, variations
in diastereoselectivity (8:9) and the enantiomeric purity of
anti diastereomer 8 (Table 1, entries 8–10) shed light on the
ability of chiral NHC 3 to control the outcome of the catalytic
double AAA. A transformation that proceeds to completion
and is fully controlled by the catalyst would be a parallel
kinetic resolution[12] that furnishes a 1:1 mixture of 8:9.
Specifically, anti isomer 8 would be the sole product from
AAA of the faster reacting R-7 (conv. ꢀ 50%), and syn
isomer 9 would be generated exclusively through the remain-
ꢁ
der of the process (the C C bond would be formed with the
same sense of enantioselectivity in both cases). Any amount
of ent-8 formed would be as a result of substrate control.
Variations in diastereoselectivity
(from 1:1) or lowering of enantio-
selectivity in the formation of 8 at
Table 1: Initial investigation ofCu-catalyzed AAA. [a]
high conversion would imply loss
of catalyst control in alkylation of
the slower-reacting S-7. As the
catalytic AAA approaches com-
Entry Alkyl metal Catalyst (mol%)
Conv. t [h] SN2’:SN2[b] 8:9[b] e.r. [%] 8[c] ee [%] 8[c]
[%][b]
plete conversion,
obtained in 1.5:1 ratio and enan-
tiopurity of decreases only
8 and 9 are
1
2
3
4
5
6
7
8
9
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me3Al
Me3Al
Me3Al
Me3Al
Me3Al
Me3Al
CuCN (200)
10 24
>20:1
–
–
9:1
–
–
–
–
–
–
–
–
–
–
8
1 (7.5); CuCl2·2H2O (15)
2 (7.5); CuCl2·2H2O (15)
3 (7.5); CuCl2·2H2O (15)
CuCN (15)
1 (7.5); CuCl2·2H2O (15)
2 (7.5); CuCl2·2H2O (15)
3 (7.5); CuCl2·2H2O (15)
3 (7.5); CuCl2·2H2O (15)
3 (7.5); CuCl2·2H2O (15)
<2 24
<2 24
<2 24
slightly (Table 1, entries 8–10),
indicating that the Cu complex
derived from 3 would be effective
in promoting the double AAA.
The requisite substrate (13)
was prepared from commercially
available 10 in seven steps with
greater than 98% E selectivity
(Scheme 5).[13] The high stereo-
chemical purity of the trisubsti-
–
–
>98
4
45 24
15 24
>20:1
>20:1
nd
9:1
20:1
9:1
2.6:1
1.7:1
–
–
99:01
nd
97:03
95:05
98
nd
94
90
89
68
89
95 24
1
>20:1
4.5 >20:1
>20:1
10
1.5:1 94.5:5.5
1
[a] Reactions were performed under N2. [b] Determined by 400-MHz H NMR analyses ofunpuriifed
mixtures. [c] Determined by chiral GLC analysis (see the Supporting Information for details). nd=not
determined.
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81% ee but with substantially higher efficiency
(Table 2, entry 2): greater than 98% conversion
is observed in 15 h (vs. 96% conv. in 44 h with
5b). The higher activity of 6b, generated in situ
from 22 and NaI,[3f] allows the catalyst loading
to be reduced to 2.5 mol% (Table 2, entry 3)
without loss of selectivity. The reaction pro-
ceeded to greater than 98% conversion even
with 0.7 mol% 6b (Table 2, entry 4), albeit with
diminution of selectivity (73% ee vs. 81% ee).
Importantly, the improved activity of Ru cata-
lyst 6b (vs. 6a) and the possibility of perform-
ing AROM/CM at ꢁ158C results in enhanced enantioselec-
tivities (88–89% ee vs. 73–81% ee), lower amounts of oligo-
meric by-products (derived from 18 or 20) and higher isolated
Scheme 4. Product distribution as an indication ofcatalyst versus substrate control in
Cu-catalyzed AAA of rac-7.
tuted olefins was secured by treatment of commercially
available 10 with Br2, followed by elimination with DBU to
afford 11 (> 98% E) after reduction (DIBAL-H) and
protection of the resulting primary alcohol. Conversion of
vinyl bromide 11 to 13 was accomplished as shown in
Scheme 5.[14] Treatment of 13 with 7.5 mol% 3, 15 mol%
CuCl2·2H2O, and Me3Al (ꢁ158C, 16 h) afforded the desired
14 in greater than 98% ee and 61% yield. The meso diene 15
was isolated in 8% yield along with 16 in 27% yield and
98% ee. Alkylation with CuCN (200 mol%) afforded a 1:1.5
mixture of 14:15; thus, in the second alkylation catalyst
control overcomes substrate preferences with 8:1 selectivity
(14:15). Formation of 16 (98% ee and > 98% de), arising
from an SN2’/SN2 sequential alkylation, underlines the higher
barrier to the SN2’ mode of reaction (to give 14 and 15) in the
second alkylation. Zirconocene-mediated removal of the allyl
group[15] and ozonolytic cleavage of the olefins furnished 17 in
greater than 98% ee and de.
Enantioselective synthesis of the other acyclic segment
(see IV, Scheme 2) began with Ru-catalyzed AROM/CM of
oxabicycle 18. As reported before, with 5 mol% of chiral
complex 5b[3e] (Scheme 1) and styrene, pyran 19 can be
obtained in 55% yield and 80% ee (Table 2, entry 1); 5 mol%
catalyst loading and 44 h are required for greater than 90%
conversion. In search of a more efficient and selective process,
we turned to the recently developed chiral carbene 6b.[3f]
Under similar conditions, with complex 6b, 19 is formed in
Table 2: Initial investigation ofRu-catalyzed AROM/CM. [a]
Entry Substrate Catalyst
(mol%)
Equiv T [8C];
styrene t [h]
Conv.
ee
[%][b]
Yield
[%][c]
;
[%][d]
1
2
3
18
18
18
5b (5)
6b (5)
2+22+Nal
(2.5)
4
4
4
22; 44
96; 55 80
22; 15 >98; 56 81
22; 14 >98; 44 81
4
5
6
18
18
20
2+22+Nal
(0.7)
2+22+Nal
(2.0)
2+22+Nal
(2.0)
4
8
8
22; 14 >98; 46 73
ꢁ15; 20 >98; 64 89
ꢁ15; 20 >98; 62 88
[a] Reactions were performed under N2. [b] Conversions were determined
by 400-MHz 1H NMR analyses ofunpurief d mixtures. [c] Yields of
isolated product after purification. [d] Determined by chiral HPLC
analysis (see the Supporting Information for details).
Scheme 5. Enantioselective synthesis ofdiketone rfagment 17. a) Br2, CH2Cl2, 08C, 4 h; DBU, THF, 658C, 1 h. b) 1.1 equivalents ofDIBAl-H,
toluene, 08C to 228C, 1 h; 72% overall yield. c) TBSCl, 5 mol% DMAP, Et3N, CH2Cl2, 4 h; 90% yield. d) 2.1 equivalents of tBuLi, THF, ꢁ788C,
=
15 min; 0.5 equivalents ofHCO 2Et, ꢁ788C to 228C, 45 min. e) NaH, H2C CHCH2Br, DMF, 228C, 12 h; 43% overall yield. f) nBu4NF, THF, 228C,
3 h; 91% yield. g) (EtO)2P(O)Cl, 5 mol% DMAP, Et3N, CH2Cl2, 4 h; 87% yield. h) 7.5 mol% 3, 15 mol% CuCl2·2H2O, 4 equivalents ofMe 3Al,
THF, ꢁ158C, 16 h. i) 1.1 equivalents of[Cp 2ZrCl2], 2.2 equivalents of nBuLi, THF, ꢁ788C, 1 h; 80% yield. j) O3, pyridine/CH2Cl2, ꢁ788C, 5 min;
PPh3, 1 h; 65% yield. DBU=1,8-diazobicyclo[5.4.0]undec-7-ene; DIBAl-H=diisobutylaluminum hydride; TBSCl=tert-butyldimethylsilyl chloride;
DMAP=4-dimethylaminopyridine.
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yields (62–64% vs. 44–56%). The Ru-catalyzed AROM/CM
is easily carried out on a multigram scale.[16]
The primary alcohols of 28 exhibit different rates of
reaction when subjected to TBSOTf and 2,6-lutidine (ꢁ788C,
CH2Cl2). When 28 was treated with 1.2 equivalents of
TBSOTf, 50% of desired product was obtained; 30% of the
bis(silyl) product was also formed, but the undesired mono-
silyl product was not detected (< 2%). To facilitate selective
silylation, substoichiometric amounts of TBSOTf were used
and the unreacted starting material was recycled (60% yield
after four runs). The remaining primary alcohol was oxidized,
affording 29 in 98% yield.
We utilized the aldol addition of an enolate derived from
30 to aldehyde 29 as the first step towards installment of the g-
pyrone moiety. Reactions involving a variety of enolate
derivatives were investigated. The lithium enolate obtained
from reaction of ketone 30 (> 98% Z) with LDA proved to be
the most efficient in furnishing 31 (88% yield). The mixture
of the resulting enol ether isomers (4:1) was subjected to
Dess–Martin periodinane and the diketone was treated with
DBU to afford g-pyrone 32 in 64% overall yield for two
steps.[23] Removal of the silyl ethers in 32 required the use of
TAS-F in DMF[24] (98% yield).[25] Synthesis of carboxylic acid
33 and fragment coupling with 17 was accomplished according
to previously reported procedures, delivering (+)-baconipyr-
one C (unnatural enantiomer).[8]
The total synthesis was completed as shown in Scheme 6.
The precursor to the acyclic g-pyrone-containing polypropi-
onate segment was unmasked by treatment of 21 with Na/
NH3, providing 23 as a single alkene isomer (< 2% con-
jugated b-alkylstyrene) in 70% yield. Synthesis of 23 pro-
ceeded site-selectively: 4-hydroxypyran derived from com-
petitive cleavage of the PMB ether was not detected (< 2%),
and the acyclic diol corresponding to 23 was isolated as the
only by-product (22% yield).[17] Preparation of allylic phos-
phate 26 (or its trans isomer) required access to allylic alcohol
25. Attempts to synthesize 25 (or its trans isomer) through
catalytic cross-metathesis[18] of 23 (or its protected deriva-
tives) with various olefin partners and catalysts resulted in less
than 20% conversion.[19] An alternative approach, involving
catalytic Si-tethered ring-closing metathesis,[20] was therefore
pursued. Subjection of 23 to chlorodimethylallylsilane, fol-
lowed by treatment of the resulting diene with Ru carbene
4
[21] and oxidation of the cyclic product 24 with H2O2 and KF
furnished cis allylic alcohol 25 in 73% yield. Conversion to
phosphate 26 and subsequent diastereoselective allylic alky-
lation with Me2Zn and CuCN[22] provided 27 in 98% de and
75% overall yield. Protection of the secondary alcohol,
ozonolytic cleavage, and reductive workup afforded 28 (72%
yield).
The present total synthesis is based on bond disconnec-
tions rendered feasible by the availability of new chiral Ag-,
Scheme 6. Enantioselective synthesis ofrfagment 32 and completion ofthe total synthesis. a) Na, NH 3, tBuOH, Et2O, ꢁ788C, 3 min.; 70% yield.
=
b) 1.2 equivalents ofClMe 2Si(CH2(H)C CH2), imidazole, CH2Cl2, 228C, 45 min; 2 mol% 4, toluene, 228C, 40 min; H2O2, KF, KHCO3, THF/MeOH,
16 h; 73% yield. c) 1.1 equivalents of(EtO) 2P(O)Cl, Et3N, 5 mol% DMAP, CH2Cl2, 4 h. d) 4 equivalents ofMe 2Zn, 1.5 equivalents ofCuCN, THF,
ꢁ158C, 22 h; 75% overall yield for two steps. e) 1 equivalent of TBSOTf, 2,6-lutidine, CH2Cl2, ꢁ788C, 1 h. f) O3, CH2Cl2/MeOH, ꢁ788C, 10 min;
NaBH4, 228C, 2 h; 72% overall yield for two steps. g) 0.4 equivalents of TBSOTf, 2,6-lutidine, CH2Cl2, ꢁ788C; 60% yield after four runs. h) DMP,
CH2Cl2, 228C, 30 min; 98% yield. i) 1.1 equivalents ofLDA, 30, THF, ꢁ788C, 2 h; 29, ꢁ788C, 2 h; 88% yield. j) DMP, CH2Cl2, 228C, 1 h. k) DBU,
THF, 608C, 4 h; 64% overall yield for two steps. l) 8 equivalents of TAS-F, DMF, 4 h; 98% yield. m) (COCl)2, DMSO, ꢁ788C; NEt3, ꢁ308C,
=
CH2Cl2. 2 h. n) NaClO2, Na2HPO4, Me2C CMe2, tBuOH, H2O, 1 h; 61% overall yield for two steps. o) 1 equivalent of 17, 30 equivalents of1,3,5-
trichlorobenzoyl chloride, 50 equivalents ofDMAP, 20 equivalents ofEt 3N, toluene, 228C, 30 min; 68% yield. p) 2 equivalents ofDDQ, 10% pH 7
buffer in CH2Cl2, 1 h; 90% yield. THF=tetrahydrofuran; TBSOTf=tert-butyldimethylsilyl triflate; LDA=lithium diisopropylamine; DMP=Dess–
Martin periodinane; DMSO=dimethylsulfoxide; DDQ=2,3-dichloro-5,6-dicyanoquinone; TAS-F=tris(dimethylamino)sulfonium difluorotrimethyl-
silicate; TIPS=triisopropylsilyl; PMB=p-methoxybenzyl.
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Communications
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utility of enantioselective (NHC)Ru-catalyzed olefin meta-
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lations.[26]
[9] a) C. A. Falciola, K. Tissot-Croset, A. Alexakis, Angew. Chem.
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2277; Angew. Chem. Int. Ed. 2005, 44, 2235 – 2237.
[10] For use of trialkylaluminum reagents in Cu-catalyzed asymmet-
ric conjugate additions, see: M. dꢁAugustin, L. Palais, A.
Alexakis, Angew. Chem. 2005, 117, 1400 – 1402; Angew. Chem.
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[11] M. K. Brown, T. L. May, C. A. Baxter, A. H. Hoveyda, Angew.
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[12] E. Vedejs, M. Jure, Angew. Chem. 2005, 117, 4040 – 4069; Angew.
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Received: February 4, 2007
Published online: April 5, 2007
Keywords: allylic alkylation · asymmetric catalysis ·
.
natural products · N-heterocyclic carbenes · olefin metathesis
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[13] Preliminary studies indicated that a benzyl ether gives rise to
side products during AAA; the alcohol was therefore masked as
an allyl ether.
[14] See the Supporting Information for full experimental details
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[22] Lower amounts of CuCN (e.g., 20 mol%) led to the formation of
substantial amounts of dihydrofuran by-product derived from
phosphate displacement by the secondary allylic alcohol. With
1.5 equiv CuCN, about 10% of this by-product is generated.
[23] Previously reported methods for synthesis of g-pyrones through
triketone cyclizations proved to be inefficient; see: a) H.
Arimoto, S. Nishiyama, S. Yamamura, Tetrahedron Lett. 1990,
31, 5619 – 5620; b) T. Lister, M. V. Perkins, Angew. Chem. 2006,
118, 2622 – 2626; Angew. Chem. Int. Ed. 2006, 45, 2560 – 2564.
[24] K. A. Scheidt, H. Chen, B. C. Follows, S. R. Chemler, D. Coffey,
W. R. Roush, J. Org. Chem. 1998, 63, 6436 – 6437.
[25] Alternative protocols (e.g., aqueous HOAc, nBu4NF) led to low
yields owing to decomposition of starting material and/or
product.
[6] For catalytic AAA reactions promoted by chiral NHC-based
complexes, see: a) A. O. Larsen, W. Leu, C. Nieto-Oberhuber,
J. E. Campbell, A. H. Hoveyda, J. Am. Chem. Soc. 2004, 126,
11130 – 11131; b) S. Tominaga, Y. Oi, T. Kato, D. K. An, S.
Okamoto, Tetrahedron Lett. 2004, 45, 5585 – 5588; c) referen-
ce [2f]; d) S. Okamoto, S. Tominaga, N. Saino, K. Kase, K.
Shimoda, J. Organomet. Chem. 2005, 690, 6001 – 6007; e) Y. Lee,
A. H. Hoveyda, J. Am. Chem. Soc. 2006, 128, 15604 – 15605.
[7] Modern Aldol Reactions (Ed.: R. Mahrwald), Wiley-VCH,
Weinheim, 2004.
[26] The full scope of the Cu-catalyzed AAA with alkylaluminum
reagents will be reported in a separate account.
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Angew. Chem. Int. Ed. 2007, 46, 3860 –3864