Enantioselective Total Synthesis of Erogorgiaene: Applications of Asymmetric Cu-Catalyzed Conjugate Additions of Alkylzincs to Acyclic Enones

Article abstract of DOI:10.1021/ja0305407

The first enantioselective synthesis of erogorgiaene (1), an inhibitor of mycobacterium tuberculosis, is disclosed. The total synthesis highlights the utility of asymmetric conjugate additions (ACA) of alkylzincs to acyclic α,β-unsaturated ketones catalyzed by peptidic phosphine ligands and (CuOTf)₂·C₆H₆. Moreover, several critical attributes of this catalytic C-C bond-forming reaction are illustrated in the context of the total synthesis; these include the significance of various structural features of the amino acid-based chiral ligands and the chiral ligand's effectiveness in reactions involving achiral and chiral substrates. In addition, the total synthesis showcases some of the special properties of nonphosphine Ru complex 3 as a highly effective catalyst for olefin cross-metathesis.

Full text of DOI:10.1021/ja0305407

Published on Web 12/13/2003
Enantioselective Total Synthesis of Erogorgiaene:
Applications of Asymmetric Cu-Catalyzed Conjugate
Additions of Alkylzincs to Acyclic Enones
Richard R. Cesati, III, Judith de Armas, and Amir H. Hoveyda*
Contribution from the Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
Received September 18, 2003; E-mail: amir.hoveyda@bc.edu
Abstract: The first enantioselective synthesis of erogorgiaene (1), an inhibitor of mycobacterium tuberculosis,
is disclosed. The total synthesis highlights the utility of asymmetric conjugate additions (ACA) of alkylzincs
to acyclic R,â-unsaturated ketones catalyzed by peptidic phosphine ligands and (CuOTf)2‚C6H6. Moreover,
several critical attributes of this catalytic C-C bond-forming reaction are illustrated in the context of the
total synthesis; these include the significance of various structural features of the amino acid-based chiral
ligands and the chiral ligand’s effectiveness in reactions involving achiral and chiral substrates. In addition,
the total synthesis showcases some of the special properties of nonphosphine Ru complex 3 as a highly
effective catalyst for olefin cross-metathesis.
enones.6,7 Thus, in the course of this study we demonstrate that
(i) Cu-catalyzed ACA can be carried out reliably on multigram
scale to obtain the desired acyclic â-alkylcarbonyls in high yield
and with excellent enantioselectivity and (ii) Cu-catalyzed ACA
can be used to control relative stereochemistry in instances
Introduction
During the past several years, efforts in these laboratories
have been focused on the discovery and development of new
catalytic enantioselective C-C bond-forming reactions.1
A
critical aspect of these investigations has been to utilize such
asymmetric methods in the total syntheses of biologically active
molecules.2 Through these studies, we explore the utility and
determine the limitations of different processes, as well as
identify ways in which various catalytic protocols can be used
sequentially3 to access a target molecule efficiently.4
It was in this context that we set out to develop an efficient
route for the enantioselective total synthesis of antimycobacterial
agent erogorgiaene 1.5 Our synthesis strategy was devised so
(2) For example, see: (a) Xu, Z.; Johannes, C. W.; Houri, A. F.; La, D. S.;
Cogan, D. A.; Hofilena, G. E.; Hoveyda, A. H. J. Am. Chem. Soc. 1997,
119, 10302-10316. (b) Johannes, C. W.; Visser, M. S.; Weatherhead G.
S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 8340-8347. (c) Murphy,
K. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4690-4691. (d) Deng,
H.; Jung, J.-K.; Liu, T.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2003, 125, 9032-9034.
(3) For an early application of this concept (sequential use of catalytic
transformations in a total synthesis), see: Houri, A. F.; Xu, Z.; Cogan, D.
A.; Hoveyda, A. H. J. Am. Chem. Soc. 1995, 117, 2943-2944.
(4) For examples of enantioselective total syntheses where catalytic reactions
play a prominent role, see: (a) Han, X.; Corey, E. J. Org. Lett. 1999, 1,
1871-1872. (b) Fox, M. E.; Li, C.; Mariano, J. P., Jr.; Overman, L. E. J.
Am. Chem. Soc. 1999, 121, 5467-5480. (c) Lebel, H.; Jacobsen, E. N. J.
Org. Chem. 1998, 63, 9624-9625. For a review on the utility of catalytic
enantioselective reactions in target oriented synthesis, see: (d) Hoveyda,
A. H. In Stimulating Concepts in Chemistry; Vogtle, F., Fraser Stoddart,
J., Shibasaki, M., Eds.; Wiley-VCH: Weinheim, Germany, 2000; pp 145-
162.
(5) Rodriguez, A. D.; Ramirez, C. J. Nat. Prod. 2001, 64, 100-102.
(6) (a) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
124, 779-781. (b) Hird, A. W.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2003, 42, 1276-1279. For related transformations involving cyclic
substrates, see: (c) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 755-756. (d) Luchaco-Cullis, C. A.; Hoveyda, A.
H. J. Am. Chem. Soc. 2002, 124, 8192-8193. (e) Degrado, S. J.; Mizutani,
H.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 13362-13363.
(7) The uniqueness of amino acid-based ligands such as 2 (refs 6a,b) is tied to
the fact that the large majority of Cu-catalyzed asymmetric conjugate
additions of alkylmetals to enones involve cyclic systems, and nearly all
the reported cases regarding acyclic substrates (predominantly chalcones)
relate to reactions only with Et2Zn. For Cu-catalyzed enantioselective
conjugate addition of MeMgI to an acyclic enone (<10-76% ee), see:
(a) van Klaveren, M.; Lambert, F.; Eijkelkamp, J. F. M.; Grove, D. M.;
van Koten, G. Tetrahedron Lett. 1994, 35, 6135-6138. For Cu-catalyzed
asymmetric conjugate addition of Me3Al to acyclic enones (80-93% ee),
see: (b) Fraser, P. K.; Woodward, S. Chem.-Eur. J. 2003, 9, 776-783.
For related reviews, see: (c) Krause, N.; Hoffmann-Roder, A. Synthesis
2001, 171-196. (d) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002,
3221-3236. (e) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In
Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Wein-
heim, Germany, 2002, pp 224-258.
that it would benefit from the unique ability of amino acid-
based chiral phosphine ligands, such as 2, to effect Cu-catalyzed
asymmetric conjugate additions (ACA) of alkylzincs to acyclic
(1) (a) Hoveyda, A. H.; Morken, J. P. Angew. Chem., Int. Ed. Engl. 1996, 35,
1262-1284. (b) Hoveyda, A. H.; Heron, N. M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, 1999; pp 431-454. (c) Hoveyda, A. H. In
Handbook of Combinatorial Chemistry; Nicolaou, K. C., Hanko, R.,
Hartwig, W., Eds.; Wiley-VCH: Weinheim, Germany, 2002; pp 991-
1016. (d) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003,
42, 4592-4633.
9
96
J. AM. CHEM. SOC. 2004, 126, 96-101
10.1021/ja0305407 CCC: $27.50 © 2004 American Chemical Society

Enantioselective Total Synthesis of Erogorgiaene
A R T I C L E S
Scheme 1. Enantioselective Total Synthesis of Erogorgiaenea
a
(a) 5 mol % Pd(OAc)2, 2 equiv H2CdC(H)COMe, 2.5 equiv NaHCO3, 1 equiv n-Bu4NCl, DMF, 4 Å molecular sieves, 60 °C; 88%. (c) 5 mol %
Pd(PPh3)4, 1.2 equiv Bu3SnCCSiMe3, 1 mol % BHT, toluene, 100 °C; 96%. (d) 1.25 equiv LiTMP, 1.33 equiv TMSCl, THF, -78 °C; 9:1 selectivity, 97%.
(e) 1.2 equiv MeLi, THF, 0 °C; 1.2 equiv Tf2NPh, THF, -78 °C f 4 °C; 76%. (f) 5 mol % Pd(PPh3)4, 1.2 equiv Bu3SnH, 3 equiv LiCl, 5 mol % BHT,
THF, 60 °C; 82%. (g) K2CO3, MeOH, H2O, 22 °C; 96%. (k) 2 equiv NaBH4, MeOH, 0 °C. (l) 10 equiv Li, NH3, THF, -78 °C. (m) 1.2 equiv Dess-Martin
periodinane, CH2Cl2, 0 °C; 73% overall from 13. (n) 1.25 equiv LDA, 1.33 equiv TMSCl, THF; -78 °C; >95% regioselectivity, 95%. (o) O3, 10 equiv
NaHCO3, CH2Cl2, MeOH, -78 °C; 10 equiv Me2S; 83%. (p) 5 equiv LAH, Et2O, 22 °C; 98%. (q) 1.2 equiv I2, 1.2 equiv PPh3, 1.8 equiv imid, C6H6, 22
°C; 86%. (r) 20 mol % CuI, 1.4 equiv Me2CdC(H)MgBr, THF, 4 °C; 58%.
where the more classical cuprate reagents prove inadequate. The
total synthesis also showcases the special activity of Ru complex
3 in promoting olefin cross-metathesis reactions.8,9
as the catalyst in the presence of an amine base, the derived
saturated ketone was isolated as the major product. Subjection
of enone 5, on multigram scale, to 2.4 mol % chiral phosphine
2 and 1.0 mol % (CuOTf)2‚C6H6 in the presence of 3 equiv of
Me2Zn (48 h, at -15 °C) delivered â-methyl ketone 6 in
94% isolated yield and >98% ee. At this point, a Pd-cata-
lyzed Stille coupling with 5 mol % Pd(PPh3)4 and 1.2 equiv of
Bu3SnCCSiMe3 at 100 °C afforded terminal alkyne 7 in 96%
yield after silica gel chromatography. Attempts to obtain 7
through Pd-catalyzed Sonogashira coupling (10 mol % (PPh3)2-
(9) For an overview of chemistry regarding unique catalytic activity of Ru
complex 3 and related derivatives, see: (a) Hoveyda, A. H.; Gillingham,
D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.;
Harrity, J. P. A. Org. Biol. Chem., in press. For representative examples,
see: (b) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet. Chem.
2001, 624, 327-332. (c) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451-
1454. (d) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett 2001,
430-432. (e) Randl, S.; Connon, S. J.; Blechert, S. Chem. Commun. 2001,
1796-1797. (f) Cossy, J.; BouzBouz, S.; Pradaux, F.; Willis, C.; Bellosta,
V. Synlett 2002, 1595-1606. (g) Grela, K.; Harutyunyan, S.; Michrowska,
A. Angew. Chem., Int. Ed. 2002, 41, 4038-4040. (h) Grela, K.; Kim, M.
Eur. J. Org. Chem. 2003, 963-966. (i) Wakamatsu, H.; Blechert, S. Angew.
Chem., Int. Ed. 2002, 41, 2403-2405. (j) Royer, F.; Vilain, C.; Elkaim,
L.; Grimaud, L. Org. Lett. 2003, 5, 2007-2009. (k) Murphy, K. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4690-4691. (l) Lazarova,
T.; Chen, J. S.; Hamann, B.; Kang, J. M.; Homuth-Trombino, D.; Han, F.;
Hoffmann, E.; McClure, C.; Eckstein, J.; Or, Y. S. J. Med. Chem. 2003,
46, 674-676. (m) Hale, K. J.; Domostoj, M. M.; Tocher, D. A.; Irving,
E.; Scheinmann, F. Org. Lett. 2003, 5, 2927-2930. (n) Nosse, B.; Chhor,
R. B.; Jeong, W. B.; Bohm, C.; Reiser, O. Org. Lett. 2003, 5, 941-944.
(10) Jeffery, T. Tetrahedron 1996, 52, 10113-10130.
Results and Discussion
In the first section, the final synthetic route is presented
(Scheme 1). In subsequent sections, more detailed studies that
shed light on inner workings of several catalytic processes
encountered in the total synthesis will be discussed.
1. Enantioselective Total Synthesis of Erogorgiaene. Heck
coupling of methyl vinyl ketone with commercially available
dihalide 4 under the Jeffery conditions afforded R,â-unsaturated
ketone 5 in 88% isolated yield;10 when (PPh3)2PdCl2 was used
(8) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168-8179.
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J. AM. CHEM. SOC. VOL. 126, NO. 1, 2004 97

A R T I C L E S
Cesati, III et al.
Scheme 2 a
a
Although one stereoisomer is shown, the stereochemical identity of the trisubstituted enol ethers has not been determined.
PdCl2, 2 mol % CuI, HCCSiMe3, Et3N, DMF, 75 °C) led to
sluggish transformations that gave rise to complex mixtures of
products (<50% conv after 14 h).
one-pot operation resulted in the formation of the desired product
in <20% yield. In contrast, filtration of the unpurified 10
through a plug of silica gel before its subjection to a fresh batch
of 3 and methyl vinyl ketone resulted in clean cross-metathesis.
Attempts to effect conversion of 10 to 11 in the presence of
Grubbs’s second generation catalyst19 led to formation of side
products and lower reaction rates (70% recovered starting
material vs 20% with 3 after 3 h).
Diastereoselective conjugate addition of Me2Zn to enone 11
was carried out in the presence of 12 mol % chiral phosphine
12, 5 mol % (CuOTf)2‚C6H6, and Me2Zn (toluene, 4 °C); the
desired ketone 13 was obtained in excellent diastereoselectivity
(97:3), high regioselectivity (1,4:1,6 ) 9:1), and 50% yield after
silica gel chromatography (see below for more details on this
transformation). It is noteworthy that when dipeptide ligand
2 was used in this reaction (vs 12), although high enantiose-
lectivity was obtained for the desired product (92% ee), the
conjugate addition proceeded with significantly lower regiose-
lectivity (1,4:1,6 ) 1.5:1).
Diastereoselective reduction of the trisubstituted alkene in
13 was effected in three highly efficient steps, as catalytic or
ionic hydrogenation of this substrate under a variety of con-
ditions afforded the undesired isomer predominantly. Thus,
treatment of 13 with NaBH4 and subjection of the resulting
secondary alcohol to dissolving metal conditions (Li/NH3 at -78
°C) and reinstallation of the ketone group through a Dess-
Martin oxidation afforded 14 in 73% overall yield and with 85:
15 diastereoselectivity;20 the desired diastereomer was obtained
in the pure form after silica gel chromatography. Protection of
the ketone group was required as the dissolving metal reduction
in the presence of the carbonyl moiety led to the formation of
significant amounts of undesired compounds.
The total synthesis was completed through conversion of the
ketone in 14 to the derived primary alcohol in 77% overall
yield (via the corresponding carboxylic acid). Conversion of
the primary alcohol to the terminal iodide was followed by
Cu-catalyzed alkylation in the presence of 1.4 equiv of 2-pro-
penylmagnesium bromide21 to provide optically pure erogor-
As illustrated in Scheme 1, kinetic enolization through
treatment of 7 with LiTMP and TMSCl (THF, -78 °C) led to
the formation of the desired silylenol ether 8 with 9:1 regiose-
lectivity and 97% overall yield. This selectivity, obtained
through the use of sterically hindered LiTMP, came after
extensive experimentation to identify conditions that would
avoid the surprisingly low levels of enolization regioselectivity.
As an example (Scheme 2), when LDA (1.5 equiv, THF, -78
°C, 0.5 h) was used as the base, only 5:1 selectivity (in favor
of 15) was observed. In contrast, when bromide 6 was treated
with LDA at -78 °C, the desired kinetic enol ether 16 was
obtained with >25:1 regiocontrol.11 These observations suggest
that preassociation of the lithium amide with the alkyne π system
directs the deprotonation to occur at the more sterically hindered
methylene site. This possibility finds support in a recent finding
regarding alkyne-directed conjugate addition of alkyl cuprates
to unsaturated esters12 and several Pd-catalyzed cyclizations
reported more than a decade ago.13
Conversion of enol ether 8 to alkene 9 (Scheme 1), the starting
material for a metal-catalyzed enyne metathesis, was ac-
complished through a Pd-catalyzed reduction14 of the derived
enol triflate, which was generated upon sequential treatment of
8 with MeLi and Tf2NPh.15 It is noteworthy that when the enol
triflate reduction was attempted in the presence of 5 mol %
PdCl2(dppf) and Et3SiH,16 the corresponding disubstituted olefin
(product of olefin isomerization of 9) was isolated as the
exclusive product (1:1 mixture of alkene stereoisomers).
Treatment of enyne 9 with 5 mol % Ru catalyst 38 (CH2Cl2,
22 °C) generated diene 10 in 84% yield after silica gel
chromatography.17 Subsequent treatment of 10 with 10 mol %
3 in the presence of 2 equiv of methyl vinyl ketone resulted in
the formation of R,â-unsaturated ketone 11 in 74% isolated yield
(>95:5 E:Z).18 Attempts to effect conversion of 9 to 11 in a
(11) Bromide 16 was not used in the total synthesis, since the terminal olefin
derived from the Pd-catalyzed reduction (cf. 8 f 9, Scheme 1) could not
be induced to undergo efficient cross-coupling reactions. This may be due
to interception of the organopalladium intermediates by the π cloud of the
neighboring olefin.
(18) For selected previous examples of sequential enyne ring-closing metathesis/
cross-metathesis, see: (a) ref 9l. (b) Lee, H.-Y.; Kim, B. G.; Snapper, M.
L. Org. Lett. 2003, 5, 1855-1858.
(19) (a) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem.
Soc. 2000, 122, 3783-3784. (b) Morgan, J. P.; Grubbs, R. H. Org. Lett.
2000, 2, 3153-3155. (c) Choi, T.-L.; Lee, C. W.; Chatterjee, A. K.; Grubbs,
R. H. J. Am. Chem. Soc. 2001, 123, 10417-10418.
(20) For alternative approaches to control of this 1,4-relative stereochemistry
in a related class of compounds, see: (a) McCombie, S. W.; Ortiz, C.;
Cox, B.; Ganguly, A. K. Synlett 1992, 541-547. (b) LeBrazidec, J.-Y.;
Kocienski, P. J.; Connolly, J. D.; Muir, K. W. J. Chem. Soc., Perkin Trans
1 1998, 2475-2477.
(12) Asao, N.; Lee, S.; Yamamoto, Y. Tetrahedron Lett. 2003, 44, 1803-1806.
(13) Trost, B. M.; Tasker, A. S.; Ruther, G.; Brandes, A. J. Am. Chem. Soc.
1991, 113, 670-672.
(14) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(15) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982.
(16) Kotsuki, H.; Datta, P. K.; Hayakawa, H.; Suenaga, H. Synthesis 1995,
1348-1350.
(17) For an earlier example where enyne ring-closing metathesis is used to
synthesize dihydronaphthalenes, see: Rosillo, M.; Casarrubios, L.; Domingu-
ez, G.; Perez-Castells, J. Tetrahedron Lett. 2001, 42, 7029-7031.
9
98 J. AM. CHEM. SOC. VOL. 126, NO. 1, 2004

Enantioselective Total Synthesis of Erogorgiaene
A R T I C L E S
Table 1. Cu-Catalyzed Asymmetric Conjugate Additions to
Various 4-Phenyl-3-butene-2-ones
Table 2. Effect of Ligand Structure on Cu-Catalyzed Asymmetric
Conjugate Addition of Me2Zn to 5
entry
R
1
R
2
conv (%)a
yield (%)b
ee (%)c
1
2
3
4
5
6
7
H
H
H
OMe
OPh
F
H
<10
50
<10
>95
>95
85
ndd
nd
nd
44
60
34
nd
86
91
nd
94
98
97
91
CF3
OMe
H
H
H
Me
H
19
a
1
Conversions determined by analysis of 400 MHz H NMR spectrum
b
of unpurified product mixtures. Isolated yields of purified products after
silica gel chromatography. Yields are unoptimized. Determined by chiral
GLC and HPLC analysis (see the Supporting Information for details).
c
d
nd ) not determined.
giaene 1. The synthetic material is identical to the natural
compound based on comparison of 1H NMR, 13C NMR, LRMS,
HRMS, and optical rotation.
2. Studies Regarding Cu-Catalyzed Asymmetric Conju-
gate Addition of Me2Zn to Enone 5. The efficient and
enantioselective Cu-catalyzed ACA of Me2Zn to unsaturated
ketone 5 was an unexpected finding because, in general, â-aryl-
substituted acyclic enones are not effective substrates for this
class of reactions.6a For example, as illustrated in entry 1 of
Table 1, when a similar substrate bearing an unsubstituted
phenyl group is used, <10% conversion to the desired product
is observed. To gain further insight regarding the positive
influence of the o-Br substituent in 5 (i.e., steric vs electronic
effects), we examined Cu-catalyzed additions of Me2Zn to
analogous substrates; the results of these studies are summarized
in Table 1.
Comparison of the data in entries 2 and 3 of Table 1 suggests
that electron-deficient aryl enones undergo Cu-catalyzed ACA
more readily and the positive effect of the Br substituent in 5
may only be partially due to electronic factors. The results in
entries 4-6 of Table 1 indicate that the presence of a substituent
at the ortho site of the phenyl ring (R1 * H), regardless of
whether it is electron-donating (entries 4-5) or electron-
withdrawing (entry 6), is beneficial to the rate of Cu-catalyzed
ACA. Comparison of data in entries 4 and 5 suggests that
oxygen-heteroatom chelation is likely not a key factor in
determining reactivity. The lower rate of the reaction shown in
entry 7 (R ) Me) may be due to a prohibitive steric effect
imposed by the larger Me substituent.22 It is therefore plausible
that the presence of an ortho group forces rotation of the aryl
unit out of conjugation with the neighboring olefin, increasing
the reactivity of the enone toward Cu-catalyzed addition.
However, if the ortho substituent is too large, the steric bulk
serves to inhibit addition.
a
1
Conversions determined by analysis of 400 MHz H NMR spectrum
b
of unpurified product mixtures. Isolated yields of purified products after
silica gel chromatography. Determined by chiral GLC analysis (see the
Supporting Information for details). nd ) not determined.
c
d
of the optimal chiral ligand; key data obtained are depicted in
Table 2. In contrast to Schiff base 2, amine dipeptide 17 (entry
2, Table 2) is significantly less efficient in promoting C-C bond
formation (30% conv and 87% ee vs >98% conv and 95% ee
with 2). The derived amide phosphine 18 (entry 3) is less
effective than 2 and delivers nearly racemic products under the
same conditions. As shown in entry 4 of Table 2 (ligand 19),
replacement of L-t-Leu at the AA1 site with L-Val leads to lower
conversion and enantioselectivity as well.
It should be noted that, as illustrated in entries 5 and 6 of
Table 2, chiral ligands bearing a single amino acid moiety,
including Schiff base 20 bearing inexpensive L-Val, readily
promote the enantioselective addition of Me2Zn to enone 5.
However, in comparison to ACA catalyzed by dipeptide 2,
transformations effected by 12 and 20 provide unidentified
byproducts and, as a result, lower isolated yields of the desired
ketone (71-73% vs 91% yield with 2). Comparison of data in
entries 1, 4, 5, and 6 points to some degree of cooperativity
between AA1 and AA2 segments of dipeptidic chiral ligands:
whereas installment of L-Tyr(Ot-Bu) as AA2 enhances the
performance of a ligand that carries L-t-Leu as AA1 (entry 5 vs
Another noteworthy aspect of the Cu-catalyzed addition of
Me2Zn to enone 5 (see Scheme 1) is in connection to the identity
(21) Fuganti, C.; Serra, S. J. Chem. Soc., Perkin Trans 1 2000, 3578-3764.
(22) This argument is consistent with the A values reported for OMe, OPh, and
Me groups (0.75, 0.65, and 1.74, respectively). See: Eliel, E. L.; Wilen,
S. H. Stereochemistry of Organic Compounds, Wiley-Interscience: New
York, 1994; pp 696-697.
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J. AM. CHEM. SOC. VOL. 126, NO. 1, 2004 99

A R T I C L E S
Cesati, III et al.
Scheme 3. Control of Relative Stereochemistry through Cu-Catalyzed ACA Reactionsa
Conclusions
entry 1), incorporation of L-Phe as AA2 is deleterious to the
catalytic activity of a chiral ligand that has L-Val as AA1 (entry
6 vs entry 4).
Through the enantioselective total synthesis of erogorgiaene
we have illustrated the utility and demonstrated several critical
aspects of Cu-catalyzed ACA of alkylzincs to acyclic R,â-
unsaturated ketones. These studies demonstrate that in a
synthesis scheme the catalytic process may be utilized to control
absolute and relative stereochemistry. Together with catalytic
metathesis reactions, both as a means to functionalize products
of conjugate additions (e.g., Ru-catalyzed RCM of 9 to obtain
10 in Scheme 1) and as a way to access enones for additional
C-C bond-forming transformations (e.g., Ru-catalyzed cross-
metathesis of 10 to obtain 11), catalytic ACA can be used to
access a range of enantio- and diastereomerically pure cyclic
and acyclic products. Another lesson learned from this study is
that the versatility of amino acid-based ligands is not confined
to screening of various dipeptidic systems; in certain cases, chiral
ligands bearing a single amino acid should also be carefully
examined (e.g., 11 f 13 in Scheme 1).26
3. Studies Regarding Stereoselective Cu-Catalyzed Con-
jugate Addition of Me2Zn to Acyclic Enone Intermediates
(cf. 11 f 13 in Scheme 1). With a chiral substrate, generation
of new stereogenic centers is often influenced by those that are
already present in the molecule.23 In this context, the use of
chiral optically pure reagents or catalysts for control of
stereochemistry (“reagent control”) is an attractive strategy in
synthesis, particularly when internal relay of stereochemistry
(“substrate control”) is unlikely due to the remoteness of a
neighboring stereogenic center(s). There are also instances where
asymmetric induction, even by a proximal stereogenic center,
is ineffective. In such cases, a chiral catalyst can only be used
if it is able to override completely the inherent preference for
induction of stereochemistry imposed by the adjacent stereogenic
site. That is, chiral ligandsand not the neighboring stereogenic
centersmust serve as the source of asymmetric induction.
(25) Compound 21 was prepared through Zr-catalyzed intramolecular olefin
alkylation, as shown below. See: (a) Cesati, R. R., III; de Armas, J.;
Hoveyda, A. H. Org. Lett. 2002, 4, 395-398. For related studies, see: (b)
de Armas, J.; Kolis, S. P.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122,
5977-5983. (c) de Armas, J.; Hoveyda, A. H. Org. Lett. 2001, 3, 2097-
2100. (d) Terao, J.; Watanabe, T.; Saito, K.; Kambe, N.; Sonoda, N.
Tetrahedron Lett. 1998, 39, 9201-9204.
The data presented in Scheme 3 were obtained while we
investigated alternative approaches to establishing the stereo-
chemistry of the side-chain Me group of erogorgiaene.24 These
findings indicate that in the Cu-catalyzed ACA to acyclic
enones, the stereochemical identity of the product may not be
affected by stereogenic sites present within the substrate but is
largely dictated by the chiral ligand. Thus, treatment of a 1:1
mixture of diastereomers of 2125 with Me2CuLi resulted in the
formation of a 3-3.5:1 ratio of stereoisomers (each) of 22 and
23 (neither set bears proper stereochemistry for use in the total
synthesis of erogorgiaene). In contrast, with Cu-catalyzed
addition of Me2Zn in the presence of chiral ligand 2, both
substrate diastereomers undergo highly stereoselective conjugate
addition to afford 14 and 23 (96:4), regardless of the stereo-
chemical identity of the adjacent site.
(a) 1.5 equiv LDA, 1.5 equiv TMSCl, THF, -78 °C. (b) O3, 1.5 equiv
pyr; 4 equiv Me2S, 96% for two steps. (c) 1.3 equiv LAH, THF/Et2O, -50
°C f 4 °C; 90%. (d) 10 mol % PdCl2(PPh3)2, 700 psi ethylene, 3 equiv
Et3N, DMF, 90 °C, 93%. (e) 1.2 equiv TsCl, pyr, 0 °C f 22 °C, 93%. (f)
5 mol % Cp2ZrCl2, 5 equiv (2-cyclohexyl)ethylmagnesium bromide, THF,
55 °C; O2, THF, 0 °C; 61% (7:1 diastereomeric ratio). (g) 1.2 equiv Dess-
Martin periodinane, CH2Cl2, H2O, 22 °C; 95%. (h) 1.1 equiv NaH, 1.2
equiv (MeO)2P(O)CH2C(O)Me, THF, 22 °C; 69% (1:1 diastereomeric ratio).
(23) For a review of substrate-directed reactions, see: Hoveyda, A. H.; Evans,
D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.
(24) For a related example involving diastereoselective conjugate addition of a
cuprate, see: Benoit-Marguie, F.; Csaky, A. G.; Esteban, G.; Martinez,
E.; Plumet, J. Tetrahedron Lett. 2000, 41, 3355-3358.
9
100 J. AM. CHEM. SOC. VOL. 126, NO. 1, 2004

Enantioselective Total Synthesis of Erogorgiaene
A R T I C L E S
The present studies point to the need for additional ACA
methods. For example, the synthesis sequence illustrated in
Scheme 1 would be more concise if effective catalytic asym-
metric conjugate additions of alkylmetals to unsaturated esters
were to become available.27 Studies toward the development
of these and related catalytic enantioselective processes are in
progress.
grateful to the NIH for a postdoctoral fellowship (GM-64151).
We are grateful to Sylvia Degrado and Alex Hird for helpful
discussions.
Supporting Information Available: Experimental procedures
and spectral data for products (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support was provided by the
JA0305407
NIH (GM-47480) and the NSF (CHE-0213009). R.R.C. is
(27) Attempted conjugate additions of Me2Zn to unsaturated N-acyloxazoli-
dinones (see ref 6b) corresponding to enones 5 (Scheme 1) and 21
(Scheme 3) proved to be highly inefficient. Such low rates of reaction are
at least partially due to the fact that the typically less reactive Me2Zn was
employed.
(26) For additional examples where related chiral ligands bearing a single amino
acid have proven superior to the corresponding dipeptides, see: (a) ref 6e.
(b) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2003, 125, 4018-4019.
9
J. AM. CHEM. SOC. VOL. 126, NO. 1, 2004 101