Enantioselective total synthesis of (-)-acylfulvene and (-)-irofulven

Article abstract of DOI:10.1021/jo901926z

(Chemical Equation Presented) We report our full account of the enantioselective total synthesis of (-)-acylfulvene (1) and (-)-irofulven (2), which features metathesis reactions for the rapid assembly of the molecular framework of these antitumor agents. We discuss (1) the application of an Evans Cu-catalyzed aldol addition reaction using a strained cyclopropyl ketenethioacetal, (2) an efficient enyne ring-closing metathesis cascade reaction in a challenging setting, (3) the reagent IPNBSH for a late-stage reductive allylic transposition reaction, and (4) the final RCM/dehydrogenation sequence for the formation of (-)-acylfulvene (1) and (-)-irofulven (2).

Full text of DOI:10.1021/jo901926z

pubs.acs.org/joc
Enantioselective Total Synthesis of (-)-Acylfulvene and (-)-Irofulven
Dustin S. Siegel, Grazia Piizzi, Giovanni Piersanti, and Mohammad Movassaghi*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
movassag@mit.edu
Received September 8, 2009
We report our full account of the enantioselective total synthesis of (-)-acylfulvene (1) and
(-)-irofulven (2), which features metathesis reactions for the rapid assembly of the molecular frame-
work of these antitumor agents. We discuss (1) the application of an Evans Cu-catalyzed aldol addi-
tion reaction using a strained cyclopropyl ketenethioacetal, (2) an efficient enyne ring-closing
metathesis cascade reaction in a challenging setting, (3) the reagent IPNBSH for a late-stage reductive
allylic transposition reaction, and (4) the final RCM/dehydrogenation sequence for the formation of
(-)-acylfulvene (1) and (-)-irofulven (2).
Introduction
The illudins are a family of highly cytotoxic sesquiterpenes
isolated from the bioluminescent mushroom Omphalotus
illudens (Jack O’Lantern mushroom) and other related
fungi.1 Illudin M (3) and illudin S (4) (Figure 1) are among
(1) Isolation of Illudin M and S: (a) Anchel, M.; Hervey, A.; Robbins, W.
J. Proc. Natl. Acad. Sci. U.S.A. 1950, 36, 300. (b) Anchel, M.; Hervey, A.;
Robbins, W. J. Proc. Natl. Acad. Sci. U.S.A. 1952, 38, 927. (c) Nakanishi, K.;
Tada, M.; Yamada, Y.; Ohashi, M.; Komatsu, N.; Terekawa, H. Nature
1963, 197, 292. (d) McMorris, T. C.; Anchel, M. J. Am. Chem. Soc. 1963, 85,
831. (e) McMorris, T. C.; Anchel, M. J. Am. Chem. Soc. 1965, 87, 1594.
(f) Nakanishi, K.; Ohashi, M.; Tada, M.; Yamada, Y. Tetrahedron 1965, 21,
1231. (g) Matsumoto, T.; Shirahama, H.; Ichihara, A.; Fukuoka, Y.; Takahashi, Y.;
Mori, Y.; Watanabe, M. Tetrahedron, 1965, 21, 2671. Isolation of Illudin A and
B: (h) Arnone, A.; Cardillo, G.; Nasini; De Rava, O. V. J. Chem. Soc., Perkin
Trans. 1991, 1, 733. Isolation of Illudin C, C2, and C3: (i) Arnone, A.; Cardillo,
R.; Modugno, V.; Nasin, G. Gazz. Chim. Ital. 1991, 121, 345. (j) Lee, I.-K.; Jeong,
C. Y.; Cho, S. M.; Yun, B. S.; Kim, Y. S.; Yu, S. H.; Koshino, H.; Yoo, I. D.
J. Antibiot. 1996, 49, 821. Isolation of Illudin F, G, and H: (k) Burgess, M. L.;
Zhang, Y. L.; Barrow K. D. J. Nat. Prod. 1999, 62, 1542-1544. Isolation of
Illudin I, I2, J, and J2: (l) Reina, M.; Orihuela, J. C.; Gonzales-Coloma, A.; de Ines,
C.; de la Crus, M.; Gonzalez del Val, A.; Torno, J. R.; Fraga, B. M. Phytochem-
istry 2004, 65, 381.
(2) Kelner, M. J.; McMorris, T. C.; Beck, W. T.; Zamora, J. M.; Taetle, R.
FIGURE 1. Illudin family of sesquiterpenes.
Cancer Res. 1987, 47, 3186.
(3) Kelner, M. J.; McMorris, T. C.; Taetle, R. J. Natl. Cancer Inst. 1990,
82, 1562.
the most cytotoxic members of this family and have been
studied extensively for their promising antitumor activity.2
Despite their high cytotoxicity, these illudins exhibit low
therapeutic indices in solid-tumor systems.3 Consequently,
several analogues of the natural illudins have been prepared
and evaluated for the treatment of various cancers.4 One
such semisynthetic derivative, irofulven (2), was prepared
(4) For synthetic studies of illudin derivatives, see: (a) Kinder, F. R.;
Wang, R. M.; Bauta, W. E.; Bair, K. W. Bioorg. Med. Chem. Lett. 1996, 6,
1029. (b) McMorris, T. C.; Yu, J.; Hu, Y. J. Org. Chem. 1997, 62, 3015.
(c) McMorris, T. C.; Yu, J.; Lira, R.; Dawe, R.; MacDonald, J. R.; Waters,
S. J.; Estes, L. A.; Kelner, M. J. J. Org. Chem. 2001, 66, 6158. (d) McMorris,
T. C.; Cong, Q.; Kelner, M. J. J. Org. Chem. 2003, 68, 9648. (e) Pirrung,
M. C.; Liu, H. Org. Lett. 2003, 5, 1983. (f) Gregerson, L. N.; McMorris, T. C.;
Siegel, J. S.; Baldridge, K. K. Helv. Chim. Acta 2003, 86, 4133.
9292 J. Org. Chem. 2009, 74, 9292–9304
Published on Web 11/25/2009
DOI: 10.1021/jo901926z
r
2009 American Chemical Society

Siegel et al.
JOCArticle
SCHEME 1. Proposed Mechanism of Biological Activity of
(-)-Irofulven (2)a
SCHEME 2. Retrosynthetic Analysis
aNuca = glutathione, cysteine, or hydride (NADPH). Nucb = DNA
from illudin S through treatment with excess acid and
formaldehyde and has demonstrated greatly enhanced ther-
apeutic potential against several solid tumor systems.5 The
superior pharmacological properties of irofulven (2) are
accompanied by a cytotoxicity markedly lower than that of
illudin S (4).6 Several studies have been directed toward
elucidating the mechanism of biological activity of the
illudins, acylfulvene (1), and irofulven (2) in order to under-
stand the nature of this selective toxicity.7 The mechanism is
believed to involve an initial activation step by conjugate
addition of a hydride (NADPH) or thiol (glutathione or
cysteine) nucleophile into the enone moiety followed by
nucleophilic addition of DNA to the strained cyclopro-
pane ring to generate a stable aromatic DNA adduct 18
(Scheme 1). The observed onset of apoptosis is believed to be
a result of DNA alkylation followed by strand cleavage
through this general mechanism. Irofulven (2) is currently
undergoing clinical trials for the treatment of various cancers
as both a monotherapy and in combination with other
chemotherapeutics.8
The promising antitumor properties and the highly reac-
tive molecular framework of (-)-irofulven (2) and other
illudins have rendered them interesting synthetic targets.9
Our laboratory has disclosed concise enantioselective synth-
eses of (-)-acylfulvene (1) and (-)-irofulven (2).10 Key
features of our approach include a stereoselective aldol
addition of a strained ketenehemithioacetal 26, which se-
cures the C2 stereocenter and enables ready access to alde-
hyde (þ)-22 (Scheme 2). A key enyne ring-closing metathesis
(EYRCM)11 cascade reaction of trienyne 21 generates the
AB-ring system 20. A reductive allylic transposition then sets
the stage for the final ring-closing olefin metathesis (RCM)
to build the C-ring and complete the syntheses of (-)-
acylfulvene (1) and (-)-irofulven (2). Herein we describe
the development of our general synthetic strategy to these
fascinating molecules.
(5) McMorris, T. C.; Kelner, M. J.; Wang, W.; Yu, J.; Estes, L. A.; Taetle,
R. J. Nat. Prod. 1996, 59, 896.
(6) Woynarowsky, J. M.; Napier, C.; Koester, S. K.; Chen, S.-F.; Troyer,
D.; Chapman, W.; MacDonald, J. R. Biochem. Pharmacol. 1997, 54, 1181.
(7) (a) McMorris, T. C.; Kelner, M. J.; Chadha, R. K.; Siegel, J. S.; Moon,
S.; Moya, M. M. Tetrahedron 1989, 45, 5433. (b) McMorris, T. C.; Kelner,
M. J.; Wang, W; Yu, J.; Estes, L. A.; Taetle, R. Chem. Res. Toxicol. 1990, 3,
574. (c) Gregerson, L. N.; McMorris, T. C.; Siegel, J. S.; Baldridge, K. K.
Helv. Chim. Acta 2003, 86, 4133. (d) Dick, R. A.; Yu, X.; Kensler, T. W. Clin.
Cancer Res. 2004, 10, 1492. (e) Gong, J.; Vaidyanathan, V. G.; Yu, X.;
Kensler, T. W.; Peterson, L. A.; Sturla, S. J. J. Am. Chem. Soc. 2007, 129,
2101. (f) Neels, J. F.; Gong, J.; Yu, X.; Sturla, S. J. Chem. Res. Toxicol. 2007,
20, 1513.
Results and Discussion
Synthesis of Key Aldehyde 22. Since aldehyde 22 contains
the reactive cyclopropane and tertiary alcohol substruc-
ture common to acylfulvene (1), irofulven (2), and most
members of the illudin family, its efficient synthesis was of
critical importance. Initially, we developed a synthetic route
that enabled us to rapidly generate large quantities of the
racemic aldehyde 22 for evaluation of our synthetic strategy
(Scheme 3).12 This route involved treatment of pentane-2,4-
dione (27) with 1,2-dibromoethane and potassium carbonate
(8) (a) Alexandre, J.; Raymond, E.; Kaci, M. O.; Brian, E. C.; Lokiec, F.;
Kahatt, C.; Faivre, S.; Yovine, A.; Goldwasser, F.; Smith, S. L.; MacDonald,
J. R.; Misset, J.-L.; Cvitkovic, E. Clin. Cancer Res. 2004, 10, 3377. (b) Serova,
M.; Calvo, F.; Lokiec, F.; Koeppel, F.; Poindessous, V.; Larsen, A. K.; Van
Laar, E. S.; Waters, S. J.; Cvitkovic, E.; Raymond, E. Cancer Chemother.
Pharmacol. 2006, 57, 491. (c) Seiden, M. V.; Gordon, A. N.; Bodurka, D. C.;
Matulonis, U. A.; Penson, R. T.; Reed, E.; Alberts, D. S.; Weems, G.; Cullen,
M.; McGuire, W. P., III Gynecol. Oncol. 2006, 101, 55. (d) Hilgers, W.;
Faivre, S.; Chieze, S.; Alexandre, J.; Lokiec, F.; Goldwasser, F.; Raymond,
E.; Kahatt, C.; Taamma, A.; Weems, G.; MacDonald, J. R.; Misset, J. -L.;
Cvitkovic, E. Invest. New Drugs 2006, 24, 311. (e) Paci, A.; Rezai, K.;
Deroussent, A.; De Valeriola, D.; Re, M.; Weill, S.; Cvitkovic, E.; Kahatt,
C.; Shah, A.; Waters, S.; Weems, G.; Vassal, G.; Lokeic, F. Drug Metab.
Dispos. 2006, 34, 1918. (f) Wang, Y.; Wiltshire, T.; Senft, J.; Wenger, S. L.;
Reed, E.; Wang, W. Mol. Cancer Ther. 2006, 5, 3153. (g) Yeo, W.; Boyer, M.;
Chung, H. C.; Ong, S. Y. K.; Lim, R.; Zee, B.; Ma, B.; Lam, K. C.; Mo, F. K.
F.; Ng, E. K. W.; Ho, R.; Clarke, S.; Roh, J. K.; Beale, P.; Rha, S. Y.; Jeung,
H. C.; Soo, R.; Goh, B. C.; Chan, A. T. C. Cancer Chemother. Pharmacol.
2006, 59, 295. (h) Wiltshire, T.; Senft, J.; Wang, Y.; Konat, G. W.; Wenger, S.
L.; Reed, E.; Wang, W. Mol. Pharmacol. 2007, 71, 1051. (i) Alexandre, J.;
Kahatt, C.; Berthault-Cvitkovic, F.; Faivre, S.; Shibata, S.; Hilgers, W.;
Goldwasser, F.; Lokiec, F.; Raymond, E.; Weems, G.; Shah, A.; MacDo-
nald, J. R.; Cvitkovic, E. Invest. New Drugs 2007, 25, 453. (j) Escargueil, A.
E.; Poindessous, V.; Soares, D. G.; Sarasin, A.; Cook, P. R.; Larsen, A. K.
J. Cell Sci. 2008, 121, 1275. (k) Kelner, M. J.; McMorris, T. C.; Rojas, R. J.;
Estes, L. A.; Suthipinijtham, P. Invest. New Drugs 2008, 26, 407. (l) Kelner,
M. J.; McMorris, T. C.; Rojas, R. J.; Estes, L. A.; Suthipinijtham, P. Cancer
Chemother. Pharmacol. 2008, 63, 19. (m) Dings, R. P. M.; Van Laar, E. S.;
Webber, J.; Zhang, Y.; Griffin, R. J.; Waters, S. J.; MacDonald, J. R.; Mayo,
K. H. Cancer Lett. 2008, 265, 270.
(9) For total synthesis of illudin M (1), see: (a) Matsumoto, T.; Shirahama,
H.; Ichihara, A.; Shin, H.; Kagawa, S.; Sakan, F.; Matsumoto, S.; Nishida, S.
J. Am. Chem. Soc. 1968, 90, 3280. (b) Matsumoto, T.; Shirahama, H.; Ichihara,
A.; Shin, H.; Kagawa, S.; Sakan, S.; Miyano, K. Tetrahedron Lett. 1971, 2049.
(c) Kinder, F. R.; Bair, K. W. J. Org. Chem. 1994, 59, 6965. For representative
synthetic studies towards illudins, see: (d) Padwa, A.; Sandanayaka, V. P.;
Curtis, E. A. J. Am. Chem. Soc. 1994, 116, 2667. (e) Primke, H.; Sarin, G. S.;
Kohlstruk, S.; Adiwidjaja, G.; de Meijere, A. Chem. Ber. 1994, 127, 1051.
Synthesis of (-)-1: (f) Brummond, K. M.; Peterson, J. J. Am. Chem. Soc. 2000,
122, 4915. (g) McMorris, T. C.; Staake, M. D.; Kelner, M. J. J. Org. Chem.
2004, 69, 619. (h) Gong, J.; Neels, J. F.; Yu, X.; Kensler, T. W.; Peterson, L. A.;
Sturla, S. J. J. Med. Chem. 2006, 49, 2593.
(10) Movassaghi, M.; Piizzi, G.; Siegel, D. S.; Piersanti, G. Angew. Chem.,
Int. Ed. 2006, 45, 5859.
(11) For representative examples, see: (a) Kim, S.-H.; Bowden, N.;
Grubbs, R. H. J. Am. Chem. Soc. 1994, 116, 10801. (b) Zuercher, W. J.;
Scholl, M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 4291. (c) Layton, M. E.;
Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773.
(d) Fukumoto, H.; Takanishi, K.; Ishihara, J.; Hatakeyama, S. Angew.
Chem., Int. Ed. 2006, 45, 2731. For a review, see: (e) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490.
(12) Movassaghi, M.; Piizzi, G.; Siegel, D. S.; Piersanti, G. Tetrahedron
Lett. 2009, 50, 5489.
J. Org. Chem. Vol. 74, No. 24, 2009 9293

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JOCArticle
SCHEME 3. Synthesis of Aldehyde (()-22a
SCHEME 5. Asymmetric Oxidation Approaches To Secure the
Tertiary Alcohol Stereocentera
aConditions: (a) (CH2Br)2, K2CO3, DMSO, 61%. (b) MePh3PBr,
tBuOK, Et2O, 56%. (c) TMSCN, InBr3 (5 mol %), CH2Cl2, 81%.
(d) DIBAL-H, Et2O, -78 °C, 69%.
SCHEME 4. Asymmetric Silylcyanation Reactions with Ketone 29a
t
aConditions: (a) MePh3PBr, BuOK, Et2O, 8%. (b) AD-mix R, Me-
SO2NH2, tBuOH, H2O, 50%, 0% ee. (c) TrisNHNH2, cat. TsOH,
s
MeCN, 73%. (d) BuLi, TMEDA, hexanes; DMF, 86%. (e) NaBH4
CeCl3, CH2Cl2, MeOH, 75%. (f) Ti(OiPr)4, (-)-DET, tBuOOH,
CH2Cl2. (g) HCCiBu, Zn(OTf)2, (-)-NME, Et3N, PhMe, 25%, 99%
ee. (h) mCPBA, CH2Cl2.
aConditions: (a) TMSCN, 31, TFE, CH2Cl2, 50 h, 13%, 53% ee; 8 d, 71%,
i
34% ee. (b) TMSCN, Al(OPr)3, 32, MeOH, PhMe, 3 A MS, 79%, 0% ee.
˚
including a Sharpless dihydroxylation, a Sharpless epoxida-
tion, and a substrate-directed epoxidation relying on a
(c) TMSCN, (DHQD)2AQN, CH2Cl2, 7 d, 11%, 0% ee.
in dimethylsulfoxide (DMSO) to afford cyclopropyl dike-
tone 28 in 61% yield (Scheme 3). Mono-olefination using the
Wittig reaction afforded intermediate 29 in 56% yield.
Silylcyanation with stoichiometric TMSCN in the presence
of catalytic InBr3 then afforded cyanohydrin 30 in 81% yield,
and DIBAL-H reduction afforded the racemic aldehyde 22
in multigram quantities.
stereocenter set by
a Carreira alkynylation reaction
(Scheme 5). Double olefination of diketone 28 afforded the
volatile diene 33, which was subjected to Sharpless dihy-
droxylation conditions.17 While the desired diol 34 was
generated in 50% yield, the diene 33 proved to be a poor
substrate for enantioselective dihydroxylation. We pro-
ceeded to explore the Sharpless asymmetric epoxidation18
reaction with alcohol 35, which was prepared from ketone 29
through a Shapiro reaction with dimethylformamide (DMF)
followed by a Luche reduction. Unfortunately, the Sharpless
epoxidation of diene 35 provided a complex mixture of
products likely resulting from the oxidation of the undesired
olefin. Also, alternative synthesis of racemic 36 highlighted
its undesired propensity to undergo a Lewis acid catalyzed
rearrangement to aldehyde 37. An approach based on asym-
metric alkynylation of aldehyde 37 followed by substrate-
directed epoxidation also did not provide the desired
C2-stereocenter.19 While Carreira’s alkynylation reaction
provided the desired product 38 with excellent stereoselec-
tivity (99% ee) using superstoichiometric Zn(OTf)2 and
N-methylephedrine (NME), the subsequent epoxidation of
the allylic alcohol 38 using m-chloroperbenzoic acid
(mCPBA) resulted in the formation of a complex mixture
of products. Since oxidation reactions20 aimed at forming
the stereocenter adjacent to the cyclopropane proved to be
problematic, we pursued an alternative route.
The enantioselective total synthesis of the target com-
pounds required an enantioselective synthesis of aldehyde
22. Initially, we considered an asymmetric silylcyanation
strategy to generate the tertiary alcohol stereocenter
(Scheme 4), based on the route to the racemic aldehyde 22.
Examination of Jacobsen’s thiourea catalyst 3113 provided
the desired optically enriched cyanohydrin 30; however, the
conversion and level of stereoselection with ketone 29 was
non-ideal (50 h, 13%, 53% ee). Furthermore, the selectivity
was detrimentally affected by the long reaction times that
were required for full conversion of the starting material (8 d,
71%, 34% ee). The use of ketone 29 as substrate with
Hoveyda’s catalyst 3214 in the presence of Al(OiPr)3 and
Ph3PO afforded the desired compound in good yields (79%)
but unfortunately without enantioselection. Likewise, the
use of Deng’s silylcyanation reaction15 conditions employing
a cinchona alkaloid based catalyst ((DHQD)2AQN) also
proved problematic, highlighting the challenge in developing
a solution strictly based on the proven route to racemic 30.16
We investigated several asymmetric oxidation reactions
as a means of accessing the tertiary alcohol stereocenter
(17) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, B. Chem. Rev. 1994,
94, 2483.
(13) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964.
(14) Deng, H.; Isler, M. P.; Snapper, M. L.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2002, 41, 1009.
(15) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6195.
(16) No attempts were made to determine the absolute stereochemistry of
the product of these reactions.
(18) Gao, Y; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(19) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806.
(20) No attempts were made to determine the absolute stereochemistry of
these reactions.
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SCHEME 6. Enolization of 1-Cyclopropylethanone (44)a
SCHEME 7. Synthesis of Ketenehemithioacetals 26a and 26ba
aConditions: (a) LDA, TMSCl, THF, -78 °C, 84%. (b) TMSOTf, Et3N,
CH2Cl2, -78 °C, 87%.
aConditions: (a) LDA, TMSCl, THF, -78 °C.
We sought to use Evans’ copper-catalyzed aldol reaction
fortheformation of the desiredtertiaryalcoholstereocenter,21
in which we needed to generate a highly strained cyclopropyl
silylketenehemithioacetal nucleophile 26 (Scheme 2). Initial
studies by Ainsworth and co-workers aimed at generating the
O-silylated cyclopropyl keteneacetal 41 revealed that forma-
tion of this strained exocyclic double bond was problematic.
They reported that the product 41 was generated in at most
10% yield (R = Me, eq 1).22 Instead, the C-silylated product
42 was formed as the major product (40%, R = Me, eq 1).
Following this report, Pinnick and co-workers observed
the formation of the trimer 43 in addition to the C- and
O-silylated products 41 and 42 (R = Et, eq 1).23 These
cyclopropyl ester enolate anions are generally regarded as
pyramidalized carbanion centers rather than the O-lithiated
planar methylene cyclopropane species.24
afforded an inseparable mixture of the O- and C-silylated
products 26 and 47. The highest selectivity was achieved with
the ethylthiol ester 26b to generate a 9:1 mixture of 26b and
47b in 70% yield, whereas the tert-butylthiol ester 46a led to a
3:2 mixture of 26b and 47b in 67% yield. Fortunately, the
undesired C-silylated products 47a and 47b did not interfere
with the planned aldol reaction. The mixture of compounds
26b/47b (9:1) could be generated on multigram scale and
could be stored under an argon atmosphere at -10 °C for
greater than a month without any decomposition or O- to C-
silyl transfer. To the best of our knowledge, this is the first
example of the formation of a cyclopropyl silylketenehe-
mithioacetal that can be applied in a Mukaiyama aldol
reaction.27
As a result of the strain associated with the exocyclic
double bond, the cyclopropyl ketenehemithioacetals 26a
and 26b are highly reactive and are excellent substrates for
Evans’ copper-catalyzed aldol reaction21 (Table 1). Under
optimal conditions, treatment of silylketenehemithioacetal
26b (1.1 equiv, mixture of 26b:47b = 9:1) with methylpyr-
uvate (25) in the presence of 10 mol % of (R,R)-CuBox
provided the enantiomerically enriched thiol ester (þ)-48b
(R2 = TMS) in 95% yield and 92% ee (entry 10, Table 1).28
This reaction was performed on large scale to generate a 20-g
batch of the desired product (þ)-48b, and the (R,R)-Box
ligand was recovered in approximately 85% yield from the
reaction mixture. As a part of these studies, we also evaluated
the (R,R)-CuPybox catalyst, but it proved to be inferior to
the CuBox system for this transformation (entries 2 and 3,
Table 1). Although the tert-butylketenehemithioacetal sub-
strate, 26a, was competent for this transformation under the
optimized conditions (entry 6, Table 1), attempts to deriva-
tize the resulting tert-butylthiol ester 48a proved to be
ineffective (vide infra, Scheme 8).
Our studies revealed that enolization of 1-cyclopropy-
lethanone (44) at the cyclopropyl carbon is problematic if
competing enolization pathways are accessible. Both hard
and soft enolization conditions afforded the undesired silyl
enol ether 45 exclusively (Scheme 6).25
Interestingly, Seebach and co-workers were able to gen-
erate a lithium cyclopropanecarbothioate anion from the
corresponding thiol ester and characterize it through X-ray
crystallographic analysis.26 This structure exhibited features
characteristic of a normal planar O-lithiated enolate, as
opposed to a pyramidal C-lithiated center. Guided by this
observation, we reasoned that the enolate of cyclopro-
pylthiol esters might prefer the formation of the O-silylated
ketenehemithioacetal rather than the C-silylated product.
To our delight, the O-silylated ketenehemithioacetals 26a
and 26b were generated as the major products through
treatment of the cyclopropylthiol esters 46a and 46b with
lithium diisopropylamide (LDA) and trimethylsilyl chloride
(TMSCl) in THF at -78 °C (Scheme 7). This reaction
With the bisesters 48a and (þ)-48b in hand, we proceeded
to derivatize the thiol ester selectively. Initially, we investi-
gated methylcuprate addition into the C4 thiolester.29 At-
tempts to functionalize the tert-butylthiol ester 48a proved to
be inefficient (Scheme 8). Surprisingly, using a large excess of
methylcuprate (10 equiv), methyl addition occurred exclu-
sively at the C1 methyl ester to afford the lactone 49 in 45%
yield. In contrast, addition of 1 equiv of methylcuprate to the
more reactive ethylthiol ester (þ)-48b afforded the desired
product (þ)-50 in 25% yield. However, this reaction was
complicated by significant decomposition of the sensitive
cyclopropylketone (þ)-50 under the reaction conditions.
(21) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am.
Chem. Soc. 1999, 121, 686.
(22) Ainsworth, C.; Chen, F.; Kuo, Y.-N. J. Organomet. Chem. 1972,
46, 59.
(23) Pinnick, H. W.; Chang, Y.-H.; Foster, S. C.; Govindan, M. J. Org.
Chem. 1980, 45, 4505.
(24) (a) Itoh, O.; Yamamoto, N.; Fujimoto, H.; Ichikawa, K. J. Chem.
€
Soc., Chem. Commun. 1979, 101. (b) Reissig, H.-U.; Bohm, I. J. Am. Chem.
Soc. 1982, 104, 1735. (c) Feit, B. A.; Elser, R.; Melamed, U.; Goldberg, I.
(27) For an approach using C-silyl cyclopropyl esters as nucleophiles in
the aldol reaction, see: Paquette, L. A.; Blankenship, C.; Wells, G. J. J. Am.
Chem. Soc. 1984, 106, 6442.
€
Tetrahedron 1984, 40, 5177. (d) Haner, R.; Maetzke, T.; Seebach, D. Helv.
Chim. Acta 1986, 69, 1655. (e) Blankenship, C.; Wells, G. J.; Paquette, L. A.
Tetrahedron 1988, 44, 4023.
(25) For an alternative approach using acylsilanes for the formation of
cyclopropylsilylenolethers see: Reich, H. J.; Holtan, R. C.; Bolm, C. J. Am.
Chem. Soc. 1990, 112, 5609.
(28) The enantiomeric excess of the desilylated C2 alcohol (þ)-48b (R2 =
H) was established by chiral HPLC analysis, and the absolute stereochem-
istry of this reaction was verified through X-ray crystallographic analysis
(Scheme 10).
(26) Hahn, E.; Maetzke, T.; Plattner, D. A.; Seebach, D. Chem. Ber. 1990,
123, 2059.
(29) Anderson, R. J.; Henrick, C. A.; Rosenblum, L. D. J. Am. Chem.
Soc. 1974, 96, 3654.
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TABLE 1. Use of Cyclopropyl Ketenehemithioacetal in Evans’ Asymmetric Aldol Addition Reactiona
entry
substrate
catalyst
solvent
temp (°C)
time (h)
yield (%) R2 = TMS, H
% ee
1
26a
26a
26a
26a
26a
26a
26b
26b
26b
26b
Cu(OTf)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
THF
THF
THF
THF
-78
-78
-78
-78
23
-78
-78
-78
-78
-78
2
48
18
6.5
2
2
8
1
12
12
-, 51
-, 20
-, 19
-, 73
-, 77
-, 92
71, 8
76, 19
-, 93
95, 0
2
R,R-CuPybox
R,R-CuPybox
S,S-CuBox
S,S-CuBox
S,S-CuBox
S,S-CuBox
S,S-CuBox
R,R-CuBox
R,R-CuBox
0
0
3b
4
-90
-85
-95
-99
-95
93
5
6
7c
8b,c
9
10c
92
aReactions were run at [25] = 0.25M, with 10 mol % catalyst loading, and were quenched with TBAF followed by filtration through a plug of silica
gel. Enantiomeric excess (ee) determined by HPLC using a chiralcel AD-H column with the corresponding free alcohol 48 (R2 = H) after desilylation.
bReactions were run in the presence of TMSOTf (1 equiv). cReactions were directly filtered through a plug of silica gel without TBAF treatment.
SCHEME 8. Cuprate Addition to Thiol Esters 48a and 48ba
TABLE 2. Thiolester Cross-Couplinga
aConditions: (a) 48a, Me2CuLi (10 equiv), Et2O, 0 °C, 2 h, 45%.
(b) (þ)-48b Me2CuLi (1 equiv), Et2O, 23 °C, 30 min, 25%.
entry
catalyst
ligand
solventb temp (°C) time (h) yield (%)
We found that the ethanethiol ester (þ)-48b could be
selectively derivatized through a modified Fukuyama
cross-coupling protocol.30 Using the reported reaction con-
ditions,30a we obtained the desired product (þ)-50 in 42%
yield (entry 1, Table 2). Under these conditions, the reaction
suffered from incomplete conversion of the starting material
(27% recovered (þ)-48b) and the instability of the catalyst,
which was evident from the precipitation of palladium black
over the course of the reaction. We developed the optimal
conditions for the substrates of interest by evaluating various
ligands, reaction temperatures, and solvents (Table 2). Using
the optimal conditions, multigram quantities of the methyl
ketone (þ)-50 were efficiently prepared in 83% yield via the
cross-coupling of thiol ester (þ)-48b with iodomethylzinc
using 2-dicyclohexylphosphino-20,60-dimethoxy-1,10-biphe-
nyl (SPhos)30b as a supporting ligand in a 1:1.5 THF-
NMP30c solvent mixture (entry 7, Table 2). SPhos proved
to be the ideal ligand for this difficult transformation,
providing improved stability for the palladium metal center
and increased reaction rates.
1
2
3
4
5
6
7
8
9
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
PhMe
THF/NMP
SPhos PhMe
SPhos THF
SPhos PhMe
SPhos THF
SPhos THF/NMP
XPhos THF/NMP
RuPhos THF/NMP
23
65
23
23
65
65
65
65
65
11
15
11
11
11
11
2
42
66
0
0
19
42
83
70
66
Pd2(dba)3
Pd2(dba)3
2
2
aReactions were run with PdLn (5 mol %), ligand (20 mol %), MeZnI
(5 equiv), [(þ)-48b] = 0.3 M. bTHF/NMP = 1:1.5.
Methylenation of the sensitive and sterically hindered
ketone (þ)-50 was achieved through a Takai olefination
(Scheme 9).31 Treatment of ketone (þ)-50 with CH2I2, Zn
dust, TiCl4, and catalytic PbCl2 afforded olefin (þ)-51 in
89% yield.32 The ester (þ)-51 was then treated with DIBAL-
H to afford a mixture of the desired aldehyde (þ)-22 and the
(31) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K J. Org. Chem.
1994, 59, 2668.
(32) Alternative olefination protocols including the Wittig, Petasis,
Tebbe, Peterson, and standard Takai reactions were ineffective at carrying
out this transformation. For references, see: (a) Petasis, N. A.; Lu, S.-P.
J. Am. Chem. Soc. 1995, 117, 6394. (b) Tebbe, F. N.; Parshall, G. W.; Reddy,
G. S. J. Am. Chem. Soc. 1978, 100, 3611. (c) Peterson, D. J. J. Org. Chem.
1968, 33, 780. (d) Okazoe, T.; Takai, K.; Utimoto, k. J. Am. Chem. Soc. 1987,
109, 951.
(30) (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189. (b) Milne, J. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2004, 126, 13028. (c) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003,
125, 12527. Synthesis of MeZnI in NMP: (d) Huo, S. Org. Lett. 2003, 5,
423.
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SCHEME 11. Acetylide Addition to Aldehyde 22 and
SCHEME 9. Synthesis of Aldehyde (þ)-22a
Allyldimethylsilyl Tether Formationa
aConditions: (a) CH2I2, Zn, TiCl4, PbCl2, THF, 89%. (b) DIBAL-H,
Et2O; DMP, CH2Cl2, 91%.
SCHEME 10. Thermal Ellipsoid Representation of the
Carboxylic Acid 52 Salt with (-)-Brucinea
aConditions: (a) LDA or LiHMDS, THF, -78 °C; TBAF or
Et3N (HF)3. (b) Allyldimethylsilyl chloride, Et3N, CH2Cl2.
3
aConditions: (a) LiOH, THF, 82% (b) (-)-brucine.
SCHEME 12. Initial EYRCM Approach
corresponding fully reduced primary alcohol (1:2.5
respectively). Without purification, this mixture was imme-
diately oxidized with Dess-Martin periodinane (DMP) to
give aldehyde (þ)-22 exclusively in 91% yield over the two
steps.
The configuration of C2 in aldehyde (þ)-22 was verified
through X-ray crystallographic analysis of a corresponding
derivative with (-)-brucine (Scheme 10).10,33 This efficient
aldol-based approach for securing the C2 stereochemistry
enabled us to generate multigram quantities of the key
aldehyde (þ)-22. Notably, aldehyde (þ)-22 possesses a sub-
structure that can be mapped on to most of the illudin
sesquiterpenes.
SCHEME 13. Initial Studies of the EYRCMa
Preparation of Substrates for Evaluation in the EYRCM
Cascade. With the routes to the racemic and optically
enriched aldehyde 22 established, we developed a two-step
sequence to generate several substrates for the evaluation of
the EYRCM reaction.12 Addition of a series of alkynes
53a-m to aldehyde 22 followed by desilylation provided
the diols 54a-m as a mixture of C3 diastereomers (3S:3R,
4-9:1) favoring the Felkin-Ahn mode of carbonyl addition
(Scheme 11).34 We then added the allylsilane tether12 for the
planned enyne metathesis cascade. Thus, monosilylation of
diols 54a-j with allyldimethylsilyl chloride afforded the
enynes 55a-j (Scheme 11).
Evaluation of the EYRCM Cascade. The EYRCM se-
quence described in Scheme 12 represented our planned
approach toward the synthesis of the functional AB-ring
system common to the illudins. The enyne metathesis be-
tween the tethered olefin and the alkyne of 56 could generate
a ruthenium alkylidene 58, which would undergo a ring-
closing olefin metathesis to afford a tetrasubstituted alkene
aConditions: G1 or G2, C6D6 (0.02M), 80 °C, 12-36 h.
on a highly substituted B-ring 59.35 We envisioned that
elaboration of the functionalized side chain of 59 would
potentially allow rapid access to various members of the
illudin family.
The initial studies of the key EYRCM step were carried
out on the enynes 55a-d containing a functional side chain
potentially en route to our targets. These trienynes 55a-d
were treated with the first- or second-generation Grubbs’
ruthenium catalyst (G136 and G237 respectively), and the
reactions were monitored by 1H NMR spectroscopy
(Scheme 13).12 However, none of the trienynes 55a-d
afforded the desired EYRCM products 60a-d. The lack of
reactivity of these substrates indicated that the efficiency of
the EYRCM is highly sensitive to steric congestion around
(33) Structural parameters for the carboxylic acid 52 salt with (-)-brucine
are freely available from the Cambridge Crystallographic Data Center under
CCDC-622286. Also see Supporting Information of ref 10.
(34) For clarity, only the major diastereomer is shown throughout the
text.
(35) For examples of synthesis of cyclohexenes containing tetrasubsti-
tuted olefin via enyne metathesis, see: (a) Kitamura, T.; Sato, Y.; Mori, M.
Chem. Commun. 2001, 14, 1258. (b) Kitamura, T.; Sato, Y.; Mori, M. Adv.
Synth. Catal. 2002, 344, 678.
(36) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996,
118, 9606.
(37) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
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SCHEME 14. 1H NMR Analysis of the EYRCM with Trienyne
SCHEME 16. EYRCM of Enynes 55f-pa
55fa
aConditions: (a) G2 (10 mol %), C6D6 (0.02M), 65 °C, 1 h, 90% (1H
NMR). (b) G1 (10 mol %), C6D6 (0.02M), 65 °C, 1 h, 25% (1H NMR).
SCHEME 15. Plausible Mechanism for the Formation of 60f
and 61a
aConditions: (a) G2 (10 mol %), PhH, (0.02M), 65 °C, 1 h. bReaction
was run in toluene at 80 °C for 40 min. cReaction was run for 6 h.
the less reactive G1 allows reversible formation of ruthenium
alkylidene 64, which undergoes a more facile enyne metath-
esis reaction to produce cyclopentene 61.41
The encouraging result obtained with enyne 55f using G2
prompted us to evaluate the efficiency of the key metathesis
reaction on other substrates. Thus, enynes 55f-p were
subjected to G2 (10 mol %) in PhH at 65 °C for 1 h to afford
the desired tricyclic dienes 60f-p in modest to good yields
1
(Scheme 16).10 In situ H NMR monitoring of these reac-
tions revealed clean conversion in all cases. Thus, the mod-
erate yields are attributed to the sensitivity of these silanes
toward silica gel chromatography. Notably, the enyne me-
tathesis conditions proved to tolerate sensitive functional
groups such as the aldehyde of 55o42 and the primary iodide
of 55p.43
Relay Ring-Closing Metathesis Strategy for the C-Ring
formation. Encouraged by these results, we focused our
efforts on building the C-ring of the illudins. Our initial
strategy was inspired by the work of Hoye and co-workers
on the relay ring-closing metathesis reaction (Scheme 17).44
Initial metathesis of the allyl group of a tetraene 68, obtained
from the cyclic silyl ether 59, would generate the ruthenium
alkylidene 69. This would set the stage for an intramolecular
olefin metathesis providing compound 70 with the ruthenium
at the site required for the final cyclization to generate 71.45
Thus, we prepared the substrates 73 and 74 for the relay
ring-closing metathesis (Scheme 18). Wittig olefination of
60o afforded 60n in a low 30% yield, complicated by the
sensitivity of the allylic silane. The triol, 72, was then
prepared in 30% yield through a Tamao oxidation.46 The
allyl silane tether was then selectively appended to the
aConditions: (a) G2 (10 mol %), C6D6 (0.02M), 65 °C, 1 h, 90% (1H
NMR). (b) G1 (10 mol %), C6D6 (0.02M), 65 °C, 1 h, 25% (1H NMR).
the alkyne. A similar lack of reactivity was observed with the
trienyne 55n,38 which suggested that unhindered terminal
olefins competitively reacted with and reduced the activity of
the metathesis catalyst toward the desired EYRCM cascade.
Accordingly, we selected trienyne 55f bearing a side chain
with a less reactive trisubstituted olefin and monitored the
EYRCM reaction of this substrate using 1H NMR (Scheme
14). We were delighted to find that treatment of trienyne 55f
with G2 for 1 h at 65 °C generated the desired cyclic silane 60f
with good conversion (90%, 1H NMR). Interestingly, when
the G1 catalyst was used, the enyne 55f was converted to the
cyclopentenyl product, 61. Extensive 2D-NMR analysis and
X-ray crystallographic analysis of a related product39 allowed
for the assignment of the structure of the cyclopentene 61.40
A plausible mechanism for the formation of the two
metathesis products 60f and 61 is described in Scheme 15.
In the presence of the G2 catalyst, the initial metathesis
occurs at the terminal olefin 62 to give, after the EYRCM,
the desired cyclic silane 60f. Conversely, it is plausible that
(41) It may also be plausible that the formation of product 63 occurs
through initial complexation of the metathesis catalyst (LnRudCH2) with
the alkyne followed by EYRCM.
(42) The enyne substrate 55o was prepared from the dienyne 55h by
sequential cleavage of the pivaloate ester (DIBAL-H, CH2Cl2, -78 °C, 93%)
followed by Dess-Martin periodinane oxidation (55%) of the resulting
alcohol.
(43) The iodide 55p was prepared from the dienyne 55i by sequential
cleavage of the pivaloate ester (DIBAL-H, CH2Cl2, -78 °C, 93%) followed
by hydroxyl displacement (I2, PPh3, imid., CH2Cl2, 75%).
(44) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H.
J. Am. Chem. Soc. 2004, 126, 10210.
(45) For applications of the Relay-RCM strategy, see: (a) Wang, X.;
Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2004,
43, 3601. (b) Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44, 1912.
(46) (a) Tamao, K.; Ishida, N.; Kumada, M. Org. Synth. 1990, 69, 96. For
examples of Tamao oxidation of silicon tethered metathesis products, see:
(b) Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757. (c) Yao, Q.
Org. Lett. 2001, 3, 2069.
(38) The enyne 55n was prepared from the dienyne 55i by sequential
cleavage of the pivaloate ester (DIBAL-H, CH2Cl2, -78 °C, 93%) followed
by hydroxyl displacement (I2, PPh3, imid., CH2Cl2, 75%) and base-promoted
elimination (tBuOK, THF, 66%).
(39) See ref 12. The X-ray crystal structure of the related cyclopentenyl
structure has been deposited at the Cambridge Crystallographic Data
Center; please see CCDC 735275.
(40) 63 could be isolated in 15% yield (G1 (10 mol%), CH2Cl2 (0.02M),
23 °C, 16 h). For the preparation of tetraene 63 and its spectroscopic data, see
the Supporting Information.
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SCHEME 17. Relay Ring-Closing Metathesis Strategy
SCHEME 19. Reductive Allylic Transposition Strategy
SCHEME 20. Introduction of the Diethylallyloxysilyl Tethera
SCHEME 18. Synthesis of Intermediates for the Relay
Ring-Closing Metathesisa
aConditions: (a) Et3N, CH2Cl2, 23 °C.
SCHEME 21. Synthesis of Trieneol 86 via Stille Couplinga
t
aConditions: (a) Ph3PMeBr, BuLi, THF, 30%. (b) H2O2, KF, NaH-
CO3, MeOH, THF, 23 °C, 30%. (c) Allylchlorodimethylsilane, Et3N,
CH2Cl2, 23 °C, 47%. (d) AllylMgCl, THF, 0 °C, 45%. (e) G1 or G2,
various conditions.
aConditions: (a) G2, PhMe, 110 °C; TBAF, 64%. (b) TBSCl, imid.,
DMF, 23 °C, 36 h, 83%. (c) Triphosgene, pyr., 23 °C, 1 h, 93%. (d)
DDQ, H2O, CH2Cl2, 0 °C, 5.5 h, 80%. (e) DDQ, PPh3, TBABr, 23 °C,
5 min, 86%. (f) PdCl2(MeCN) (10 mol %), isopropenyl-tributylstan-
nane, NMP, 23 °C, 1 h, 35%. (g) TBAF, THF, 0 °C, 45 min, 79%.
terminal allylic alcohol to afford 73 in 47% yield. Alterna-
tively, the cyclic ether 60n could be treated with allylmagne-
sium bromide to afford the allylsilane 74 directly in 45%
yield. Unfortunately, when we evaluated the relay RCM with
the tetraenes 73 and 74 using G1 or G2 catalysts, we only
observed dimerization or decomposition of the substrates.47
These findings prompted us to consider a different approach
for assembling the C-ring of the target illudins that would
involve a more reactive olefin.
First Generation Synthesis of (-)-Acylfulvene (1) via a
Reductive Allylic Transposition Strategy. Accordingly, we
revised our synthesis to incorporate a reductive allylic trans-
position reaction (Scheme 19). Through this strategy, alcohol
76 could be elaborated to the terminal olefin 77, which could
then be converted to tricycle 78 via a RCM reaction. Oxida-
tive dehydrogenation would then provide the fulvene 79.
Because of the difficulty of forming the triol 76 from the
allylsilane through oxidative methods(60nf 72, Scheme18),
we investigated alternative olefin tethers for the EYRCM
cascade.12 In the midst of these studies, we made a tactical
change to use allyloxydialkylsilyl tethers in the EYRCM
(Scheme 20). These tethers obviated the problematic oxida-
tion step and allowed direct access to the stable triol product
from the EYRCM reaction via in situ removal of the tether.
During the preliminary screening of several tethers using a
model substrate,12 allyloxydiethylsilyl tether 80 demon-
strated an optimal combination of stability and reactivity.
Selective monosilylation of diols 54k-m with allyloxy-
diethylsilyl chloride 8048 gave the enyne metathesis sub-
strates 81k-m in good yields (83-95%).
Our first generation synthesis of the tricyclic system began
with the OPMB substrate 81m and featured a Stille cross-
coupling reaction to append the appropriate isopropenyl
side chain for the final RCM step (Scheme 21). EYRCM of
the p-methoxybenzyl ether substrate 81m followed by in situ
TBAF cleavage of the oxysilane tether furnished the desired
cyclohexenyl product 82m directly in 64% yield.12 In con-
trast to the allyldimethylsilyl tether (Scheme 16), the allylox-
ysilane tethered substrate 81m required a higher temperature
(47) We did not observe any evidence of the formation of the relay RCM
intermediate 70 (Scheme 18) in these reactions, which highlighted the
difficulty of carrying out an RCM with a conjugated trisubstituted olefin.
(48) 80 was prepared according to the procedure of Krolevets: A. A.;
Antipova, V. V.; Popov, A. G.; Adamov, A. V. Zh. Obsch. Khim. 1988, 58,
2274.
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SCHEME 22. First Generation Synthesis of Acylfulvene (1) via
TABLE 3. EYRCM with 81k
a Reductive Allylic Transposition Reactiona
entry
catalyst (mol %)
concn (M)
yield (%)
1
2
3
4
5
6
10
10
20
30
30
100
0.02
0.04
0.01
0.01
0.003
0.001
18
21
25
52
45
29
aConditions: (a) NBSH, DEAD, PPh3, NMM, -30 to 23 °C, 30%
(6S:6R, 3:1). (b) G2 (10 mol %), C6D6, 65 °C, 45 min, 45% (6S:6R, 3:1).
(c) DDQ, C6H6, 23 °C, 12 h, 93%. (d) NaOH, dioxane, 1 h, 23 °C, 99%.
(e) IBX, DMSO, 83%.
SCHEME 23. EYRCM Cascade with 91k and 91la
(110 °C) to achieve complete conversion in the EYRCM
reaction. Selective TBS protection of the triol 82m at the
primary allylic alcohol followed by protection of the diol as a
carbonate with triphosgene afforded compound 83. Re-
moval of the PMB group by the action of 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) followed by bromination
of the pendant alcohol then afforded intermediate 84, poised
for a Stille cross-coupling. Isopropenyltributylstannane was
coupled to the allylic bromide to generate substrate 85 in
35% yield to set up the olefinic side chain for the final RCM
reaction. Desilylation of ether 85 gave the allylic alcohol 86,
which was primed for a reductive allylic transposition reac-
tion.
Exposure of allylic alcohol 86 to 2-nitrobenezenesulfonyl
hydrazide (NBSH)49 under Mitsunobu conditions furnished
the terminal olefin 87 (30%, 6S:6R, 3:1)34 via Myers’ re-
ductive allylic transposition chemistry (Scheme 22). Gratify-
ingly, the planned RCM reaction employing G2 in benzene
at 65 °C generated the C-ring to afford cyclopentene 88 in
45% yield (6S:6R, 3:1). Dehydrogenation with DDQ furn-
ished the fulvene 89 in 93% yield, and hydrolytic cleavage of
the carbonate afforded the diol 90 in 99% yield. o-Iodox-
ybenzoic acid (IBX) oxidation9g then provided acylfulvene
(1) in 83% yield.50 In the course of these studies, we found a
more efficient route that would circumvent derivatization of
the side chain (Scheme 20). Thus, we used the optimal
acetylides 53k and 53l (Scheme 11) that could be directly
applied in the C-ring RCM step for the synthesis of acylful-
vene (1).
aConditions: (a) G2 (15 mol %), PhMe (0.01M), 90 °C, 30 min; TBAF,
AcOH, THF, 23 °C, 10 min.
52% yield, after removal of the silyl moiety with TBAF
(entry 4, Table 3). Decreasing the concentration and raising
the catalyst loading did not improve the yield of the final triol
82k (entries 5 and 6). Moreover, the use of milder desilylation
condition or use of ruthenium scavengers51 during isolation
afforded similar yields of the triol 82k. We speculated that, at
high temperature, partial loss of the allyloxydiethylsilyl
tether, promoted by the vicinal hydroxyl group, was respon-
sible for the low efficiency of the reaction.
To increase the stability of the enyne metathesis substrate
and improve the yield of desired triol, the C2 tertiary hydro-
xyl group was converted to the corresponding trimethylsilyl
ether. The reactivity of the silyl ether substrates 91k and 91l
were significantly enhanced under the EYRCM conditions
and required only 15 mol % catalyst loading of G2 at 90 °C
(Scheme 23).10 After in situ desilylation of the EYRCM
product, a mixture of the desired triol 82k and byproduct
92 were isolated in 52% and 20% yield, respectively. Con-
versely, the styrenyl derivative 91l10 containing a C7-C8
trisubstitued styrenyl alkene underwent the EYRCM cas-
cade and desilylation reaction smoothly to afford the desired
triol 82l exclusively in 79% yield (Scheme 23). The undesired
product 92 was not observed for substrate 91l, which is
consistent with the lower reactivity of styrenyl olefins under
the EYRCM conditions.
Optimization of the EYRCM. We first evaluated the
tandem EYRCM-desilylation sequence with the phenethyl
derivative 81k (Table 3). As with intermediate 81m
(Scheme 21), the EYRCM of 81k required high temperature
(110 °C) and high catalyst loading of G2 (30 mol %) to
achieve complete conversion. We reasoned that at this high
temperature, the lifetime of the catalyst might be reduced.
Using the optimal concentration (0.01M) and catalyst load-
ing of G2 (30 mol %), the desired triol 82k was isolated in
The formation of the unexpected triol 92 was investigated
in detail. In situ 1H NMR studies revealed that some trienyne
91k diverges from the desired EYRCM pathway (91k f 82k,
Scheme 24) to undergo a competing olefin metathesis with
the C7-C8 alkene affording a 10-membered ring intermedi-
ate 95 (Scheme 24). Subsequent enyne metathesis and olefin
(49) (a) Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841.
(b) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62, 7507.
(50) These initial studies for the synthesis of acylfulvene via the Stille
coupling of the OPMB side chain were carried out on racemic material.
(51) Maynard, H.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 4137.
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SCHEME 25. One-Pot Synthesis of Carbonates 97k,la
SCHEME 24. Proposed Mechanism for Formation of Triols
82k and 92
aConditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C; triphosgene,
23 °C; TBAF.
TABLE 4. Reductive Allylic Transposition Using NBSHa
additive
(equiv)b
concn
(M)
yield
(%)
entry
substrate
solvent
1
2
3
4
5
6
7
97k
97k
97k
97l
97l
97l
97l
NMM
NMM
NMM
NMM
NMM
THF
0.20
0.25
0.30
0.30
0.30
0.20
0.30
27
43c
75
54
35
27
54
A (15)
A (10)
A (10), B (2)
A (10), B (2)
A (10), B (2)
isomerization52 of cyclic alkyne 95 produced the tricyclic
disiloxane 96. In situ NOE analysis of intermediate 96
confirmed the E geometry for the C7-C8 olefin, which
was opposite to the triol derived from desilylation of alkyne
95. Interestingly, lower reaction temperatures (80 °C) led to
an increase in the yield of the olefin metathesis product 95,
which is attributed to the higher energy barrier generally
required for an EYRCM as compared to a RCM. The
sensitive cyclic alkyne 95 was isolated and resubmitted to
the optimal enyne metathesis conditions at higher tempera-
ture (90 °C) to give the triol 92 after silyl cleavage.
NMM-
THFd
8
97l
NMM-
THFd
A (10), B (1)
0.20
67
aNBSH(3.0 equiv), DEAD(3.0 equiv), and PPh3 (3.1equiv) were used.
bAdditives: A = allylbenzene, B = neopentyl alcohol. cThe C7-C8
reduction product of 99k was also isolated (19%). dNMM-THF = 1:1.
When treated with diethylazodicarboxylate (DEAD), tri-
phenylphosphine (PPh3), and NBSH at 0.02 M concentra-
tion in N-methyl morpholine (NMM), the allylic alcohol 97k
provided the desired product 99k (6S:6R, 3:1) along with a
significant amount of unreacted starting material (entry 1,
Table 4). By increasing the concentration of the reaction
mixture49a we observed full consumption of the alcohol 97k;
however, the yield was still unsatisfactory (43%, entry 2,
Table 4). Careful examination of this reaction revealed that
thermal decomposition of the unreacted NBSH generated
diimide in the reaction mixture, which reduced a significant
amount (19%) of the product 99k at the C7-C8 terminal
olefin. Gratifyingly, addition of allylbenzene as a scavenger
for the diimide and further increasing the reaction concen-
tration afforded the desired product 99k in 75% yield
(entry 3). Unfortunately, when we tried to apply these
conditions to the reductive allylic transposition of substrate
97l, the yield of the isolated product 99l was modest (54%,
entry 4) as a result of the poor solubility of this substrate.10
To address the lack of reactivity of alcohol 97l, we added
neopentyl alcohol to improve the efficiency of the Mitsuno-
bu displacement.53 Unfortunately, neopentyl alcohol further
decreased the solubility of the substrate, resulting in poor
With the key triols 82k and 82l in hand, we evaluated the
reductive allylic transposition reaction and RCM reaction
for the completion of the synthesis of (-)-acylfulvene (1) and
(-)-irofulven (2). We found it necessary to mask the tertiary
and secondary alcohols, and developed a tandem process to
generate the carbonates 97k and 97l (Scheme 25). Mono-
t
silylation of the allylic alcohols 82k and 82l with butyldi-
methylsilyl trifluoromethanesulfonate (TBSOTf, 1 equiv)
selectively protected the primary alcohol. Sequential treat-
ment with triphosgene and treatment with TBAF afforded
the desired carbonates 97k and 97l in good overall yields in a
single flask.
Optimization of the Reductive Allylic Transposition Reac-
tion. Substrates 97k and 97l were subjected to Myers’ re-
ductive allylic transposition reaction to give desired trienes
(Table 4).49 Low temperature Mitsunobu displacement with
NBSH generates the allylic hydrazide derivatives, which
upon warming spontaneously lose 2-nitrobenzene sulfinic
acid followed by dinitrogen to afford the desired terminal
olefins 99k,l.
(52) For examples of olefin isomerization catalyzed by ruthenium com-
plexes, see: (a) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L.
J. Am. Chem. Soc. 2002, 124, 13390. (b) Hong, S. H.; Day, M. W.; Grubbs,
R. H. J. Am. Chem. Soc. 2004, 126, 7414. (c) Hong, S. H.; Sanders, D. P.; Lee,
C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160.
(53) (a) Walker, M. A. J. Org. Chem. 1985, 60, 5352. (b) Myers, A. G.;
Movassaghi, M.; Zheng, B. J. Am. Chem. Soc. 1997, 119, 8572.
J. Org. Chem. Vol. 74, No. 24, 2009 9301

Siegel et al.
JOCArticle
TABLE 5. IPNBSH-Mediated Transposition Reactionsa
SCHEME 26. RCM of Triene 99k and Synthesis of Acylfulvene
(1)a
aConditions: (a) G2 (15 mol %), C6D6, 65 °C, 82% (6S:6R, 7.6:1).
(b) DDQ, PhH, 93%. (c) Aqueous NaOH, Dioxane, 99%. (d) IBX,
DMSO, 83%.
entry
concn (M)
ROH
yield (%)
1
2
3
4
5
0.20
0.25
0.10
0.10
0.10
none
33
57
58
57
71
MeOH
iPrOH
EtOH
TFE
conversion to the desired diene 88 (82%, 6S:6R, 7.6:1,
Scheme 26), which was accessed in our first generation
synthesis (Scheme 22). Isolation of the carbonate from this
reaction mixture was found to be problematic. The (6R)-
diastereomer of carbonate 88 was particularly sensitive to
silica gel chromatography. Furthermore, oxidation of the
minor isomer (6R)-88 proved to be very slow. Therefore, we
carried forward only the major diastereomer 6S-88 through
the remaining steps of the sequence shown in Scheme 26.
We were pleased to find that oxidation of the cyclopentene
(6S)-88 with DDQ afforded the desired fulvene carbonate 89
in 93% yield (Scheme 26) in a manner similar to the first
generation route described above (Scheme 22). Subsequent
hydrolysis of the carbonate 89 gave the diol fulvene 90 as
reported by Brummond and co-workers.9f The synthesis of
acylfulvene (1)55 was then completed by oxidation of the
secondary alcohol with IBX.9g
With the final steps of the synthesis of acylfulvene (1) in
place, we focused on streamlining the final stages of synth-
eses of (-)-acylfulvene (1) and (-)-irofulven (2). These final
optimizations were performed on enantiomerically enriched
samples of triene 99l prepared from the key aldehyde (þ)-22.
To efficiently convert both diastereomers of triene 99l to the
final diol fulvene 90 we bypassed the isolation of the sensitive
carbonate 88 (Scheme 27) via an in situ hydrolysis of the
carbonate. Thus, after the RCM of triene 99l, the mixture
was sequentially diluted with dimethylformamide (DMF)
and treated with aqueous lithium hydroxide. The resulting
diol 101 was quickly subjected to aqueous workup, filtered
through silica gel, and immediately oxidized to the desired
diol fulvene 90 using chloranil in 70% yield over the three
steps.
aThe reactions were performed with 2 equiv of IPNBSH, DEAD,
and PPh3.
yield of olefin 99l (35%, entry 5). The use of THF in place of
NMM improved the homogeneity of the reaction mixture
but also increased the formation of undesired byproducts
(entry 6). Furthermore, a mixture of THF and NMM as
solvent did not improve the efficiency of allylic transposition
(entries 7-8). As a result of the insolubility of the substrate in
the reaction media at low temperature and at high concen-
tration, variable yields of the desired product were obtained.
To address the complications associated with substrate
97l, we considered the use of a more stable derivative of
NBSH that would allow us to carry out the challenging
Mitsunobu displacement at higher temperatures and lower
solvent concentrations. Thus, the acetone hydrazone deri-
vative, N-isopropylidene-N0-2-nitrobenzenesulfonyl hydra-
zine (IPNBSH),54 was prepared and used for the reductive
allylic transposition of alcohol 97l (Table 5). We were
pleased to find that the Mitsunobu displacement of alcohol
97l with IPNBSH proceeded smoothly at temperatures
between 5 and 23 °C and at lower concentrations to give
the stable hydrazone intermediate 100l. Exposure of inter-
mediate 100l to hydrolytic conditions then afforded trans-
position product 99l. Water alone was insufficient for the
hydrolysis of the hydrazone (entry 1, Table 5); however,
the addition of alcoholic cosolvent greatly enhanced the
yield and rate of formation of the product 99l (entries
2-5). Interestingly, the solvolysis of hydrazone 100l using
2,2,2-trifluoroethanol (TFE) at 0 °C occurred with the great-
est efficiency to afford the desired olefin 99l in 71% yield
(entry 5).
We then established a tandem process to include the
RCM, hydrolysis, and dehydrogenation in a single flask.
Thus, the triene 99l was subjected to a three-step sequence
involving the RCM, carbonate hydrolysis, and sequential
chloranil oxidation to afford the desired diol fulvene 90
directly in 70% yield (Scheme 28). Interestingly, by replacing
chloranil with DDQ, a more potent oxidant, the triene 99l
could be converted directly to the target (-)-acylfulvene (1)
in 30% yield without isolation of any intermediates
Completion of the Synthesis of (-)-Acylfulvene (1) and (-)-
Irofulven (2). Preliminary studies on the final steps of the
synthesis were carried out using triene 99k. Treatment of
triene 99k with 15 mol % of G2 at 65 °C resulted in clean
(54) For an evaluation of the scope of IPNBSH, see: (a) Movassaghi,
M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838. For use of IPNBSH in
a stereospecific palladium-catalyzed route to monoalkyl diazenes, see:
(b) Movassaghi, M.; Ahmad, O. K. Angew. Chem., Int. Ed. 2008, 47, 8909.
(55) These initial studies for the synthesis of acylfulvene with 99k were
performed using racemic material.
9302 J. Org. Chem. Vol. 74, No. 24, 2009

Siegel et al.
JOCArticle
SCHEME 27. Conversion of Triene 99l to Fulvene Diol 90a
SCHEME 29. Summary of the Enantioselective Total Synthesis
of (-)-Acylfulvene (1) and (-)-Irofulven (2)a
aConditions: (a) G2 (15 mol %), PhH, 80 °C; aq LiOH, DMF, 23 °C,
12 h. (b) Chloranil, PhH, 70% (3 steps).
SCHEME 28. Synthesis of (-)-Acylfulvene (1) and (-)-Iroful-
ven (2)a
aConditions: (a) 99l f (-)-(1): G2 (15 mol %), PhH, 80 °C, 50 min;
NaOMe, MeOH, 23 °C, 18 h; AcOH; DDQ, MeCN, 14 h, 30%. (b) 99l f
90: G2 (15 mol %), PhH, 80 °C, 50 min; NaOMe, MeOH, 23 °C, 18 h;
AcOH; chloranil, MeCN, 13 h, 70%. (c) IBX, DMSO, 83%. (d) H2SO4,
CH2O aq, Me2CO, 63%.
aFor clarity, only the major diastereomer of the intermediates 54l-99l is
shown. Conditions: (a) (R,R)-2,20-isopropylidene-bis(4-tbutyl-2-oxazo-
line), Cu(OTf)2, THF, -78 °C, 12 h, 95%, 92% ee. (b) MeZnI, Pd2-
(dba)3, SPhos, THF, NMP, 65 °C, 2 h, 83%. (c) CH2I2, TiCl4, Zn, PbCl4,
CH2Cl2, THF, 23 °C, 4 h, 89%. (d) DIBAL-H, Et2O, -78 °C;
Dess-Martin periodinane, CH2Cl2, 23 °C, 91%. (e) 53l, LHMDS,
THF, -78 f -40 °C; TBAF, AcOH, 75%. (f) (Et)2Si(Cl)OCH2-
CHdCH2, 2,6-lutidine, CH2Cl2; TMSOTf, -78 °C, 83%. (g) G2
(15 mol %), PhMe, 90 °C, 30 min; TBAF, AcOH, 79%. (h) TBSOTf,
2,6-lutidine, CH2Cl2, -78 °C; triphosgene; TBAF, 67%. (i) IPNBSH,
DEAD, Ph3P, THF, 0-23 °C; TFE, H2O, 71%. (j) G2 (15 mol %), PhH,
80 °C; NaOMe; AcOH; DDQ (99l f 1, 30%) or use chloranil to isolate
90 (70%), then IBX, DMSO, 83%. (k) H2SO4, aqueous CH2O, 63%.
(Scheme 28). Finally, (-)-acylfulvene (1) was converted to
(-)-irofulven (2) in 63% yield using the protocol described
by McMorris and co-workers.5,10 All spectroscopic data for
(-)-acylfulvene (1) and (-)-irofulven (2) matched those
reported in the literature.
Conclusion. We have described the development of our
synthesis of the two potent antitumor agents (-)-acylfulvene
(1) and (-)-irofulven (2). The optimal sequence is summar-
ized in Scheme 29. The asymmetric copper-catalyzed Evans
aldol addition reaction with the strained ketene acetal 26
secured the C2 stereocenter of the target compounds. The
powerful EYRCM cascade reaction with the allyloxysilane
tether was successfully employed for the B-ring construction.
The successful implementation of this strategy required the
identification of optimal derivatives for rapid post-EYRCM
derivatization. The reagent IPNBSH efficiently provided the
necessary reductive transposition of an advanced allylic
alcohol. Finally, a tandem RCM/dehydrogenation process
was employed for the C-ring construction to complete the
synthesis of (-)-acylfulvene (1) and (-)-irofulven (2).
syringe. After 19 h, the reaction mixture was diluted with diethyl
ether (300 mL) and filtered through a plug of silica gel
(6 ꢀ 6 cm, eluent 1% triethyamine in diethyl ether). The filtrate
was concentrated under reduced pressure and the residue was
purified by flash column chromatrography (silica gel, diameter
9 cm, height 15 cm; eluent 1% triethylamine in [2% ethyl acetate
in hexanes] to 1% triethylamine in [20% ethyl acetate in
hexanes]) to afford the desired (2R)-2-(1-ethylsulfanylcarbo-
nyl-cyclopropyl)-2-(trimethyl-silanyloxy)-propionic acid methyl
ester (48b, 19.8 g, 95%, [R]20 = þ30.2 (c 2.22, CHCl3)) as a
D
colorless liquid. Protodesilylation of the C2-trimethylsilyloxy
group of 48b afforded samples of the corresponding C2-alcohol
that were found to be of 92% ee by chiral HPLC analysis
i
[Chirapak AD-H; 1.5 mL/min; 10% PrOH in hexanes; tR-
Experimental Section
(minor) = 4.65 min, tR(major) = 5.17 min]. The (R,R)-2,20-
isopropylidene-bis(4-tert-butyl-2-oxazoline) ligand was recov-
ered from the reaction mixture (∼85%) and purified by flash
column chromatography (silica gel, diameter 2.5 cm, height
10 cm; eluent 20% ethyl acetate in dichloromethane). TLC
(þ)-(R)-Methyl-2-(1-((ethylthio)carbonyl)cyclopropyl)-2-((tri-
methylsilyl)oxy)propanoate (48b). A flame-dried flask was
charged with (R,R)-2,20-isopropylidene-bis(4-tert-butyl-2-oxa-
zoline) (2.03 g, 6.90 mmol, 0.10 equiv)56 and copper(II) trifluor-
omethanesulfonate (2.50 g, 6.90 mmol, 0.10 equiv) in a glovebox
under a dinitrogen atmosphere. The flask was sealed with a
rubber septum and removed from the glovebox. The flask
containing the solids was charged with THF (304 mL) at 23 °C
and was flushed with argon. After 1 h, the resulting bright green
solution was cooled to -78 °C, and methyl pyruvate (25, 7.80 g,
76.0 mmol, 1.10 equiv) was added via syringe followed by
(cyclopropylidene-ethylsulfanyl-methoxy)-trimethyl-silane (26b
[mixture of 26b:47b = 9:1], 15.5 g, 69.0 mmol, 1 equiv 26b) via
1
(10% ethyl acetate in hexanes): Rf 0.4 (UV, CAM). H NMR
(500 MHz, CDCl3): δ 3.72 (s, 3H), 2.79 (q, J = 7.3 Hz, 2H),
1.58-1.54 (m, 1H), 1.53 (s, 3H), 1.27-1.19 (m, 2H), 1.19 (t, J =
7.3 Hz, 3H), 1.12-1.08 (m, 1H), 0.07 (s, 9H). 13C NMR (125.8
MHz, CDCl3): δ 200.9, 173.4, 75.4, 52.1, 41.8, 24.2, 23.0, 15.3,
14.8, 11.6, 1.5. FTIR (neat) cm-1: 2954, 1747, 1666, 1456, 1413,
1372, 1289, 1263. HRMS (ESI): calcd for C13H24NaO4SSi [M þ
Na]þ 327.1057, found 327.1066.
Representative Procedure for the Synthesis of Diols 54a-54m.
Synthesis of (2R,3S)-6-(tert-Butyldimethyl-silyloxy)-7,7-dimeth-
yl-2-(1-(prop-1-en-2-yl)cyclopropyl)non-8-en-4-yne-2,3-diol (54c).
n-Butyllithium (2.50 M in hexanes, 100 μL, 250 μmol, 1.30 equiv)
was added dropwise via syringe to a solution of diisopropylamine
(56) For the preparation of (R,R)-2,20-isopropylidene-bis(4-tbutyl-2-
oxazoline), see: Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D.
M.; Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541–4544.
J. Org. Chem. Vol. 74, No. 24, 2009 9303

Siegel et al.
JOCArticle
(37.0 μL, 270 μmol, 1.40 equiv) in THF (300 μL) at 0 °C. After
30 min, the mixture was cooled to -78 °C, and a solution of
alkyne 53c (55.0 mg, 230 μmol, 1.20 equiv) in THF (0.9 mL) was
added dropwise via cannula. After 35 min, a solution of the
aldehyde 22 (43.0 mg, 190 μmol, 1 equiv) in THF (0.6 mL) was
added dropwise via cannula. After 2 h, saturated aqueous
ammonium chloride solution (0.5 mL) was added. The resulting
mixture was allowed to warm to 23 °C, diluted with diethyl ether
(40 mL), and washed with water (10 mL). The aqueous layer was
extracted with diethyl ether (2 ꢀ 40 mL), and the combined
organic layers were dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The crude silyl ether resi-
due was dissolved in THF (3 mL), and to this solution was added
hydrogen fluoride-triethylamine complex (20.0 μL, 190 μmol,
1.00 equiv) at 0 °C. After 2 h, saturated aqueous sodium
bicarbonate solution (3 mL) was added, and the resulting mixture
was warmed to 23 °C and diluted with diethyl ether (100 mL) and
water (10mL). The aqueous layerwas extracted withdiethyl ether
(2 ꢀ 40 mL), and the combined organic layers were dried over
anhydrous sodium sulfate and concentrated under reduced pres-
sure. The resulting crude oil was purified by flash column
chromatography (silica gel, diameter 2 cm, height 16 cm; eluent
75% diethyl ether in n-pentane) to afford the desired diol 54c
(46mg, 63%, (3S:3R, 4:1), 2:1 mixture of C6diastereomers). TLC
(15% diethyl ether in n-pentane): Rf 0.15 (Anis). 1H NMR (400
MHz, C6D6, 4:1 mixture of (3S)- and (3R)-diastereomers; major
(3S)-diastereomer reported): δ 6.06 (ddd, J = 17.2, 10.8, 6.3 Hz
1H), 5.11-5.03 (m, 3H), 4.90 (br-s, 1H), 4.43 (d, J = 5.6 Hz, 1H),
4.09 (br-s, 1H), 1.89 (br-s, 1H), 1.76 (br-s, 3H), 1.64 (br-s, 1H),
1.27 (s, 3H), 1.27-1.17 (m, 1H), 1.15 (s, 3H), 1.14 (s, 3H), 0.99
(s, 9H), 0.95-0.84 (m, 1H), 0.60-0.52 (m, 1H), 0.46-0.40 (m,
1H), 0.25 (s, 3H), 0.10 (s, 3H). 13C NMR (100.6 MHz, C6D6): δ
147.9, 145.2, 118.1, 113.0, 87.6, 85.3, 75.0, 71.3, 69.7, 43.1, 33.2,
26.2, 23.6, 23.2, 23.0, 22.9, 18.6, 10.9, 9.5, -3.9, -4.9. FTIR(neat)
cm-1: 3457, 3082, 2958, 1637, 1472, 1252, 1082. HRMS (ESI):
calcd for C23H40NaO3Si [M þ Na]þ 415.2639, found 415.2631.
Representative Procedure for the Synthesis of 55a-55j. Synth-
esis of (2R,3S)-3-(Allyldimethyl-silyloxy)-7-methyl-2-(1-(prop-1-
en-2-yl)cyclopropyl)-oct-4-yn-2-ol (55j). To a solution of the diol
54j (100 mg, 420 μmol, 1 equiv, (3S:3R, 6.7:1)) in dichloro-
methane (2 mL) at 23 °C was added triethylamine (175 μL,
1.26 mmol, 3.00 equiv) followed by allylchlorodimethylsilane
(79.0 μL, 510 μmol, 1.20 equiv) via syringe. After 40 min, the
resulting mixture was purified directly by flash chromatography
(silica gel, diameter 3.0 cm, height 15 cm; eluent 9% diethyl ether
in n-pentane) to afford dienyne 55j (127 mg, 83%, (3S:3R, 8:1))
as a clear colorless oil. TLC (25% diethyl ether in hexanes):
Rf 0.50 (UV, Anis). 1H NMR (400 MHz, C6D6, 8:1 mixture of
(3S)- and (3R)-diastereomers; major (3S)-diastereomer repor-
ted): δ 5.93-5.78 (m, 1H), 5.28 (d, J = 2.5 Hz), 5.02-4.91 (m,
3H), 4.64 (t, 1H, J = 1.7 Hz), 2.14 (br-s, 1H), 1.91-1.89 (m, 5H),
1.78-1.60 (m, 3H), 1.54-1.46 (m, 1H), 1.36 (br-s, 3H),
1.17-1.10 (m, 1H), 0.86 (d, J = 6.7 Hz, 6H), 0.69-0.63 (m,
1H), 0.56-0.50 (m, 1H), 0.22 (s, 3H), 0.20 (s, 3H). 13C NMR
(100.6 MHz, C6D6, 8:1 mixture of (3S)- and (3R)-diastereomers;
major (3S)-diastereomer reported): δ 147.7, 134.2, 117.7, 114.0,
86.7, 81.0, 74.6, 70.3, 32.6, 28.1, 28.0, 25.2, 23.8, 23.5, 22.0, 11.0,
9.2, -1.5, -1.9. FTIR (neat) cm-1: 3570, 3078, 2959, 2925, 2230,
1632, 1374, 1253, 1062, 859. HRMS (ESI): calcd for
C20H34NaO2Si [M þ Na]þ 357.2220, found 357.2235.
Representative Procedure for EYRCM of Allyldimethylsilyl
Ethers 60f-60p. Synthesis of 3-((8R,8aS)-8-hydroxy-2,2,6,8-tet-
ramethyl-2,3,8,8a-tetrahydrospiro[benzo[e][1,2]oxasiline-7,10-cy-
clopropane]-5-yl)propanal (60o). Silyl ether 55o (176 mg,
530 μmol, 1 equiv) was dissolved in benzene (35.0 mL) in a
Schlenk vessel. The resulting solution was degassed thoroughly
by passage of a stream of argon, and G2 (44 mg, 53 μmol, 0.10
equiv) was added as a solid. After 5 min, the light pink reaction
mixture was heated to 65 °C by placement in a preheated oil
bath. After 1 h, the catalyst was quenched by addition of
ethylvinyl ether (0.5 mL). After 5 min, the reaction mixture
was cooled to 23 °C, and the solvent volume was reduced
to ∼50% under reduced pressure. The resulting mixture was
immediately purified by flash chromatography (silica gel, dia-
meter 4 cm, height 15 cm; eluent 10% ethyl acetate in hexanes) to
afford the desired diene 60o (96 mg, 59%) as a clear colorless oil.
TLC (10% ethyl acetate in hexanes): Rf 0.3 (UV, Anis). 1H
NMR (500 MHz, C6D6): δ 9.32 (t, J = 1.5 Hz, 1H), 5.80-5.75
(m, 1H), 4.19 (s, 1H), 2.60 (br-s, 1H), 2.43-2.38 (m, 2H),
2.08-1.96 (m, 2H), 1.30 (dd, J = 13.0, 7.5 Hz, 1H), 1.20 (dd,
1H, J = 13.0, 7.5 Hz), 1.14 (s, 3H), 1.12 (s, 3H), 1.00-0.94 (m,
1H), 0.78-0.72 (m, 1H), 0.56-0.50 (m, 1H), 0.49-0.44 (m, 1H),
0.05 (s, 3H), 0.02 (s, 3H). 13C NMR (125.8 MHz, C6D6): δ 200.3,
137.9, 132.2, 128.9, 120.8, 76.4, 71.8, 43.0, 28.9, 22.3, 21.2, 14.6,
13.9, 8.1, 7.6, -0.6, -1.0. FTIR (neat) cm-1: 3535, 2927, 1720,
1377, 1253, 1102. HRMS (ESI): calcd for C17H26NaO3Si [M þ
Na]þ 329.1543, found 329.1548.
Acknowledgment. M.M. is an Alfred P. Sloan Research
Fellow, a Beckman Young Investigator, and a Camille
Dreyfus Teacher-Scholar. We thank Dr. Michael A.
€
Schmidt, Justin Kim, and Dr. Peter Muller for assistance
with X-ray crystallographic analysis. We are grateful to
Professor A. H. Hoveyda and Professor E. N. Jacobsen for
generous samples of their silylcyanation catalysts. We ac-
knowledge financial support in part by the Damon Runyon
Cancer Research Foundation (DRS-39-04), NIH-NIGMS
(GM074825), Amgen, and Astrazeneca.
Supporting Information Available: Experimental proce-
dures and spectroscopic data for new products. This material
is available free of charge via the Internet at http://pubs.acs.
org.
9304 J. Org. Chem. Vol. 74, No. 24, 2009