A rapid synthesis of hydroxymethylacylfulvene (HMAF) using the allenic Pauson-Khand reaction. A synthetic approach to either enantiomer of this illudane structure

Article abstract of DOI:10.1021/ja000546l

An allenic Pauson-Khand reaction has been employed in the preparation of (±)-hydroxymethylacylfulvene (HMAF), an anticancer agent that is currently in Phase II clinical trials for a variety of solid tumor types. The synthesis is effected in 11 steps from commercially available starting materials. In addition, an asymmetric route to the title compound has been established by intersecting the racemic synthesis with an enantiomerically pure intermediate. The preparation of the enantiomerically pure intermediate involved the Sharpless asymmetric dihydroxylation (AD) of a trisubstituted olefin of an enyne system. This approach provides access to both enantiomers of HMAF simply by changing the ligands in the Sharpless AD reaction. Optimized conditions for the stereospecific synthesis of E or Z trisubstituted enynes from an aliphatic ketone using either Peterson olefination or Horner-Wadsworth-Emmons protocols are reported. Finally, a better understanding of the stereoelectronic requirements of the allenic P-K reaction is recognized.

Full text of DOI:10.1021/ja000546l

J. Am. Chem. Soc. 2000, 122, 4915-4920
4915
A Rapid Synthesis of Hydroxymethylacylfulvene (HMAF) Using the
Allenic Pauson-Khand Reaction. A Synthetic Approach to Either
Enantiomer of This Illudane Structure
Kay M. Brummond,* Jianliang Lu, and Jeffrey Petersen‡
Contribution from the Department of Chemistry, West Virginia UniVersity,
Morgantown, West Virginia 26506-6045
ReceiVed February 15, 2000
Abstract: An allenic Pauson-Khand reaction has been employed in the preparation of (()-hydroxymethyl-
acylfulvene (HMAF), an anticancer agent that is currently in Phase II clinical trials for a variety of solid
tumor types. The synthesis is effected in 11 steps from commercially available starting materials. In addition,
an asymmetric route to the title compound has been established by intersecting the racemic synthesis with an
enantiomerically pure intermediate. The preparation of the enantiomerically pure intermediate involved the
Sharpless asymmetric dihydroxylation (AD) of a trisubstituted olefin of an enyne system. This approach provides
access to both enantiomers of HMAF simply by changing the ligands in the Sharpless AD reaction. Optimized
conditions for the stereospecific synthesis of E or Z trisubstituted enynes from an aliphatic ketone using either
Peterson olefination or Horner-Wadsworth-Emmons protocols are reported. Finally, a better understanding
of the stereoelectronic requirements of the allenic P-K reaction is recognized.
Introduction
The first total synthesis of HMAF was reported by McMorris,2b
utilizing the Padwa carbonyl ylide 1,3-dipolar cycloaddition
methodology5 to arrive at the basic illudane skeleton. One
impetus for an alternative synthesis of HMAF is that it provides
a novel substructure for the preparation of new analogues. We
have recently communicated a racemic synthesis of HMAF6
utilizing an allenic Pauson-Khand reaction that has been
developed in our group.7 In this paper we describe our racemic
approach in full detail and also disclose a route to enantiomeri-
cally pure HMAF. An asymmetric approach to hydroxymethyl-
acylfulvene (3) is desirable since, while both enantiomers
demonstrate antitumor properties, HMAF derived from the
natural illudin S is twice as potent as its unnaturally derived
enantiomer.
The naturally occurring sesquiterpenes illudin M (1) and S
(2) have been shown to possess potent antitumor activity, but
when tested in vivo were found to have a poor therapeutic
index.1 Subsequently, illudin analogues have been prepared that
show greatly improved efficacy when compared to the parent
compounds.2 One analogue in particular, hydroxymethylacyl-
fulvene (HMAF) (3), has generated a tremendous amount of
excitement since it has been proven effective against breast,
lung, and colon tumors in animal models while exhibiting
dramatically reduced toxicity.3 HMAF (3) is currently in Phase
II clinical trials which are being supported by the National
Cancer Institute and MGI Pharma, Inc. Two of the Phase II
studies, involving prostate and ovarian cancers, have been
expanded within the last year based upon signs of positive
clinical results. The mechanism by which HMAF selectively
kills cancer cells is currently being studied. It is believed that
HMAF binds covalently to protein, DNA and RNA, and that
damage induced by alkylation of these multiple targets may
contribute to the proapoptotic and antiproleferative action of
this drug.4
* To whom correspondence should be addressed. Phone: (304) 293-
3435 ext 4445. Fax: (304) 293-4904. E-mail: kbrummon@wvu.edu.
‡ X-ray crystallography.
(1) (a) McMorris, T. C.; Kelner, M. J.; Wang, W.; Diaz, M. A.; Estes,
L. A.; Taetle, R. Experientia 1996, 52, 75. (b) McMorris, T. C.; Kelner,
M. J.; Wang, W.; Yu, J.; Estes, L. A.; Taetle, R. J. Nat. Prod. 1996, 59,
896. (c) For previous syntheses of illudin M, see: Kinder, F. R., Jr.; Blair,
K. W. J. Org. Chem. 1994, 59, 6965. (d) Matsumoto, T.; Shirahama, H.;
Ichihara, A.; Shin, H.; Kagawa, S.; Sakan, F.; Matsumoto, S.; Nishida, S.
J. Am. Chem. Soc. 1968, 90, 3280.
Synthetic Plan
The illudane skeleton possesses a novel structure unrelated
to any other natural occurring compounds and synthetic methods
to arrive at this substructure are limited.8 An allenic variant of
the Pauson-Khand (P-K) type cycloaddition has been devel-
(2) (a) McMorris, T. C.; Yu, J.; Hu, Y.; Estes, L. A.; Kelner, M. J. J.
Org. Chem. 1997, 62, 3015. (b) McMorris, T. C.; Hu, Y.; Yu, J.; Kelner,
M. J. Chem. Commun. 1997, 315. (c) McMorris, T. C.; Kelner, M. J.; Wang,
W.; Estes, L. A.; Montoya, M. A.; Taetle, R. J. Org. Chem. 1992, 57, 6876.
(3) (a) MacDonald, J. R.; Muscoplat, C. C.; Dexter, D. L.; Mangold, G.
L.; Chen, S.-F.; Kelner, M. J.; McMorris, T. C.; Von Hoff, D. D. Cancer
Res. 1997, 57, 279. (b) Kelner, M. J.; McMorris, T. C.; Estes, L. A.; Wang,
W.; Samson, K. M.; Taetle, R. InVestigational New Drugs 1996, 14, 161.
(4) Woynarowski, J. M.; Napier, C.; Koester, S. K.; Chen, S.-F.; Troyer,
D.; Chapman, W.; MacDonald, J. R. Biochem. Pharmacol. 1997, 54, 1181.
(5) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org. Chem. 1996,
61, 73.
(6) Brummond, K. M.; Lu, J. J. Am. Chem. Soc. 1999, 121, 5087.
(7) (a) Brummond, K. M.; Wan, H.; Kent, J. L. J. Org. Chem. 1998, 63,
6535. (b) Brummond, K. M.; Wan, H. Tetrahedron Lett. 1998, 39, 931. (c)
Kent, J. L.; Wan, H.; Brummond, K. M. Tetrahedron Lett. 1995, 36, 2407.
10.1021/ja000546l CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/04/2000

4916 J. Am. Chem. Soc., Vol. 122, No. 20, 2000
Brummond et al.
Scheme 1
Scheme 2
oped in our group which provides access to molecules possess-
ing 4-alkylidene or R-methylene cyclopentenones depending
upon the reactant structure and reaction conditions.7 On the basis
of our preliminary investigations, the substrate selectivity
observed in the P-K type cycloadditions of 3,3-disubstituted
allenes is ideally suited for the synthesis of the illudin class of
compounds. The general retrosynthesis of our approach to
HMAF (3) is presented in Scheme 1. The target structure was
functionalized fulvene 4, which has been previously converted
to HMAF in two steps ((1) Dess-Martin periodinane, (2) H2-
SO4, CH2O).2b We reasoned that fulvene 4 represented a
thermodynamic well and could be obtained from the 4-alky-
lidene cyclopentenone 5 via the addition of a methyl anion to
the ketone moiety and subsequent dehydration of the newly
formed tertiary alcohol. The most challenging structural feature
of retron 5 is the 4-alkylidene cyclopentenone substructure
which we anticipated would result from an allenic P-K-type
cycloaddition of the densely functionalized alkynyl allene 6.
Preliminary investigations strongly suggested that the cycload-
dition would occur with the least substituted double bond of
the allene. Retrosynthetic simplification of alkynyl allene 6 is
relatively straightforward furnishing 1,1-diacetylcyclopropane
as a potential precursor. 1,1-Diacetylcyclopropane represents a
readily available starting material that can be prepared in good
yields from 2,4-pentanedione.9 In addition, 1,1-diacteylcyclo-
propane possesses C2-symmetry, providing a variety of options
for the construction of the alkynyl allene 6.
installation of the dihydroxyl moiety of compound 6 (Scheme
1). We reasoned that this substitution pattern could be achieved
by the chemoselective, asymmetric dihydroxylation (AD) of the
Z-enyne 9. Literature precedent shows that mono- and disub-
stituted olefins of enynes can be selectively dihydroxylated in
good yields and high ee’s.11 Unfortunately, initial attempts to
effect a Sharpless AD of the olefin of the corresponding enyne
moiety met with complications and recovery of the starting
material. On the basis of these results, it was decided to delay
the AD until after the key allenic P-K cyclization. Thus, the
methyl ketone moiety was converted to the desired allene in
the three-step process described below. Addition of ethynyl-
magnesium bromide in the presence of 1 equiv of cerium
trichloride resulted in the propargylic alcohol 10 in 95% yield.12
In the absence of CeCl3 the yields for this ethynylation reaction
were low (∼40%). Conversion of the sterically hindered
propargylic alcohol to the propargylic acetate 11 was sluggish
using standard acetylation conditions. For instance, treatment
of the hydroxyl moiety to acetic anhydride, pyridine, and DMAP
in CH2Cl2 gave only a 16% yield of the desired acetate 11 after
3 days. Likewise, deprotonation of 10 with sodium hydride and
addition of acetyl chloride also gave very low yields of acetate
11. The Vedejs dual-activation strategy for benzoylation of
hindered alcohols using magnesium bromide and benzoic
anhydride resulted in immediate decomposition of the starting
material.13 The rapid decomposition of 10 was attributed to the
neighboring cyclopropyl moiety, that is most likely undergoing
a Julia-type ring opening under the Lewis acidic reaction
conditions.14 Fortunately, a facile and high-yielding acylation
was observed by the treatment of 10 with excess acetic
anhydride and catalytic DMAP in neat triethylamine.15 Within
1 h, the starting material was consumed and a simple filtration
and removal of solvent furnished acetate 11 in 94% yield. To
prevent decomposition of this acid-labile acetate, it was
converted directly to the allene 12 without further purification.
The conversion of the propargylic acetate 11 to allene 12 also
Results and Discussion
Preparation of Cyclization Precursor 12. Initially, our
synthetic strategy focused on the stereospecific preparation of
the Z-enyne 8 (Scheme 2). Addition of the lithium anion of
1,3-bis(trimethylsilyl)propyne to the monoketal of 1,1-diacetyl-
cyclopropane 7 using the Yamamoto protocol10 afforded the
Peterson olefination product 8 as the Z stereoisomer in a 42%
yield. The stereoselectivity of this reaction was temperature
dependent since a mixture of E:Z enynes was obtained if the
reaction was allowed to warm above -40 °C. Subsequent
treatment of the ketal of 8 with p-toluenesulfonic acid afforded
ketone 9 in 95% yield. We initially turned our attention to the
(11) (a) Jeong, K.-S.; Sjo¨, P.; Sharpless, K. B. Tetrahedron Lett. 1992,
33, 3833. (b) Tani, K.; Sato, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett.
1993, 34, 4975. (c) Caddick, S.; Shanmugathasan, S.; Brasseur, D.; Delisser,
V. M. Tetrahedron Lett. 1997, 38, 5735. (d) Wang, Z.-M.; Shen, M.
Tetrahedron: Asymmetry 1997, 8, 3393.
(8) (a) Ahmar, M.; Locatelli, C.; Colombier, D.; Cazes, B. Tetrahedron
Lett. 1997, 38, 5281. (b) Shibata, T.; Koga, Y.; Narasaka, K. Bull. Chem.
Soc. Jpn. 1995, 68, 911. (c) Johnson, W. S.; Cox, J. M.; Graham, D. W.;
Whitlock, H. W., Jr. J. Am. Chem. Soc. 1967, 89, 4524.
(9) (a) Podder, R. K.; Sarkar, R. K.; Ray, S. Indian J. Chem. 1998, 27B,
530. (b) Ogoshi, H.; Kikuchi, Y.; Yamaguchi, T.; Toi, H.; Aoyama, Y.
Organometallics 1987, 6, 2175. 1,1-Diacetylcyclopropane was prepared from
2,4-pentanedione, 1,2-dibromoethane, and potassium carbonate in DMF.
(10) Yamakado, Y.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Am. Chem.
Soc. 1981, 103, 5568.
(12) Imamota, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392. For large scale drying of CeCl3‚
7H2O, see: Takeda, N.; Imamota, T. Org. Synth. 1998, 76, 228.
(13) Vedejs, E.; Daugulis, O. J. Org. Chem. 1996, 61, 5702.
(14) Descoins, C.; Samain, D. Tetrahedron Lett. 1976, 10, 745.
(15) Hofle, G.; Steglich, W. Synthesis 1972, 619.

A Rapid Synthesis of HydroxymethylacylfulVene
J. Am. Chem. Soc., Vol. 122, No. 20, 2000 4917
Scheme 3
Scheme 4
Figure 1.
Scheme 5
proved problematic. Treatment of the acetate 11 with Pd(PPh3)4
and SmI2 led to cyclopropane ring opening and concomitant
elimination of the acetate.16 Other methods of transforming
propargylic acetates to allenes were tried with little or no
success.17 We were gratified to find that Strykers’ reagent
[(PPh3)CuH]6 delivers a hydride to afford the desired allene 12
without serious complications.18 The low yield (38%) was in
part attributed to volatility; however, with the P-K precursor
in hand we set out to effect the key cyclization reaction.
Construction of Tricarbocyclic Skeleton. Treatment of
alkynyl allene 12 to the standard allenic P-K conditions used
in our laboratory7 afforded a cyclization product in less than
30 min (Scheme 3). To our surprise, the cyclization afforded
none of the desired 4-alkylidene cyclopentenone 13 but gave
only the R-methylene cyclopentenone 14 in 66% yield. This
was in direct contrast to all preliminary investigations7 which
suggested that cyclization would occur with the least substituted
double bond of the allene to afford 13. A more detailed
examination of models shows the overlap of the π-bond orbitals
of the internal double bond of the allene with the alkyne is more
favorable than that of the external double bond of the allene
(Scheme 4). While the desired cycloadduct 13 was not obtained
from this experiment, this result was not entirely unexpected
and provides us with a better understanding of the stereoelec-
tronic requirements of the allenic P-K reaction. On the basis
of these results we reasoned that a more conformationally
flexible P-K precursor would be required to afford the desired
skeleton.
1). These diastereomers were advanced through the synthetic
sequence in two ways. First, they were separated by column
chromatography and converted to acylfulvene 21 independently,
and second, they were taken on as a mixture to the final product,
HMAF (3). Conversion of the methyl ketone 16 to the alkynyl
allene 20 was achieved in a fashion analogous to the preparation
of the alkynyl allene 12 (vide supra). Addition of ethynylmag-
nesium bromide to ketone 16 in the presence of cerium
trichloride gave the desired propargylic alcohol 17 in 97% yield.
Independent conversion of the diastereomers of ketone 16 to
the propargylic alcohol 17 showed the major isomer (anti-16)
affording a 9.2:1 mixture of inseparable diastereomers and the
minor isomer (syn-16) affording only one diastereomer. Next,
selective formation of the propargylic acetate of the less hindered
tertiary alcohol gave diyne 18 in 98% yield. Treatment of
propargylic acetate 18 with [CuH(PPh3)]6 afforded the allene
19 in 54% yield.20 Finally, the trimethylsilyl moiety was
removed from the alkyne terminus using a standard protocol to
afford the desired cyclization precursor 20 in 95% yield.
Preparation of Precursor 18b. In an approach to a more
conformationally flexible cyclization substrate, 1,1-diacetylcy-
clopropane 159 was treated with the lithium anion of the tert-
butyldimethylsilyl ether of 3-trimethylsilyl-3-propyn-1-ol (Scheme
5) to afford ketone 16 as a 1.3:1 (anti/syn) mixture of dia-
stereomers in 57% yield.19 The relative stereochemistry of the
two newly generated centers was unambiguously assigned by
X-ray crystallographic analysis of the syn-diastereomer (Figure
The Allenic P-K Reaction and the Synthesis of Racemic
Hydroxymethylacylfulvene. We were very pleased to discover
(19) We did not observe any product derived from the addition of the
allenyl anion. For a review of the preparation and application of propargyl
and allenyl organometallics, see: Yamamoto, H. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 2, p
81.
(20) Attempts to convert the methyl ketone 16 directly to the allene 19
using (1-bromovinyl)trimethylsilane under Peterson olefination conditions
were not successful. (a) Hudrlik, P. F.; Kassim, A. M.; Agwaramgbo, E. L.
O.; Doonquah, K. A.; Roberts, R. R.; Hudrlik, A. M. Organometallics 1993,
12, 2367. (b) Paquette, L. A.; Wells, G. J.; Horn, K. A.; Yan, T.-H.
Tetrahedron 1983, 39, 913.
(16) (a) Tabuchi, T.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986,
27, 5237. (b) Mikami, K.; Yoshida, A.; Matsumoto, S.; Feng, F.; Matsumoto,
Y. Tetrahedron Lett. 1995, 36, 907. (c) Yoshida, A.; Mikami, K. Synlett
1997, 1375.
(17) (a) Borden, W. T.; Corey, E. J. Tetrahedron Lett. 1969 313. (b)
Leclair, M.; Jean, P.; Lopez, R.; Ricard, L.; Lallemand, H. P. Tetrahedron
1995, 51, 6983.
(18) Daeuble, J. F.; McGettigan, C.; Stryker, J. M. Tetrahedron Lett.
1990, 31, 2397.

4918 J. Am. Chem. Soc., Vol. 122, No. 20, 2000
Brummond et al.
Scheme 6
Scheme 7
Figure 2.
Figure 3.
Scheme 8
that alkynyl allene 20 undergoes a rapid cycloaddition (10 min)
under the standard allenic P-K conditions [Mo(CO)6, DMSO,
toluene, 110 °C] to produce the 4-alkylidene cyclopentenone
21 as the only observed cycloadduct in 69% yield (Scheme 6).
With the successful construction of the key intermediate
4-alkylidene cyclopentenone 21, we turned our attention to the
completion of the racemic synthesis of the target compound 3.
Treatment of the ketone moiety of alkylidene cyclopentenone
21 with excess methyllithium in the presence of cerium
trichloride gave the desired tertiary alcohol which underwent
spontaneous dehydration upon acidic workup to afford fulvene
22 in 96% yield (Scheme 7). Removal of the TBS protecting
group of the silyl ether was effected using tetra-n-butylammo-
nium fluoride that provided diol 23 in 97% yield. The secondary
alcohol of compound 23 was oxidized to the ketone with the
Dess-Martin periodinane reagent to give the acylfulvene 24
the treatment of 1,1-diacetylcyclopropane with (2R,3R)-(-)-
butanediol and catalytic PTSA in refluxing benzene. Addition
of the lithio anion of tert-butyldimethylsilyl ether of 3-trimeth-
ylsilyl-3-propyn-1-ol to ketone 7a afforded 26a in a 33% yield
as a 10:1 anti/syn mixture of diastereomers. Separation of the
diastereomers followed by deketalization and removal of the
tert-butyldimethylsilyl protecting group afforded the dihydroxy
ketone. The major anti-diastereomer was converted to the mono
Mosher ester22 by acylation of the more reactive propargylic
hydroxyl group.23 1H NMR analysis of the Mosher ester
indicated the asymmetric addition had occurred in a disappoint-
ing 13% ee.
1
in 78% yield. The H NMR spectrum of synthetic 24 was
We felt that higher enantiomeric excesses might be accessible
by incorporating a chiral ketal with groups capable of chelation.
In particular, chelation between the ketone and benzyloxy-
substituted ketal might limit the conformational mobility of the
ketone and enhance the selectivity of the addition (Figure 3).
Chiral ketal 7b was prepared in 37% yield from (2R,3R)-(+)-
1,4-dibenzyloxy-2,3-butanediol in a manner analogous to the
preparation of 7a. Addition of the propargyl anion in the
presence of lithium bromide resulted in 37% yield of 26b as a
10:1 anti/syn mixture of diastereomers. Conversion of 26b to
the mono Mosher ester as previously described23 and analysis
by 1H NMR showed only a 15% ee. Since the levels of
asymmetric induction as well as the chemical yields were
undesirably low, this approach was abandoned. Other strategies
identical with the spectrum of an authentic sample provided by
MGI Pharma, Inc. The synthesis of HMAF (3) was completed
using the previously reported procedure, whereby the hy-
droxymethyl moiety is introduced by treatment of acylfulvene
24 with formaldehyde and sulfuric acid in acetone/water.2b
An Enantioselective Synthesis of Hydroxymethylacylful-
vene (3). Having developed a method for the rapid synthesis
of (()-hydroxymethylacylfulvene, we became interested in
applying this method in an asymmetric approach to the title
compound. This is of particular importance since HMAF derived
from the natural illudin S (2) is two times more potent than the
unnatural enantiomer. From a practical perspective, the ideal
situation would be to develop an enantioselective route to one
of the chiral intermediates in the racemic synthesis. We thus
set about exploring this potential strategy.
Our first approach to enantiopure material involved a chiral
ketal protecting group. During our investigations we had
observed an unusual diastereoselectivity in the addition of the
lithio derivative of the tert-butyldimethylsilyl ether of 3-tri-
methylsilyl-3-propyn-1-ol to ketone 7 (Scheme 8). We felt that
this diastereoselectivity might be utilized to synthesize enan-
tiomerically enriched material in the presence of a chiral ketal
protecting group (Figure 2).21
(21) Chiral ketals have been successfully employed as chiral auxiliaries
in Diels-Alder reactions. Nemoto, H.; Nagai, M.; Kohzuki, K.; Fukumoto,
K. J. Chem. Soc., Perkin Trans 1 1988, 2835.
(22) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543.
(23) For analysis of the enantiomeric excesses the Mosher esters were
synthesized by the following transformations.
Chiral Ketal Approach. To explore the directing potential
of a chiral protecting group, chiral ketal 7a was prepared by

A Rapid Synthesis of HydroxymethylacylfulVene
J. Am. Chem. Soc., Vol. 122, No. 20, 2000 4919
Table 1. Asymmetric Dihydroxylation of Enyne 28a
Scheme 9
entry
ligand
% yieldb
% eec
1
(DHQD)2PHAL
(DHQD)2PHAL
(DHQD)2AQN
DHQD-MQE
15
12
8
83
86
51
2d
3
4
9
82
5
(DHQD)2PYR
(DHQD)2PYR
39
37
>95
>95
6e
a The standard conditions for the AD reaction use K2OsO2(OH)4 (2
mol %), ligand (10 mol %), K3Fe(CN)6 (3 equiv), K2CO3 (3 equiv),
CH3SO2NH2 (1 equiv), 0.1 M solution in t-BuOH, and H2O for 48 h.
b Isolated yield. c Determined by 1H NMR analysis of the Mosher ester.
d The reaction was carried out at 0 °C for 6 days. e Three equivalents
of CH3SO2NH2 were employed.
Scheme 10
Scheme 11
involving the asymmetric addition of the propargyl anion to
1,1-diacetylcyclopropane were examined (BOX ligands)24 but
none led to satisfactory chiral induction.
With the stereoselective synthesis of E-enyne 27 secured, we
turned our attention to the Sharpless asymmetric dihydroxyla-
tion. Sharpless reports that the optimum conditions for the
dihydroxylation of mono- and disubstituted enynes utilize 1,4-
bis(9-O-dihydroqunidine)phthalazine (DHQD2-PHAL).11a Sub-
jection of enyne 27 to the commercial AD-mix-â [K2OsO2-
(OH)4, K3Fe(CN)3, (DHQD)2PHAL] showed negligible amounts
of product formation even after 2 days. Increasing the amount
of potassium osmate to 2 mol % and the ligand (DHQD)2PHAL
to 10 mol % did allow us to isolate 28 in a 15% yield (83% ee)
(entry 1, Table 1).28 Lowering the temperature showed no
increase in yield or enantioselectivity (entry 2, Table 1). The
enantiomeric excesses were determined by the conversion of
the diol to the Mosher ester. With these promising results in
hand, we set forth to optimize the efficiency and enantioselec-
tivity of the AD reaction.
Other commercially available dihydroquinidine (DHQD)-
derived ligands were surveyed for their ability to carry out the
AD reaction and these results are summarized in Table 1. Under
the standard conditions (2 mol % K2OsO2(OH)4, 10 mol %
ligand), inferior results were obtained from the recently
developed anthraquinone ligand (DHQD)2AQN (entry 3, Table
1) and 4-methyl-2-quinolyl ligand DHQD-MQE (entry 4, Table
1). In each of these cases the diol 28 was isolated in very low
yields and moderate enantiomeric excesses. Significant im-
provements were observed when using 2,5-diphenyl-4,6-pyri-
midinediyl derived ligands. For example, when (DHQD)2PYR
was used as a ligand, diol 28 was obtained in 39% yield as a
single enantiomer by Mosher ester analysis (entry 5, Table 1).
Increasing the amount of CH3SO2NH2 had no effect on the AD
reaction (entry 6, Table 1). In addition, increasing the amount
of K2OsO2(OH)4 to 5 mol % had a detrimental effect on the
yield giving rise to only a 5% yield of the diol 28. Protection
of the acetylenic moiety of the enyne 27 with Co2(CO)8 prior
to effecting the AD reaction resulted in extensive decomposition
of the starting material.
Asymmetric Dihydroxylation Approach. With the dis-
appointing results from the various attempts at the asymmetric
addition reaction, we decided to reinvestigate the Sharpless
asymmetric dihydroxylation protocol as an alternative approach
to the enantiomerically pure material.11 Upon review of the
literature, we noticed only a few examples of asymmetric
dihydroxylation of enynes with no reported examples of
trisubstituted enynes undergoing a Sharpless AD reaction. The
unreactivity associated with the AD reaction of the trisubstituted
enynes is presumably due to both sterics and the electron
deficient nature of the enyne system. Further examination of
the literature reveals that E-olefins are more reactive toward
the asymmetric dihydroxylation conditions than Z-olefins. On
the basis of this precedent we felt that our initial difficulty with
the AD reaction might have been due to the Z-stereochemistry
of 9 (Scheme 2) and that we might establish the absolute
stereochemistry of our system utilizing a Sharpless AD reaction
on a trisubstituted E-enyne system.
There are many methods which have been developed for the
stereoselective preparation of enynes but each suffers from its
own set of limitations. Among them, the Peterson olefination10,25
and the Wittig26 reaction have been used to generate terminal
enynes. However, while both of these methods work well with
aldehydes, lower E/Z selectivities and yields are reported when
aliphatic ketones are employed.
The stereoselective conversion of monoprotected diketone 7
was effected as follows. Peterson olefination of 7 with 1,3-bis-
(trimethylsilyl)propyne afforded the Z-enyne 9 exclusively upon
careful control of the temperature (Scheme 2). In contrast, the
Horner-Wadsworth-Emmons protocol involving treatment of
ketone 7 with the ylide of diethyl 3-trimethylsilylpropynyl
phosphonate27 affords the E-enyne 27 selectively (Scheme 10).
Interestingly, when n-BuLi was used as the base, enyne 27 was
obtained in a 64% yield with an E/Z ratio of 40:1. However,
sodium hexamethyldisilyl azide afforded the enyne 27 in an
86% yield as the E-isomer exclusively.
Since it is known that the AD reactions are sensitive to steric
effects, the ketal protecting group was removed and enyne 29
was subjected to the optimized AD conditions (Scheme 12).
Diol 30 was obtained in a 49% yield (>95% ee) accompanied
by diol 31 in 11% yield (>95% ee) where the TMS moiety
(24) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am.
Chem. Soc. 1991, 113, 726.
(25) (a) Corey, E. J.; Rucker, C. Tetrahedron Lett. 1982, 23, 719. (b)
Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc. 1988, 110, 2248.
(26) Lipshutz, B. H.; Lindsley, C. J. Am. Chem. Soc. 1997, 119, 4555;
(27) Gibson, A. W.; Humphrey, G. R.; Kennedy, D. J.; Wright, S. H. B.
Synthesis 1991, 414.
(28) Walsh, P. J.; Sharpless, K. B. Synlett 1993, 605.

4920 J. Am. Chem. Soc., Vol. 122, No. 20, 2000
Brummond et al.
Scheme 13
Scheme 14
Figure 4.
also be noted that (DHQ)2PYR is known to afford the opposite
diol stereochemistry with similar reactivity as (DHQD)2PYR
in the Sharpless AD. Thus, this synthetic approach provides
access to both enantiomers of HMAF (3).
Scheme 12
Conclusions
We have rapidly assembled the potent antitumor agent
hydroxymethylacylfulvene (3) in 11 steps from commercially
available starting materials. This synthesis features a novel
application of the allenic P-K-type cycloaddition to provide
rapid entry into the illudane skeleton. In addition, we have
reported optimized conditions for the stereospecific synthesis
of E or Z trisubstituted enynes from an aliphatic ketone using
either Peterson olefination or Horner-Wadsworth-Emmons
protocols. Finally, we have established an asymmetric route to
the title compound by intersecting the racemic synthesis with
an enantiomerically pure intermediate (R,R)-16. The preparation
of (R,R)-16 involves an asymmetric dihydroxylation of a
trisubstituted olefin of an enyne using (DHQD)2PYR. This is
the first reported example of a trisubstituted olefin of an E-enyne
undergoing a Sharpless AD reaction. This approach also
provides access to the enantiomeric (S,S)-16 and consequently
both enantiomeric forms of HMAF (3) simply by changing the
ligands in the Sharpless AD reaction.
was removed under the reaction conditions. Conversion of diol
31 to 30 can be effected in good yield by deprotonation with
lithium diisopropylamide and addition of trimethylsilyl chloride.
The structural assignments of compounds 30 and 31 and their
absolute configuration warrants further comment. The absolute
stereochemistry of the two centers has been assigned (R,R) based
upon Sharpless’ mnemonic device.29 The structure and relative
stereochemistry of diols 30 and 31 were established unambigu-
ously by X-ray crystallographic analysis of diol 31 (Figure 4).
The 1H and 13C NMR spectra of diols 30 and 31 were
complicated due to diastereomeric intramolecular hemiketal
formation that occurred spontaneously upon dissolution (Scheme
13).
Enantiomerically pure diol 30 was transformed into the
O-TBS protected propargyl alcohol (R,R)-16 using TBSOTf and
2,6-lutidine in CH2Cl2 in 74% yield (Scheme 14). At this point,
the enantioselective route intersects with the previously com-
pleted racemic synthesis of HMAF (3). This constitutes a formal
enantioselective synthesis of HMAF (3) since conversion of
(R,R)-16 to the final product results in enantiopure 3. It should
We are currently investigating the synthesis of HMAF
derivatives. A benefit of this approach to the target structure is
that it provides ready access to derivative structures not available
from the degradative synthesis from illudin S (2) or the
McMorris approach. These derivatives will be tested for
antitumor activities and the results reported in subsequent
publications.
Acknowledgment. We gratefully acknowledge the financial
support provided by the National Institutes of Health (GM54161).
We also thank Professor Mukund Sibi and his group for
obtaining optical rotations for us.
Supporting Information Available: Details for the prepara-
tions and characterizations of all new compounds, including
1
copies of H NMR, 13C NMR, and IR spectra (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(29) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483. (b) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.;
Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
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