Total synthesis of thyrsiferyl 23-acetate, a specific inhibitor of protein phosphatase 2A and an anti-leukemic inducer of apoptosis

Article abstract of DOI:10.1021/ja000001r

A convergent synthetic entry to the squalenoid polyether system has been developed and applied to the biologically active marine natural products thyrsiferyl 23-acetate (1a), thyrsiferol (1b), thyrsiferyl 18-acetate (1c), and thyrsiferyl 18,23-diacetate (

Full text of DOI:10.1021/ja000001r

J. Am. Chem. Soc. 2000, 122, 9099-9108
9099
Total Synthesis of Thyrsiferyl 23-Acetate, a Specific Inhibitor of
Protein Phosphatase 2A and an Anti-Leukemic Inducer of Apoptosis
Isabel C. Gonza´lez and Craig J. Forsyth*
Contribution from the Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
ReceiVed January 3, 2000. ReVised Manuscript ReceiVed May 3, 2000
Abstract: A convergent synthetic entry to the squalenoid polyether system has been developed and applied to
the biologically active marine natural products thyrsiferyl 23-acetate (1a), thyrsiferol (1b), thyrsiferyl 18-
acetate (1c), and thyrsiferyl 18,23-diacetate (1d). This involved the separate construction of two advanced
intermediates representing the C1-C15 (4) and C16-C24 (5) domains, followed by their organochromium-
mediated coupling, installation of the tertiary alcohol at C15, and manipulation of the C18 and C23 acetate
moieties. The C1-C15 (4) intermediate containing the three tetrahydropyranyl rings (A-B-C) was derived
from two preconstructed tetrahydropyran-containing units representing the functionalized A (C2-C6) and C
(C10-C14) rings (6 and 7, respectively). The bromotetrahydropyranyl A ring was obtained via bromoetheri-
fication of the hydroxyalkene 16, which was synthesized from (2R,3R)-epoxy geraniol. The C ring was
stereoselectively constructed by acid-catalyzed opening of the hydroxy epoxide 32, derived from D-glutamic
acid. Intermediates 6 and 7 were joined using organochromium conditions, and ketone and hydroxyl
functionalities were installed at carbons 7 and 11, respectively. Closure of the B ring was accomplished
stereoselectively by formation of species derived from a C7, C11 keto-alcohol and in situ reduction of a
tetrahydropyranyl oxonium. The complementary tetrahydrofuran D (C19-C22) ring was obtained from a
geraniol-derived tertiary hydroxy alkene (44) via a stereoselective Re(VII)-induced syn-oxidative cyclization.
The side chain appended to the D ring was elaborated into trans-alkenyl iodide 5 under Takai reaction conditions.
CrCl2-mediated coupling of aldehyde 4, containing the secondary bromide at C3 of the natural products, with
iodide 5 bearing acetate moieties at C18 and C23, installed the C15-C16 carbon-carbon bond. The resultant
C15 allylic carbinol was converted into an R,â-saturated ketone, and the final methyl group was added
stereoselectively using methylmagnesium bromide. Saponification of the C18 acetate yielded 1a, whereas
cleavage of both C18 and C23 acetates gave the triol 1b. This modular entry into the squalenoid-polyether
system may facilitate further evaluation of the antileukemic, apoptosis-inducing, protein serine/threonine
phosphatase 2A inhibitory and anti-multidrug resistance activities of the thyrsiferol-derived natural products.
A variety of squalene-derived natural products that present
strong cytotoxic properties have been isolated from marine red
algae of the genus Laurencia.1 Among this class of compounds,
thyrsiferyl 23-acetate (1a, Figure 1) appears to elicit the most
intriguing array of biological responses.2 Compound 1a exhibits
superior in vitro cytotoxic activity against P-388 murine leu-
kemia (IC50 ) 0.5 nM)2 and specific inhibition of protein serine/
threonine phosphatase 2A (PP2A) (IC50 ) 4-16 µM),3 whereas
several other phosphatases, including protein phospatases 1
(PP1), 2B (PP2B), and 2C (PP2C) or protein tyrosine phospha-
tases, are not affected by 1a at concentrations up to 1 mM. More
recently, 1a and several related analogues4 induced rapid
apoptotic cell death in a variety of human leukemic T- and B-cell
lines.5 However, among these compounds only 1a also apprec-
iably inhibits PP2A and may be a useful probe for identification
of cellular processes reliant upon PP2A activity.6 Exogenous
compounds that induce apoptotic death of cancer cells represent
a mechanistically important class of potential therapeutic agents,7
whereas very few highly specific inhibitors of PP2A are known.8
Remarkably, the close structural analogue 15(28)-anhydroth-
yrsiferol (2b) was found to circumvent multidrug resistance
(4) Thyrsiferol (1b), 15(28)-anhydrothyrsiferyl-23-acetate (2a), thyrsiferyl
18-acetate (1c), and thyrsiferyl 15, 18, 23-triacetate.
* E-mail forsyth@chem.umn.edu. Phone: (612) 624-0218. Fax: (612)
626-7541.
(5) (a) Matsuzawa, S.-I.; Kawamura, T.; Mitsuhashi, S.; Suzuki, T.;
Matsuo, Y.; Suzuki, M.; Mizuno, Y.; Kikuchi, K. Bioorg. Med. Chem. 1999,
7, 381-387. (b) Kikuchi, K.; Shima, H.; Mitsuhashi, S.; Suzuki, M.;
Oikawa, H. Int. J. Mol. Med. 1999, 4, 395-401.
(1) (a) Blunt, J. W.; Hartshorn, M. P.; McLennan, T. J.; Munro, M. H.
G.; Robinson, W. T.; Yorke, S. C. Tetrahedron Lett. 1978, 69-72. (b)
Gonza´lez, A. G.; Arteaga, J. M.; Ferna´ndez, J. J.; Mart´ın, J. D.; Norte, M.;
Ruano, J. Z. Tetrahedron 1984, 40, 2751-2755. (c) Sakemi, S.; Higa, T.;
Jefford, C. W.; Bernardinelli, G. Tetrahedron Lett. 1986, 27, 4287-4290.
(d) Suzuki, T.; Takeda, S.; Suzuki, M.; Kurosawa, E.; Kato, A.; Imanaka,
Y. Chem. Lett. 1987, 361-364. (e) Suzuki, M.; Matsuo, Y.; Takahashi,
Y.; Masuda, M. Chem. Lett. 1995, 1045-1046. (f) Norte, M.; Ferna´ndez,
J. J.; Souto, M. L.; Garc´ıa-Gra´valos, M. D. Tetrahedron Lett. 1996, 37,
2671-2674. (g) Norte, M.; Ferna´ndez, J. J.; Souto, M. L.; Gav´ın, J. A.;
Garc´ıa-Gra´valos, M. D. Tetrahedron 1997, 53, 3173-3178. (h) Norte, M.;
Ferna´ndez, J. J.; Souto, M. L. Tetrahedron 1997, 53, 4649-4654.
(2) Suzuki, T.; Suzuki, M.; Furusaki, A.; Matsumoto, T.; Kato, A.;
Imanaka, Y.; Kurosawa, E. Tetrahedron Lett. 1985, 26, 1329-1332.
(3) Matsuzawa, S.-I.; Suzuki, T.; Suzuki, M.; Matsuda, A.; Kawamura,
T.; Mizuno, Y.; Kikuchi, K. FEBS Lett. 1994, 356, 272-274.
(6) Scho¨nthal, A. H. Front. Biosci. 1998, 3, 1262-1273.
(7) (a) Uckun, F. M.; Evans, W. E.; Forsyth, C. J.; Waddick, K. G.;
Ahlgren, L. T.; Chelstrom, L. M.; Burkhardt, A.; Bolen, J.; Myers, D. E.
Science 1995, 267, 886-891. (b) Myers, D. E.; Jun, X.; Waddick, K. G.;
Chelstrom, L. M.; Forsyth, C. J.; Gunther, R.; Turner, N.; Bolen, J.; Uckun,
F. M. Proc. Natl. Acad. Sci. USA 1995, 9575-9579.
(8) Okadaic acid: IC50 PP1/PP2A ) 102-103, IC50 PP2A ) 32 pM (Takai,
A.; Sasaki, K.; Nagai, H.; Mieskes, G.; Isobe, M.; Isono, K.; Yasumoto, T.
Biochem. J. 1995, 306, 657-665; Bialojan, C.; Takai, A. Biochem. J. 1988,
256, 283-290). Fostriecin: IC50 PP1/PP2A ) 104-105, IC50 PP2A ) 3.2-40
nM (Roberge, M.; Tudan, C.; Hung, S. M. F.; Harder, K. W.; Jirik, F. R.;
Anderson, H. Cancer Res. 1994, 54, 6115-6121; Walsh, A. H.; Cheng,
A.; Honkanen, R. E. FEBS Lett. 1997, 416, 230-234).
10.1021/ja000001r CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/06/2000

9100 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
Gonza´lez and Forsyth
mediated by P-glycoprotein and might therefore be an interesting
candidate for detailed future investigations on these grounds.9
In addition, 2b has been reported to cause growth inhibition in
KB cancer cells without inducing apoptosis.10
Scheme 1
However, the hydroxyl at C18 may be important in light of the
lower cytotoxic activity of 1c.12 In addition, recent studies have
suggested that the induction of apoptosis by 1a may require
structural features that are different from those involved in the
inhibition of PP2A. However, the structural bases for these
diverse activities have not been established.
The biogenetic features and classic structures of these
polyethers have stimulated considerable synthetic activity,13-15
which had previously culminated in total syntheses of 1a14c,14d
and 1b,14b,14d as well as 3.14b,14d,15 The recent recognition of
distinct biological activities of thyrsiferyl derivatives, including
the induction of apoptosis, selective inhibition of PP2A by 1a,
and anti-multidrug resistance by 2b, has prompted renewed
interest in this class of compounds. However, dissection and
exploitation of the manifold activities of the thyrsiferol deriva-
tives will require the emergence of a reliable and general source
of these compounds.
Reported here is a modular total synthesis of thyrsiferyl 23-
acetate (1a) and its derivatives (1b, 1c, and 1d) that highlights
a rapid and convergent entry into the squalenoid/polyether
system. This involves the optimal sequencing of distinct
etherification processes to construct each of the cyclic ethers
and strategic derivatization of hydroxyl groups in concert with
chemoselective carbon-carbon bond formation. This novel entry
into the thyrsiferol system may provide unique access to natural
and unnatural derivatives in support of continued biological
evaluation of these remarkable compounds.
Figure 1.
The unique squalenoid polyether structures of thyrsiferol and
its acetate derivatives feature a bromotetrahydropyranyl A ring
(C2-C6) appended directly to a trans-fused 2,7-dioxabicyclo-
[4.4.0]decane B-C ring system (C7-C14), which in turn is
tethered to a distal tetrahydrofuranyl D ring (C19-C22). X-ray
analysis of thyrsiferyl 18-acetate1a (1c) and the related
venustatriol1c (3) revealed that the B-C rings adopt a unique
chair-twist boat conformation to avoid 1,3-diaxial interactions
in the C ring. The biogenesis of these polyether natural products
has been proposed to involve attack by a bromonium ion at the
C2-C3 double bond, causing a concerted cyclization of three
epoxides at C6-C7, C10-C11, and C14-C15 as a first step
and the formation of the furan ring by protonation of either the
C18-C19 or the C22-C23 epoxides as a second step.1c This
hypothesis was reinforced by the identical configuration of the
C1-C15 moiety exhibited by most of the squalenoid polyethers
isolated from the Laurencia species. However, the isolation of
additional structural variations of these polyethers, including
callicladol,1e 10-epidehydrothyrsiferol,1f isodehydrothyrsiferol,1f
thyrsenols A and B,1g and predehydrovenustatriol acetate,1h may
suggest that the polycyclizations are not entirely concerted.
The biological activities of these squalenoid polyethers are
exquisitely sensitive to gross as well as minor changes in
structure. Degradation studies involving oxidative fragmentation
of 1b and 2b gave subunits that were devoid of significant
cytotoxic activity.11 Molecular modeling studies have suggested
that the presence of the flexible chain around C14 to C19 is
one of the fundamental factors related to the cytotoxic activity
of these metabolites.11 Apparently, the hydroxyl at the C15
position is not essential for cytotoxic activity, considering the
similar IC50 values of 1b and 2b against P-388 leukemia cells.12
Results and Discussion
Synthetic Plan. A convergent synthetic approach to these
natural products involves the separate construction of two
fragments representing C1-C15 (4)16 and C16-C24 (5)
(Scheme 1). The aldehyde 4 was synthesized from farnesol in
Corey’s seminal total synthesis of venustratriol.15 A key feature
of our synthetic plan was the independent construction of the
(12) IC50 ) 16 nM,2 IC50 ) 17 nM,11 IC50 ) 464 nM.2
1b
2b
1c
(13) (a) Broka, C. A.; Hu, L.; Lee, W. J.; Shen, T. Tetrahedron Lett.
1987, 28, 4993-4996. (b) Broka, C. A.; Lin, Y.-T. J. Org. Chem. 1988,
53, 5876-5885.
(14) (a) Hashimoto, N.; Kan, T.; Yanagiya, M.; Shirahama, H.; Matsu-
moto, T. Tetrahedron Lett. 1987, 28, 5665-5668. (b) Hashimoto, N.; Kan,
T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.; Matsumoto, T. Tetrahedron
Lett. 1988, 29, 1143-1144. (c) Kan, T.; Hashimoto, M.; Yanagiya, M.;
Shirahama, H. Tetrahedron Lett. 1988, 29, 5417-5418. (d) Hashimoto, M.;
Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.; Matsumoto, T. J. Org.
Chem. 1990, 55, 5088-5107.
(9) Pec, M. K.; Hellan, M.; Moser-Their, K.; Ferna´ndez, J. J.; Souto,
M. L.; Kubista, E. Int. J. Oncol. 1999, 14, 739-743.
(10) (a) Pec, M. K.; Hellan, M.; Moser-Their, K.; Ferna´ndez, J. J.; Souto,
M. L.; Kubista, E. Anticancer Res. 1997, 17, 4090. (b) Pec, M. K.; Hellan,
M.; Moser-Their, K.; Ferna´ndez, J. J.; Souto, M. L.; Kubista, E. Anticancer
Res. 1998, 18, 3027-3032.
(15) Corey, E. J.; Ha, D.-C. Tetrahedron Lett. 1988, 29, 3171-3174.
(16) Gonza´lez, I. C.; Forsyth, C. J. Org. Lett. 1999, 1, 319-322.
(17) Takai, K.; Kuroda, T.; Nakatsukasa, S.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1985, 26, 5585-5588.
(11) Ferna´ndez, J. J.; Souto, M. L.; Norte, M. Bioorg. Med. Chem. 1998,
6, 2237-2243.
(18) Aicher, T. D.; Kishi, Y. Tetrahedron Lett. 1987, 28, 3463-3466.

Total Synthesis of Thyrsiferyl-23 Acetate
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9101
Scheme 2
Figure 2.
Scheme 3
bromotetrahydropyranyl A ring which was joined in the form
of the C1-C7 aldehyde 6 to a fragment containing the
preformed C ring, represented by the C8-C15 bromide 7. In
previous studies toward the synthesis of the thyrsiferol and
venustatriol natural products, low-yielding intramolecular bro-
moetherifications (<26%) were employed to prepare the A ring
late in the synthetic sequences. This fact detracted from the
overall efficiency of former routes. In contrast, the problematic
A ring (6) was assembled early in the present synthetic sequence
and then was joined with alkynyl bromide 7 under organochro-
mium17,18 conditions. Subsequent reductive closure of the inter-
vening B ring concludes the preparation of the C1-C15 domain
of the thyrsiferol- and venustatriol-related natural products.
The tetrahydrofuran D ring-containing fragment (5) of
thyrsiferyl 23-acetate (1a) and derivatives was envisioned to
come from geraniol (8, Scheme 1) via stereoselective Re(VII)-
induced syn-oxidative cyclization.19-21 The utilization of acetates
at C18 and C23 in 5 would minimize protection and deprotection
manipulations at the end of the synthesis. This, however, would
require a fragment coupling under mild and chemoselective
conditions that would be unprecedented in the context of
squalenoid polyether synthesis. Hence, advanced intermediates
4 and 5 would be coupled under organochromium-mediated
conditions en route to the natural products.22 The synthesis of
1a and its derivatives thus began with the preparation of
aldehyde 6, alkynyl bromide 7, and vinyl iodide 5, and an
examination of their sequential couplings.
11a and 11b in the 10/11a/11b ratio 4.4:10:6.9.26 After partial
separation by MPLC, a mixture (86-90% pure by GC) of
tetrahydropyrans 11a and 11b (11a/11b ) 1.6-2.3:1)26 was
isolated in ∼56% yield.25 The resultant mixture of tetrahydro-
pyrans 11 was treated with osmium tetroxide, N-methyl mor-
pholine oxide, and sodium periodate to obtain a mixture of
aldehydes 12 and 6 (12/6 ) 1.6-2.3:1)26 in ∼76% combined
yield.25 After isolation of each aldehyde by MPLC, the
configuration of 12 was assigned by detection of an NOE
between the proton at C3 and the methyl group at C6 which
was not present in the desired (3R)-bromo aldehyde 6 (Scheme
2). Alternatively, oxidative cleavage of the mixture of com-
pounds 10 and 11 provided aldehyde 6 in approximately the
same yield (∼12%) from 9 after just one MPLC step at the end
of the sequence.
Synthesis of the C1-C7 Aldehyde (6). Initially, the
construction of the A ring of 1a-1d from (S)-linalool (9) via
bromoetherification using 2,4,4,6-tetrabromocyclohexa-2,5-di-
enone (TBCO)23 was explored. (S)-Linalool was efficiently
prepared from geraniol by sequential Sharpless asymmetric
epoxidation, tosylation, and Te-assisted reduction (Scheme 2).24
Thereafter, treatment of 9 with TBCO provided in good yield
(∼80%)25 a mixture of tetrahydrofurans 10 and tetrahydropyrans
(19) (a) Kennedy, R. M.; Tang, S. Tetrahedron Lett. 1992, 33, 3729-
3732. (b) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5299-
5302. (c) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5303-
5306. (d) Boyce, R. S.; Kennedy, R. M. Tetrahedron Lett. 1994, 35, 5133-
5136.
(20) (a) McDonald, F. E.; Towne, T. B. J. Org. Chem. 1995, 60, 5750-
5751. (b) Towne, T. B.; McDonald, F. E. J. Am. Chem. Soc. 1997, 119,
6022-6028.
(21) Morimoto, Y.; Iwai, T. J. Am. Chem. Soc. 1998, 120, 1633-1634.
These authors reported the use of 4 equiv of (CF3CO2)ReO3‚2CH3CN for
efficient oxidative cyclizations of homoallylic tertiary alcohols, although it
is not clear whether such an excess of reagent is necessary. In the present
case, a considerable excess of (CF3CO2)ReO3‚2CH3CN was used without
determining the optimal stoichiometry of (CF3CO2)ReO3‚2CH3CN to
homoallylic alcohol 44.
An explanation of the observed stereoselectivity in the bro-
moetherification cyclization is given in Figure 2. The diaxial
interactions in the bromonium ion 13 between the C1 methyl
group and the sp2-hybridized substituent R may be less severe
than those between two methyl groups in 14, leading to the
(3S)-bromotetrahydropyran 11a as the major product.27
The desired aldehyde 6 was synthesized in a two-step
sequence from (S)-linalool 9. However, the low yield caused
by the unfavorable stereoselectivity of the bromoetherification
step prompted an attempt to synthesize 6 from hydroxy alkene
16 (Scheme 3). In this case, the bulky substituent at C6 may
preferentially adopt an equatorial orientation, as in bromonium
ion 14, to favor the formation of the bromotetrahydropyran (3R)-
17b.
The hydroxy alkene 16 was obtained from (2R,3R)-epoxy
geraniol28 in good yield by regio- and stereoselective epoxide
ring hydrolysis using perchloric acid in 6:1 (v/v) THF/H2O15
(25) This approximate yield was obtained after purification of the crude
mixture through a short silica gel column; further purification using MPLC
caused loss of material.
(22) (a) Jin, H.; Uenishi, J.-I.; Christ, W. J.; Kishi, Y. J. Am. Chem.
Soc. 1986, 108, 5644-5646. (b) Takai, K.; Tagashira, M.; Kuroda, T.;
Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048-
6050.
(23) Kato, T.; Ichinose, I.; Hosogai, T.; Kitahara, Y. Chem. Lett. 1976,
1187-1190.
(24) Dittmer, D. C.; Discordia, R. P.; Zhang, Y.; Murphy, C. K.; Kumar,
A.; Pepito, A. S.; Wang, Y. J. Org. Chem. 1993, 58, 718-731.
(26) The ratio was determined by GC using a DB5 column (10 m × 0.1
mm × 0.1 µm film thickness).
(27) (a) Jung, M. E.; Lew, W. J. Org. Chem. 1991, 56, 1347-1349. (b)
Jung, M. E.; D’Amico, D. C.; Lew, W. Tetrahedron Lett. 1993, 34, 923-
926. (c) Jung, M. E.; Fahr, B. T.; D’Amico, D. C. J. Org. Chem. 1998, 63,
2982-2987.
(28) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masumune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.

9102 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
Gonza´lez and Forsyth
Scheme 4
readily accept ketones as substrates.33b However, (S)-ketone
cyanohydrins have been obtained by transcyanation of aldehydes
with racemic ketone cyanohydrins using almond meal as a
source of (R)-oxynitrilase.33,34 Thus, the cyanohydrin (()-19
was treated with almond meal in diisopropyl ether and citrate
buffer (0.02 M, pH 5.5) or tartrate buffer (0.1 M, pH 5.4) in
the presence of a variety of aldehydes. Unfortunately, significant
conversion of the aldehydes into their corresponding (R)-
cyanohydrins and subsequent optical enrichment of (S)-cyano-
hydrin was not observed, results that are attributable to the steric
hindrance of the ketone cyanohydrin.33c Alternative syntheses
of the (S)-cyanohydrin of 6-methyl-5-hepten-2-one have yet to
be explored.
followed by conversion of the primary and secondary hydroxyls
into benzoates. Bromoetherification of 16 with TBCO in
nitromethane gave a mixture of tetrahydropyrans 17a and 17b
and tetrahydrofurans 18 in the ratio 17a/17b/18 ) 2.4:6.9:10.
The desired tetrahydropyran 17b was isolated after chromatog-
raphy in 32% yield, as the major tetrahydropyran obtained.
This reaction was plagued by the competitive formation of
tetrahydrofurans 18, presumably because of the remaining
unfavorable diaxial interactions (methyl/methyl) encountered en
route to 17b via bromonium ion 14. However, the desired
bromotetrahydropyran (3R)-17b was easily isolated after chro-
matography more conveniently and in higher yield (32%) than
was bromotetrahydropyran (3R)-11b (17-21%), which could
only be obtained as a mixture with (3S)-11b in the previous
route, even after MPLC. Thereafter, saponification of both
benzoates of 17b with K2CO3 in methanol followed by treatment
with sodium periodate yielded aldehyde 6, with spectroscopic
and physical properties that were identical to those of 6 obtained
from (S)-linalool.
Oxymercuration was also examined in a further attempt to
enhance the synthetic access to the bromotetrahydropyran A
ring.29 Treatment of the (S)-cyanohydrin of 6-methyl-5-hepten-
2-one under mercuric trifluoroacetate-mediated brominative
conditions was expected to provide the (3S)-bromomercurial
tetrahydopyran. Subsequent treatment of the mercurial solution
with Br2 under photolytic conditions29b could then provide the
desired (3R)-bromotetrahydropyran as a result of inversion of
the configuration at the C3 position. A preliminary model study
was conducted to test the feasibility of this approach (Scheme
4). The racemic cyanohydrin (()-1930 was obtained by treatment
of 6-methyl-5-hepten-2-one with trimethylsilylcyanide and ZnI2
followed by acidic hydrolysis.31 Oxymercuration of (()-19 with
mercuric trifluoroacetate followed by treatment with a saturated
aqueous solution of KBr and NaHCO3 provided only organo-
mercurial (()-20. As expected, treatment of (()-20 with Br2
in pyridine under 300 nm irradiation provided bromide (()-21.
The axial position of the bromine atom was confirmed by the
appearance of an equatorial proton resonance as a doublet of
doublets (J ) 3.3 and 3.3 Hz) at δ 4.25. Reduction of the cyano
group using DIBAL provided aldehyde (()-6, whose 1H NMR
signals matched with those of the enantiomerically pure
aldehyde 6 prepared previously.
In summary, the most convenient route to aldehyde 6 was
found to be that illustrated in Scheme 3, which spanned five
steps from (2R,3R)-epoxy geraniol in 16% overall yield. The
yield of the bromoetherification obtained here was comparable
to those in previous total syntheses. However, the early
execution of this task, together with the possibility of recycling
the undesired isomers using Zn in acetic acid/ethanol,13-15
diminishes its impact on the overall efficiency of the present
total synthesis.
Synthesis of the C8-C15 Alkynyl Bromide (7). With
reasonable synthetic access to the A ring precursor, focus was
turned to the generation of the complementary C ring intermedi-
ate as a prelude to their convergent joining and closure of the
B ring. Regio- and stereoselective 6-endo ring opening of an
epoxide by an internal hydroxyl group would provide a
straightforward approach to the C ring of 1a and derivatives.
Three major successful tactics have been developed in line with
this strategy: activation of trans-epoxides by an adjacent vinyl
moiety leading to vinyltetrahydropyran derivatives,35,36 pal-
ladium-catalyzed cyclizations of hydroxy epoxides containing
an R,â-unsaturated ester vicinal to the epoxide,37 and ring
closure of hydroxy epoxides possessing an acetylenic moiety
adjacent to the epoxide.38
Initially, the synthesis of the C ring of thyrsiferol and
venustatriol-related derivatives was envisioned to occur via acid-
catalyzed ring opening of the vinyl hydroxyepoxide 29 (Scheme
5). The requisite epoxy alcohol 29 could be obtained from
lactone 22,39 which in turn was prepared from D-glutamic acid
in two steps (Scheme 5). Acid-catalyzed benzylation of 22
followed by reduction with diisobutyl aluminum hydride
(DIBAL) and direct treatment of the lactol with (carboethoxy-
ethylene)-triphenylphosphorane afforded the R,â-unsaturated
ester 24 in 85% yield. Silylation of the free hydroxyl group of
24 and subsequent reduction of the ester with DIBAL afforded
the allylic alcohol 26. Sharpless asymmetric epoxidation28
provided the epoxy alcohol 27, which upon oxidation with SO3‚
(32) Fo¨rster, S.; Roos, J.; Effenberger, F.; Wajant, H.; Sprauer, A. Angew.
Chem., Int. Ed. Engl. 1996, 35, 437-439.
(33) (a) Huuhtanen, T. T.; Kanerva, L. T. Tetrahedron: Asymmetry 1992,
3, 1223-1226. (b) Kiljunen, E.; Kanerva, L. T. Tetrahedron: Asymmetry
1996, 7, 1105-1116. (c) Kiljunen, E.; Kanerva, L. T. Tetrahedron:
Asymmetry 1997, 8, 1551-1557.
Encouraged by the success of this model study, attempts to
prepare the (S)-cyanohydrin of 6-methyl-5-hepten-2-one were
made. The (S)-oxynitrilase [EC 4.1.2.37] isolated from Manihot
esculenta catalyzes the formation of (S)-ketone cyanohydrins
(e90% ee); unfortunately, the enzyme preparation is not
commercially available.32 On the other hand, the commercial
(S)-oxynitrilase [EC 4.1.2.11] from Sorghum bicolor does not
(34) Mene´ndez, E.; Brieva, R.; Rebolledo, F.; Gotor, V. J. Chem. Soc.,
Chem. Commun. 1995, 989-990.
(35) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J.
Am. Chem. Soc. 1989, 111, 5330-5334.
(36) The corresponding cis epoxides have been shown to disfavor the
6-endo mode of ring closure.
(37) Suzuki, T.; Sato, O.; Hirama, M. Tetrahedron Lett. 1990, 31, 4747-
4750.
(38) (a) Mukai, C.; Sugimoto, Y.-I.; Ikeda, Y.; Hanaoka, M. Tetrahedron
Lett. 1994, 35, 2183-2186. (b) Mukai, C.; Ikeda, Y.; Sugimoto, Y.; Hanaoka,
M. Tetrahedron Lett. 1994, 35, 2179-2182.
(39) (a) Ravid, U.; Silverstein, R. M.; Smith, L. R. Tetrahedron 1978,
34, 1449-1452. (b) Herdeis, C. Synthesis 1986, 232-233.
(29) (a) Hoye, T. R.; Kurth, M. J. J. Am. Chem. Soc. 1979, 101, 5065-
5067. (b) Hoye, T. R.; Kurth, M. J. Org. Chem. 1979, 44, 3461-3467.
(30) Werner, J.; Bogert, M. T. J. Org. Chem. 1938, 3, 578-587.
(31) Gassman, P. G.; Talley, J. J. Tetrahedron Lett. 1978, 3773-3776.

Total Synthesis of Thyrsiferyl-23 Acetate
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9103
Scheme 5
Scheme 6
alkynyl epoxide 32,43 bearing the required alkynyl bromide
functionality. Subsequent cyclization of 32 catalyzed by CSA
in CH2Cl2 at 0 to 25 °C afforded a 3:1 mixture of THP/THF
isomers in 98% yield. The selectivity of the reaction was
improved by using BF3‚OEt2 in CH2Cl2 at -78 to -10 °C to
obtain regio- and stereoselectively the tetrahydropyran 33 (91%).
As expected, the presence of the methyl substituent at the δ
position of the trans-epoxy alcohol successfully stabilizes
incipient positive charge, leading to 6-endo etherification.
Finally, silylation of the hydroxyl at 33 completed the synthesis
of the alkynyl bromide 7.
Lewis acid-catalyzed cyclization of the hydroxy bromoalkynyl
epoxide 32 provided an efficient and stereoselective procedure
for the synthesis of the C ring of the thyrsiferol and venustatriol
natural products. The synthesis of the alkynyl bromide 7 from
lactone 22 was accomplished in 11 steps, with an overall yield
of 22%.
pyridine gave the epoxy aldehyde 28.40 Treatment of 28 with
methyltriphenylphosphonium bromide generated the vinyl ep-
oxide that was desilylated to the epoxy alcohol 29. Upon
treatment of 29 with catalytic camphorsulfonic acid (CSA), the
tetrahydropyran 30 was regio- and stereoselectively formed in
high yield (98%). Conversion of the vinyl tetrahydropyran 30
into the required alkynyl bromide 7 may be achievable in four
additional steps. For example, this might involve hydroxyl
silylation, oxidative cleavage of the alkene to give the corre-
sponding aldehyde, and a two-step conversion of the aldehyde
into the alkynyl bromide.
Alternatively, acid-catalyzed rearrangement of bromoalkynyl
epoxide 32 would provide 7 in a shorter synthetic sequence.
Acid-catalyzed cyclizations of adjacent acetylenic trans-epoxides
possessing electron-withdrawing substituents at the alkyne
terminus were reported to favor 5-exo etherification.38a However,
in the present case, further alkyl substitution at the propargylic
position of the trans-epoxide was anticipated to direct regiose-
lective 6-endo ring formation. Initial attempts to synthesize 31
from aldehyde 28 using Corey-Fuchs41 conditions provided a
mixture of products derived from epoxide opening. However,
31 was efficiently obtained (91%) from 28 when the reaction
was conducted in the presence of triethylamine.42 Interestingly,
treatment of 31 with an excess of TBAF (4 equiv) induced both
desilylation and monodebromination to yield the hydroxy
Synthesis of the C1-C15 Aldehyde (4). Conjoining the A
and C ring intermediates and formation of the B ring would
complete the synthesis of the tris-oxane domain of the thyrsiferol
and venustatriol natural products. For this, both the C8 carbon
and C11 oxygen of 7 would have to become covalently attached
to C7 of bromotetrahydropyran 6. This was initiated by for-
mation of the C7-C8 bond by organochromium-mediated
coupling17,18 of the C1-C7 aldehyde 6 and C8-C15 alkynyl
17
bromide 7 (Scheme 6). Treatment of 6 and 7 with CrCl2 in
DMF afforded propargylic alcohols 34 in moderate yield (66%)
after 22 h of reaction. In contrast, the use of CrCl2 doped with
NiCl2 (0.1%)18 provided propargylic alcohols 34 in better yield
(75%) after only 5 h of reaction. Importantly, the secondary
alkyl bromide of 6 withstands this mild carbon-carbon bond-
forming process. Initial attempts to saturate the alkyne of 34
by hydrogenation using Pd on C afforded complex mixtures of
products of complete and semihydrogenation with concomitant
removal of either the benzyl group or both the benzyl and the
triethylsilyl groups. Semihydrogenation of 34 with Lindlar’s
catalyst (Pd/CaCO3/Pb) gave the corresponding allylic alcohols
without cleavage of the benzyl or TES ethers, but the allylic
alcohol product was surprisingly unreactive toward treatment
with MnO2. In contrast, oxidation of propargyl alcohols 34 using
MnO2 provided the ynone 35 efficiently (89%). Subsequent
hydrogenation mediated by Pd(OH)2 or Pd on C in methanol
successfully yielded dihydroxy ketone 36, as a result of alkyne
saturation and liberation of both silyl and benzyl groups. The
next task was the reduction of the hemiketal tautomer of 36 to
(40) A diastereomer of the aldehyde 28 was prepared previously from
L-glutamic acid: Nicolaou, K. C.; Reddy, K. J.; Skokotas, G.; Sato, F.;
Xiao, X.-Y.; Hwang, C.-K. J. Am. Chem. Soc. 1993, 115, 3558-3575.
(41) Corey, E. J.; Fuchs, P. Tetrahedron Lett. 1972, 3769-3772.
(42) McIntosh, M. C.; Weinreb, S. M. J. Org. Chem. 1993, 58, 4823-
4832.
(43) For a precedent of this reaction in a cis dibromoalkenyl epoxide,
see ref 35.

9104 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
Gonza´lez and Forsyth
Scheme 7
Scheme 8
permanently close the B ring. Dihydroxyketone 36 remained
unreacted upon treatment with triethylsilane and BF3‚OEt2.44
However, using triethylsilane and trimethylsilyltriflate (TM-
SOTf)45 in CH3CN at -10 °C, fused ether 37 was afforded
stereoselectively and in generally high, although variable yield.
NOESY experiments performed on compound 37 and sum-
marized in Scheme 6 showed that the relative configuration at
C7 was as expected from the axial delivery of hydride to the
oxonium intermediate derived from 36. Thereafter, oxidation
of 37 with Dess-Martin reagent (DMP)46 buffered with
NaHCO3 provided aldehyde 4 (94%).
After successfully joining the two preconstructed tetrahydro-
pyran-containing units representing the functionalized A and C
rings (6 and 7, respectively), the synthesis of the C1-C5 tricycle
(4) was completed after four additional steps with minimum
protecting group manipulations and an overall yield of 53%.
Hence, an efficient and convergent construction of the A-B-C
ring system of thyrsiferol, venustatriol, and derivatives was
developed. This features a separate etherification method for
the closure of each oxane ring and provides aldehyde 4 from
the D-glutamic acid derivative 22 in 16 steps in the longest linear
sequence and 12% overall yield. Notably, the problematic
bromoetherification process does not impact the longest linear
sequence.
butylhydroperoxide produced a separable mixture of tetrahy-
drofurans 41 (trans/cis ) 2.4:1) in high yield (85%).53 Acety-
54
lation of 41a with acetic anhydride catalyzed by Sc(OTf)3
afforded the triacetate derivative, but selective cleavage of the
primary acetate failed because of concomitant saponification
of the secondary ester. The low stereoselectivity of the vanadyl-
induced tetrahydrofuran formation and the difficulty in the early
incorporation of acetates at the C18 and C13 hydroxyls in this
route prompted the development of an alternative route toward
the D ring. However, the C18 and C23 hydroxyls of the cis-
tetrahydrofuran 41b could be protected (MOM or TBS) in one
step to provide intermediates that may be useful for the synthesis
of venustatriol and its derivatives.
The possibility of constructing the trans-tetrahydrofuran via
the hydroxyl-directed Re(VII)-promoted syn-oxidative cycliza-
tion of bis-homoallylic alcohols seemed an attractive alternative
(Scheme 8).19-21 In particular, the recent use of (CF3CO2)-
ReO3‚2CH3CN58 in the presence of trifluoroacetic anhydride
(TFAA) for trans-tetrahydrofuran formation from tertiary bis-
homoallylic alcohols21 inspired the direct conversion of hydroxy
alkene 44 into the functionalized D ring. The trans-diastereo-
selectivity in Re(VII)-induced syn-oxidative cyclizations has
been attributed to steric interaction in an alkoxyrhenium inter-
mediate,20b,21 although cis-diastereoselectivity may be favored
by chelation control.21,55,56 In the case of 44, the electron-
withdrawing character of the neighboring acetate at C18 was
expected to diminish any metal chelation and thereby contribute
to trans selectivity in the syn-oxidative cyclization.
The synthesis of 5 began with (2S,3S)-epoxy geraniol.28
Regio- and stereoselective hydrolysis15 of the derived benzyl
ether provided diol 43, which was monoacetylated57 to give 44
(Scheme 8). Treatment of 44 with (CF3CO2)ReO3‚2CH3CN58
in the presence of TFAA21 efficiently provided (77%) the trans-
tetrahydrofuran 45 with excellent stereoselectivity (trans/cis )
Synthesis of C16-C24 Alkenyl Iodide (5). In contrast to
the tris-oxane system 4, the remaining fragment of 1a-1d
contains a solitary tetrahydrofuran ring. The stereoselective
construction of this cyclic ether47 is the key event in the
construction of the C16-C24 side chain of 1a and its deriva-
tives. Accordingly, the formation of the trans-tetrahydrofuran
ring via vanadium(V)-catalyzed epoxidation and spontaneous
cyclization,48 as suggested by the work of Shirahama,14 was
first explored (Scheme 7). Diol 3849 was delivered from benzyl
geraniol ether by Sharpless asymmetric dihydroxylation50 using
AD-mix â and methylsulfonamide in moderate yield (41%) but
excellent stereoselectivity (>98% ee). Treatment of 38 with VO-
(acac)2 and tert-butylhydroperoxide provided a mixture of
tetrahydrofurans 40 (trans/cis ) 2.4:1) in good yield (81%).51
Unfortunately, compounds 40a and 40b were not readily
separable by simple silica gel column chromatography. On the
other hand, treatment of 39,52 similarly obtained from geraniol
acetate (52% yield, >98% ee), with VO(acac)2 and tert-
(44) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976-4978.
(45) Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am. Chem. Soc.
1989, 111, 4136-137.
(46) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(47) (a) Harmange, J.-C.; Figade`re, B. Tetrahedron: Asymmetry 1993,
4, 1711-1754. (b) Koert, U. Synthesis 1995, 115-132.
(48) (a) Fukuyama, T.; Vranesic, B.; Negri, D. P.; Kishi, Y. Tetrahedron
Lett. 1978, 31, 2741-2744. (b) Nakata, T.; Schmid, G.; Vranesic, B.;
Okigawa, M.; Smith-Palmer, T.; Kishi, Y. J. Am. Chem. Soc. 1978, 100,
2933-2935.
(52) Vidari, G.; Dapiaggi, A.; Zanoni, G.; Garlaschelli, L. Tetrahedron
Lett. 1993, 34, 6485-6488.
(53) The stereochemistry of the trans-tetrahydrofuran 41a was determined
after protecting the two free hydroxyls with MOM groups, by detection of
an NOE between protons at the C18 and C22 positions.
(54) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Am. Chem.
Soc. 1995, 117, 4413-4414.
(55) Sinha, S. C.; Keinan, E.; Sinha, S. C. J. Am. Chem. Soc. 1998, 120,
9076-9077.
(56) Sinha, S. C.; Sinha, A.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc.
1997, 119, 12014-12015.
(57) Zhdanov, R. I.; Zhenodarova, S. M. Synthesis 1975, 222-245.
(58) (a) Herrmann, W. A.; Thiel, W. R.; Ku¨hn, F. E.; Fischer, R. W.;
Kleine, M.; Herdtweck, E.; Scherer, W. Inorg. Chem. 1993, 32, 5188-
5194. (b) Edwards, P.; Wilkinson, G. J. J. Chem. Soc., Dalton Trans. 1984,
2695-2702.
(49) Hoeman, M. Z.; Agrios, K. A.; Aube´, J. Tetrahedron 1997, 53,
11087-11098.
(50) 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, 2768-2771.
(51) The stereochemistry of tetrahydrofurans 40 was determined at the
stage of the diacetate derivatives. The diacetate 46, derived from 40a,
showed an NOE between protons at the C18 and C22 positions (Scheme
8).

Total Synthesis of Thyrsiferyl-23 Acetate
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9105
Scheme 9
Oxidation of alcohols 48 with buffered Dess-Martin perio-
dinane reagent46 satisfactorily gave the enone 49. Fortunately,
at this point it was possible to separate the cis-tetrahydrofuran
diastereomer from intermediate 5 by simple chromatography.
Catalytic hydrogenation of 49 with Pd(OH)2 on carbon in
methanol failed to produce the desired saturated derivative
cleanly. However, Pd on carbon-mediated hydrogenation in ethyl
acetate provided the R,â-saturated ketone. The tertiary hydroxyl
at C15 was installed following Corey’s precedent, using
methylmagnesium bromide.15 Alternatively, chemoselective
methylenation61,62 of the R,â-saturated ketone from 49 could
provide access to 2a and 2b. Selective cleavage of the secondary
acetate at C18 in the presence of the tertiary ester at C23
might be expected to occur upon methyl installation. However,
treatment of the R,â-saturated ketone with methylmagnesium
bromide at -78 °C gave efficiently and stereoselectively 1d
(87%). Upon allowing the reaction mixture to warm to 0 °C,
minor amounts of thyrsiferol (1b) and thyrsiferyl 23-acetate (1a)
were also detected. This observation is not surprising in light
of the simultaneous functionalization of the hydroxyls at C18
and C23 at the stage of 41b, which may be explained by their
similar steric environments. Partial saponification of 1d with
K2CO3 in methanol for 9 h occurred in 76% yield to provide
thyrsiferyl 23-acetate (1a) and thyrsiferol (1b).63 However,
saponification of both acetates at the C18 and C23 positions
was achieved by prolonged treatment of 1d with an excess of
K2CO3 in methanol, to obtain exclusively 1b. Finally, monoacety-
lation of 1b, as described previously,1a afforded thyrsiferyl 18-
acetate (1c) (70%).64 After joining the two halves of the
thyrsiferol derivatives, represented by fragments 4 and 5, the
synthesis of thyrsiferyl 18,23-diacetate (1d) was accomplished
in four additional steps without protecting group manipulations,
with an overall yield of 43%. At last, partial or complete
saponification of the acetates at C18 and C23 successfully gave
thyrsiferyl 23-acetate (1a) or thyrsiferol (1b), respectively.
19:1). Prior to extension of the side chain appended to the D
ring, acetylation of the tertiary alcohol of tetrahydrofuran 45
with acetic anhydride catalyzed by Sc(OTf)354 provided diacetate
46. The detection of an NOE between protons at C22 and C18
of 46 (Scheme 8) confirmed the trans selectivity in the formation
of 45. Hydrogenolytic removal of the benzyl group followed
by alcohol oxidation with buffered Dess-Martin periodinane46
gave the corresponding aldehyde, which was immediately
converted into the trans-alkenyl iodide 5 under Takai reaction
conditions.59 Overall, the trans-tetrahydrofuran 5 was stereo-
selectively obtained from (2S,3S)-epoxy geraniol in an eight-
step sequence and an overall yield of 22%. This approach
provided the C16-C24 fragment of 1a and derivatives with
acetates strategically incorporated at both the C18 and C23
hydroxyl positions to facilitate the anticipated strategic end-
game manipulations.
Synthesis of Thyrsiferyl 23-Acetate (1a) and Its Deriva-
tives (1b, 1c, and 1d). Only two major tasks remained to
complete the assembly of thyrsiferol natural products: coupling
the tris-oxane and tetrahydrofuran-containing fragments and
installation of the tertiary hydroxyl group at C15. Mild and
chemoselective organochromium-mediated conditions were
selected for the formation of the C15-C16 bond of 1a and
derivatives.22 Preliminary attempts to join 4 and 5 using CrCl2
doped with NiCl2 (0.1%) in DMF provided, after 24 h, the
mixture of allylic alcohols 48 in low yield (<40%, Scheme 9).
Under these conditions, significant elimination of the bromide
and tetrahydropyran opening were observed. The yield of the
reaction was improved using CrCl2 doped with NiCl2 (0.5%)
in DMSO to provide a mixture of allylic alcohols 4860 in 62%
yield. Although the efficiency of this organochromium-mediated
coupling was moderate, it was possible to minimize the bromide
elimination, the acetates at C18 and C23 remained intact, and
unreacted aldehyde 4 could be recovered.
Conclusions
This modular total synthesis delivers thyrsiferyl 23-acetate
(1a) and thyrsiferol (1b) in 21 steps in the longest linear
sequence. In addition to providing the scarce and uniquely
biologically active natural product 1a, a variety of other natural
and non-natural congeners may also be accessed by minor
modifications of the synthetic route. The early joining of
intermediates containing the A and C rings followed by an
efficient annulation of the B ring, convergent attachment of the
D ring intermediate, and minimal manipulation of hydroxyl-
protecting groups characterizes the flexibility and efficiency of
the synthesis. Furthermore, the tetrahydrofuranyl D ring was
constructed by a highly stereoselective Re(VII)-promoted syn-
oxidative cyclization of bis-homoallylic alcohol 44. Also
noteworthy is the use of mild and chemoselective organochro-
mium reactions for the coupling of highly functionalized
intermediates,65 which allowed the early incorporation of a
(60) By 1H NMR determination of the crude mixture it was possible to
distinguish the two possible isomers in the ratio 3:1; however, the
stereochemistry at the C15 was not assigned.
(61) Lombardo, L. Tetrahedron Lett. 1982, 23, 4293.
(62) Huang, H.; Forsyth, C. J. J. Org. Chem. 1995, 60, 5746-5757.
(63) The ratios of 1a/1b/1c were dependent upon the amount of K2CO3
and varied from ∼1:0.5-1:1-0.7. The 1H NMR and HRMS data of 1b
and 1a matched those previously reported: Blunt, J. W.; McCombs, J. D.;
Munro, M. H. G.; Thomas, F. N. Magn. Reson. Chem. 1989, 27, 792-795
and ref 14d.
(64) HRMS and 1H NMR data of 1c were consistent with the assignment,
and a 300 MHz 1H NMR spectrum of totally synthetic 1c was identical to
a 300 MHz 1H NMR spectrum of semisynthetic 1c obtained from a natural
sample of 1b, which was kindly provided by Prof. J. W. Blunt.
(59) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.

9106 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
Gonza´lez and Forsyth
as a colorless oil: Rf 0.35 (hexanes/ethyl acetate, 9:1, v/v); [R]22D +31
(c 1.0, CHCl3); IR (neat) 2961, 2923, 1710, 1250, 1231; 1H NMR
(CDCl3, 500 MHz) δ 8.05 (dd, J ) 1, 8.2 Hz, 2H), 7.95 (dd, J ) 1,
8.2 Hz, 2H), 7.27-7.60 (m, 5H), 5.45 (dd, J ) 2.5, 9 Hz, 1H), 4.80
(dd, J ) 2.5, 11.5 Hz, 1H), 4.52 (dd, J ) 9, 11.5 Hz, 1H), 3.94 (dd, J
) 4, 12.2 Hz, 1H), 2.27 (dddd, J ) 4, 13, 13, 13 Hz, 1H), 2.16 (dddd,
J ) 4, 4, 4, 13.2 Hz, 1H), 1.81 (ddd, J ) 4, 13.2, 13.2 Hz, 1H), 1.71
(ddd, J ) 4, 4, 13.5 Hz, 1H), 1.47 (s, 6H), 1.35 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 166.56, 165.85, 133.22, 132.97, 129.70, 129.65,
128.47, 128.34, 77.82, 75.76, 74.22, 63.63, 57.50, 35.24, 30.77, 27.50,
23.82, 21.35; HRMS (CI) calcd for C24H31O5N79Br [M + NH4]+
492.1378, found 492.1345, calcd for C24H28O579Br [M + H]+ 475.1113,
found 475.1085.
secondary bromide at C3 and acetates at C18 and C23 and an
expedient completion of the total synthesis. This work should
not only help to alleviate the problem of limited supply of 1a
but may also be instrumental for dissecting the structural bases
for the novel combination of anti-leukemic, apoptotic-inducing,
PP2A inhibitory, and anti-multidrug resistance activities of the
thyrsiferol-derived natural products.
Experimental Section66
Tetrahydrobromofurans (10) and Tetrahydrobromopyrans (11a
and 11b). To a stirred 0 °C solution of (S)-(+)-linalool24 (0.91 g, 5.9
mmol) in CH3NO2 (80 mL) was added TBCO (2.66 g, 6.51 mol) in
the dark. After 5 h, the reaction mixture was poured into a 1 M aqueous
NaOH solution (250 mL), diluted with ether (150 mL), and stirred for
10 min. The organic phase was separated and washed with additional
1 M NaOH solution (70 mL). The combined aqueous phases were
extracted with ether (3 × 100 mL). The combined organic phases were
washed with saturated aqueous NaCl (50 mL), dried over MgSO4,
filtered, and concentrated. Silica gel chromatography (hexanes/ethyl
acetate, 99:1, v/v) gave a mixture of tetrahydrofurans and tetrahydro-
pyrans (10/11a/11b ) 4.4:10:6.9) (1.1 g, 4.7 mmol, 80%). An analytical
sample was purified by MPLC to obtain a mixture of 11a and 11b: Rf
0.11 (hexanes); IR (neat) 2956, 2919, 2815, 1462, 1377, 1260; 1H NMR
(CDCl3, 500 MHz) 11a δ 5.98 (dd, J ) 11, 18 Hz, 1H), 4.97-5.09
(m, 2H), 3.95 (dd, J ) 4, 12 Hz, 1H), 2.24 (dddd, J ) 4, 13, 13, 13
Hz, 1H), 2.11-2.16 (m, 2H), 1.64 (dddd, J ) 1.5, 4, 14, 14 Hz, 1H),
1.38 (s, 3H), 1.33 (s, 3H), 1.15 (s, 3H), 11b δ 5.92 (dd, J ) 11, 18 Hz,
1H), 4.97-5.09 (m, 2H), 4.10 (dd, J ) 3.5, 7.5 Hz, 1H), 2.28 (dddd,
J ) 4, 4, 9, 9 Hz, 1H), 2.05-2.11 (m, 1H), 1.92 (dddd, J ) 4, 7, 9, 9
Hz, 1H), 1.82 (ddd, J ) 4, 7.5, 14 Hz, 1H), 1.40 (s, 3H), 1.37 (s, 3H),
1.30 (s, 3H); HRMS (CI) calcd for C10H21O79BrN [M + NH4]+
250.0802, found 250.0832, calcd for C10H18O79Br [M + H]+ 233.0537,
found 233.0531.
Tetrahydropyran (33). To a stirred, -78 °C solution of 32 (1.0 g,
2.9 mmol) in CH2Cl2 (85 mL) under Ar was added a borontrifluoride
etherate (2.9 mL of a 0.1 M solution in CH2Cl2, 0.29 mmol) dropwise.
After 30 min, the mixture was warmed to -10 °C. After the reaction
mixture was stirred at -10 °C for 6 h, it was diluted with H2O (50
mL) and extracted with CH2Cl2 (3 × 75 mL). The organic phase was
dried over MgSO4, filtered, and concentrated. Flash chromatography
(hexanes/ethyl acetate, 8:2, v/v) gave 33 as a colorless oil (0.89 g, 2.6
mmol, 91%): Rf 0.32 (hexanes/ethyl acetate, 7:3, v/v); [R]22D -6.3 (c
0.29, CHCl3); IR (neat) 3436, 3030-2867, 2203, 1496, 1452, 1367,
1
1262, 1202, 1124, 1094, 1071; H NMR (CDCl3, 500 MHz) δ 7.35-
7.36 (m, 5H), 4.59 (AB, J ) 12.5 Hz, 2H), 4.11-4.16 (m, 1H), 3.58-
3.62 (m, 1H), 3.54 (dd, J ) 5, 10 Hz, 1H), 3.45 (dd, J ) 5, 10 Hz,
1H), 2.21 (dddd, J ) 2.5, 5.2, 14, 14 Hz, 1H), 1.95 (d, J ) 10 Hz,
1H), 1.86 (ddd, J ) 2.5, 6.7, 14 Hz, 1H), 1.48-1.64 (m, 2H), 1.52 (s,
3H); 13C NMR (CDCl3, 75 MHz) δ 138.23, 128.39, 127.76, 127.65,
80.20, 74.35, 73.43, 73.05, 73.57, 72.57, 69.80, 47.61, 27.21, 25.29,
21.18; HRMS (CI) calcd for C16H2379BrNO3 [M + NH4]+ 356.0856,
found 356.0859, calcd for C16H2079BrO3 [M + H]+ 339.0591, found
339.0548, calcd for C16H1879BrO2 [M - OH]+ 321.0486, found
321.0459.
Propargylic Alcohols (34). To a room temperature mixture of CrCl2
containing 0.1% by wt NiCl2 (0.15 g, 1.2 mmol) in DMF (0.9 mL)
was added dropwise a solution of the aldehyde 6 (0.11 g, 0.47 mmol)
and alkynyl bromide 7 (0.27 g, 0.61 mmol) in DMF (0.3 mL) in a
glovebox under nitrogen. The reaction mixture was stirred at room
temperature for 5 h. Ethyl acetate (3 mL) and a 1 M solution of
potassium serinate (3 mL) were added, and the mixture was stirred for
20 min. The separated aqueous phase was washed with ethyl acetate
(3 × 10 mL), acidified to ∼pH 3 with a 1 M solution of HCl, and
extracted again with ethyl acetate (10 mL). The combined organic
phases were washed with saturated aqueous NaCl (5 mL), dried over
MgSO4, filtered, and concentrated. Flash chromatography (hexanes/
ethyl acetate, 8:2, v/v) gave a mixture of the two propargylic alcohols
34 as a colorless oil (0.21 g, 0.35 mmol, 75%): Rf 0.29 (hexanes/ethyl
acetate, 85:15, v/v); IR (neat) 3400, 2951, 2878, 1454, 1376, 1208,
1122, 1074, 1020; 1H NMR (CDCl3, 500 MHz) δ 7.34 (m, 5H), 4.54-
4.56 (m, 2H), 4.14 (d, J ) 3 Hz, 1H), 4.04-4.08 (m, 1H), 3.85 (dd, J
) 4, 12.7 Hz, 1H), 3.63 (dd, J ) 2.5, 2.5 Hz, 1H), 3.57 (dd, J ) 5, 10
Hz, 1H), 3.41 (dd, J ) 5, 10 Hz, 1H), 2.75 (d, J ) 3 Hz, 1H), 2.25
(dddd, J ) 4, 13, 13.3, 13.3 Hz, 1H), 2.11-2.19 (m, 2H), 2.03 (ddd,
J ) 4.5, 13.7, 13.7 Hz, 1H), 1.57-1.73 (m, 4H), 1.46 (s, 3H), 1.45 (s,
3H), 1.37 (s, 3H), 1.35 (s, 3H), 0.97 (t, J ) 8 Hz, 9H), 0.62 (q, J ) 8
Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 138.56, 128.29, 127.71,
127.49, 86.65, 84.06, 76.62, 76.39, 73.47, 73.23, 72.65, 70.29, 69.89,
57.27, 30.92, 30.72, 28.58, 27.77, 25.86, 23.06, 23.01, 21.84, 6.92,
4.90; HRMS (CI) calcd for C31H53NO5Si79Br [M + NH4]+ 626.2863,
found 626.2873.
Aldehydes (12 and 6). To a stirred, room temperature solution of
the mixture of 10, 11a, and 11b (10/11a/11b ) 4.4:10:6.9, 1.1 g, 4.7
mmol) in THF (12 mL) was added a solution of NMO (0.87 g, 6.4
mmol) in H2O (3 mL) and OsO4 (1.4 mL of a 0.15 M solution in H2O,
0.21 mmol). After the solution was stirred at room temperature for 24
h, it was cooled to 0 °C and NaIO4 (1.4 g, 6.4 mmol) and H2O (3 mL)
were added. The mixture was allowed to warm to room temperature,
and after 4 h it was diluted with H2O (75 mL) and extracted with ether
(3 × 50 mL). The organic phase was dried over MgSO4, filtered, and
concentrated. The residue was purified by MPLC to obtain 12 (0.28 g,
1.2 mmol, 25%) and 6 (0.15 g, 0.6 mmol, 13%). Data for 12: Rf 0.51
(hexanes/ethyl acetate, 8:2, v/v); IR (neat) 2980, 2960, 1730, 1450,
1
1380, 1260, 1000; H NMR (CDCl3, 500 MHz) δ 9.59 (s, 1H), 3.92
(dd, J ) 4.5, 12.5, 1H), 2.33 (ddd, J ) 3, 3, 14 Hz, 1H), 1.97-2.10
(m, 2H), 1.46-1.54 (m, 1H), 1.42 (s, 3H), 1.30 (s, 3H), 1.11 (s, 3H).
Data for 6: Rf 0.43 (hexanes/ethyl acetate, 8:2, v/v); [R]22 +18 (c
D
0.44, CHCl3); IR (neat) 2980, 2960, 1730, 1450, 1380, 1260, 1000; 1H
NMR (CDCl3, 500 MHz) δ 9.55 (s, 1H), 4.13 (dd, J ) 2.2, 3 Hz, 1H),
2.14-2.20 (m, 1H), 2.00-2.09 (m, 2H), 1.87-1.92 (m, 1H), 1.43 (s,
3H), 1.30 (s, 3H), 1.23 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 204.51,
58.27, 30.91, 26.55, 26.29, 24.45, 23.85; HRMS (CI) calcd for
C9H19O279BrN [M + NH4]+ 252.0593, found 252.0598.
Tetrahydrobromopyran (17b). To a stirred, 0 °C solution of 16
(0.58 g, 1.5 mmol) in CH3NO2 (29 mL) was added TBCO (0.66 g, 1.6
mmol) in the dark. After 20 h at 4 °C, the reaction mixture was poured
into a 1 M aqueous NaOH solution (100 mL), diluted with ether (50
mL), and stirred for 10 min. The organic phase was separated and
washed with additional 1 M NaOH solution (25 mL). The combined
aqueous phases were extracted with ether (3 × 50 mL). The combined
organic phases were washed with saturated aqueous NaCl (10 mL),
dried over MgSO4, filtered, and concentrated. Silica gel chromatography
(hexanes/ethyl acetate, 98:2, v/v) gave 17b (0.23 g, 0.47 mmol, 32%)
Tricycle (37). To a stirred, -35 °C solution of 36 (52 mg, 0.13
mmol) in CH2Cl2 (4 mL) under Ar was added HSiEt3 (0.20 mL, 1.3
mmol) and TMSOTf (28 µL, 0.15 mmol). After the reaction mixture
was stirred for 30 min, it was diluted with saturated aqueous NaHCO3
(5 mL) and extracted with ethyl acetate (3 × 10 mL). The organic
phase was washed with saturated aqueous NaCl, dried over MgSO4,
filtered, and concentrated. The residue was purified by flash chroma-
tography (hexanes/ethyl acetate, 75:25, v/v) to give 37 (38 mg, 0.10
mmol, 76%): Rf 0.28 (hexanes/ethyl acetate, 6:4, v/v); [R]22D +6.4 (c
0.73, CHCl3); IR (neat) 3444, 2951, 2867, 1456, 1379, 1122, 1102; 1H
(65) (a) Kishi, Y. Pure Appl. Chem. 1992, 64, 343-350. (b) Cintas, P.
Synthesis 1992, 248-257. (c) Wessjohann, L. A.; Scheid, G. Synthesis 1999,
1-36. (d) Fu¨rstner, A. Chem. ReV. 1999, 99, 991-1045.
(66) A complete set of experimental details is included in the Supporting
Information.

Total Synthesis of Thyrsiferyl-23 Acetate
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9107
NMR (CDCl3, 500 MHz) δ 3.93-3.98 (m, 1H), 3.89 (dd, J ) 4, 13
Hz, 1H), 3.52 (d, J ) 5.5 Hz, 1H), 3.43 (dd, J ) 5.5, 11.2 Hz, 1H),
3.09 (dd, J ) 2, 11.2 Hz, 1H), 2.25 (dddd, J ) 4, 13, 13, 13 Hz, 1H),
2.12 (dddd, J ) 4, 4, 8.5, 8.5 Hz, 1H), 1.73-1.88 (m, 6H), 1.67 (bs,
1H), 1.42-1.59 (m, 4H), 1.41 (s, 3H), 1.28 (s, 3H), 1.22 (s, 3H), 1.21
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 86.69, 78.24, 74.99, 74.35,
72.25, 70.73, 65.90, 58.97, 38.39, 37.08, 31.03, 28.23, 23.76, 23.65,
23.05, 21.09, 20.65, 20.07; HRMS (CI) calcd for C18H35O4N79Br [M
+ NH4]+ 408.1741, found 408.1724, calcd for C18H32O479Br [M + H]+
391.1476, found 391.1484.
1, 14.6 Hz), 5.21 (dd, J ) 1, 6.3 Hz, 1H), 4.07 (dd, J ) 6, 8.5 Hz,
1H), 2.11 (s, 3H), 1.99 (s, 3H), 1.78-2.00 (m, 3H), 1.64-1.70 (m,
1H), 1.47 (s, 3H), 1.44 (s, 3H), 1.20 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 170.44, 169.87, 140.94, 85.41, 83.48, 82.50, 80.69, 79.50,
33.94, 26.44, 23.54, 22.49, 22.29, 21.77, 21.08; HRMS (FAB) calcd
for C15H24O5I [M + H]+ 411.0661, found 411.0655.
Ketone (49). To a room temperature solution of 4 (17 mg, 44 µmol)
and 5 (19:1 mixture (trans/cis), 45 mg, 110 µmol) in DMSO (1.2 mL)
was added CrCl2 containing 0.5% by wt NiCl2 (27 mg, 220 µmol) in
a glovebox under nitrogen. The mixture was stirred for 21 h before a
1 M potassium serinate solution (2 mL) and ethyl acetate (2 mL) were
added. The resulting mixture was stirred for 30 min, the phases were
separated, and the aqueous phase was extracted with ethyl acetate (3
× 3 mL). The aqueous phase was acidified with 1 M HCl to ∼3 pH
and extracted again with ethyl acetate (3 mL). The combined organic
phase was washed with saturated aqueous NaCl (2 mL), dried over
MgSO4, filtered, and concentrated. Silica gel column chromatography
(hexanes/ethyl acetate, 3:1, v/v) of the residue gave 48 (18 mg, 27
µmol, 62%) as a 3:1 mixture of C15 epimers and a colorless oil: Rf
trans-Tetrahydrofuran (45). Rhenium heptoxide (2.5 g, 5.2 mmol)
was dissolved in CH3CN (30 mL) in a Schlenk flask, trifluoroacetic
anhydride (0.75 mL, 5.2 mmol) was added, and the resulting mixture
was stirred under Ar at room temperature for 1 h. The solution was
cooled to 0 °C and concentrated in vacuo to produce (CF3CO2)ReO3‚
2CH3CN as a white solid.58 To this solid were added CH2Cl2 (27 mL)
and trifluoroacetic anhydride (0.75 mL, 5.2 mmol) under Ar.21 After
the mixture was cooled to -40 °C, a solution of 44 (0.42 g, 1.3 mmol)
in CH2Cl2 (3 mL) was added via syringe. After 2 h, the reaction mixture
was allowed to warm to -20 °C and stir for an additional 2 h. The
resulting dark purple solution was filtered through silica gel with ethyl
acetate (50 mL). The filtrate was washed with saturated aqueous
NaHCO3 (20 mL) and saturated NaCl (20 mL). The aqueous phase
was washed with ethyl acetate (20 mL), and the combined organic phase
was dried over MgSO4, filtered, and concentrated to obtain a clear oil.
The residue was purified by silica gel column chromatography (hexanes/
ethyl acetate, 7:3, v/v) to give 45 and its cis-isomer in a 19:1 ratio
(trans/cis), respectively (0.34 g, 1.0 mmol, 77%), that was not separated
but characterized as a mixture after further purification by reverse-
phase HPLC (C-18, CH3OH/H2O, 99:1, v/v): Rf 0.4 (hexanes/ethyl
1
0.26 (hexanes/ethyl acetate, 7:3, v/v); H NMR (CDCl3, 500 MHz) δ
5.60-5.78 (m, 2H), 5.27-5.31 (m, 1H), 4.07-4.17 (m, 2H), 3.89-
4.00 (m, 2H), 3.53 (dd, J ) 7, 11.5 Hz, 1H, major isomer), 3.41 (dd,
J ) 5, 11.2 Hz, 1H, minor isomer), 3.04-3.11 (m, 1H), 2.35 (bs, 1H),
2.24 (dddd, J ) 4, 13, 13, 13 Hz, 1H), 2.09 (s, 3H, major isomer),
2.05 (s, 3H, minor isomer), 1.98 (s, 3H), 1.46 (s, 3H), 1.43 (s, 3H),
1.40 (s, 3H), 1.40-2.12 (m, 15H), 1.27 (s, 3H, major isomer), 1.24 (s,
3H, minor isomer), 1.20 (s, 3H), 1.90 (s, 3H), 1.18 (s, 3H); HRMS
(FAB) calcd for C33H54O979Br [M + H]+ 673.2937, found 673.2972.
To a stirred, room temperature solution of alcohols 48 (14 mg, 21 µmol)
in CH2Cl2 (1 mL) was added NaHCO3 (27 mg, 315 µmol) followed by
the Dess-Martin periodinane reagent (27 mg, 63 µmol). The resultant
mixture was stirred for 1 h. Ethyl acetate (2 mL), saturated aqueous
NaHCO3 (2 mL), and 10% aqueous Na2S2O3 (2 mL) were added, and
the mixture was stirred until the organic layer became clear. The
aqueous phase was extracted with ethyl acetate (3 × 2 mL), and the
combined organic phase was washed with saturated aqueous NaCl (2
mL), dried over MgSO4, filtered, and concentrated to give an oil. Silica
gel column chromatography (hexanes/ethyl acetate/ether/CH2Cl2, 75:
5:15:5, v/v) of the residue gave 49 (12 mg, 18 µmol, 88%) as a colorless
oil. Further purification by reverse-phase HPLC (C-18, CH3CN/H2O,
96:4, v/v) afforded an analytical sample: Rf 0.25 (hexanes/ethyl acetate/
CH2Cl2, 6.5:1.5:1.5, v/v); [R]22D +11 (c 0.88, CHCl3); IR (neat) 2963,
1702, 1678, 1631, 1548, 1529, 1461, 1443, 1413, 1371, 1261, 1102;
1H NMR (CDCl3, 500 MHz) δ 6.98 (dd, J ) 5, 16 Hz, 1H), 6.73 (dd,
J ) 1.5, 16 Hz, 1H), 5.42 (dd, J ) 1.5, 5 Hz, 1H), 4.17 (d, J ) 6.3 Hz,
1H), 4.10 (dd, J ) 6.5, 8.5 Hz, 1H), 3.89 (dd, J ) 4, 12.7 Hz, 1H),
3.14 (dd, J ) 4.5, 11.5 Hz, 1H), 3.10 (dd, J ) 2.5, 11 Hz, 1H), 2.51-
2.56 (m, 1H), 2.24 (dddd, J ) 4, 13, 13, 13 Hz, 1H), 2.15 (s, 3H), 1.99
(s, 3H), 1.65-2.15 (m, 11H), 1.40-1.60 (m, 4H), 1.47 (s, 3H), 1.45
(s, 3H), 1.40 (s, 3H), 1.27 (s, 3H), 1.21 (s, 3H), 1.18 (s, 3H), 0.96 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 200.57, 170.40, 169.87, 141.34,
127.02, 86.81, 85.45, 84.13, 82.51, 80.52, 75.93, 75.00, 74.54, 74.30,
70.00, 58.95, 37.83, 37.15, 34.42, 31.03, 28.21, 26.44, 23.60, 23.53,
23.08, 22.91, 22.46, 21.70, 21.02, 19.99, 16.92; HRMS (FAB) calcd
for C33H51O979BrNa [M + Na]+ 693.2553, found 693.2609.
acetate, 6:4, v/v); [R]22 -14 (c 2.3, CHCl3); IR (neat) 3482, 3029,
D
2974, 2871, 1740, 1496, 1455, 1373, 1236, 1126, 1057; 1H NMR
(CDCl3, 500 MHz) δ 7.29-7.37 (m, 5H), 5.20 (dd, J ) 3, 7.8 Hz,
1H), 4.53 (AB, J ) 12 Hz, 2H), 3.72-3.77 (m, 2H), 3.59 (dd, J ) 7.8,
11 Hz, 1H), 2.11 (s, 3H), 2.01-2.08 (m, 1H), 1.81-1.86 (m, 2H), 1.64-
1.76 (m, 2H), 1.19 (s, 6H), 1.11 (s, 3H); 13C NMR (CDCl3, 75 MHz)
δ 170.54, 138.08, 128.36, 127.53, 127.59, 87.04, 82.88, 76.08, 72.86,
70.42, 69.15, 35.11, 27.43, 26.02, 24.11, 23.34, 21.20; HRMS (FAB)
calcd for C19H29O5 [M + H]+ 337.2007, found 337.2028, calcd for
C19H27O4 [M - OH]+ 319.1902, found 319.1899.
Vinyl Iodide (5). To a stirred, room temperature solution of 47 (19:1
mixture (trans/cis), 0.11 g, 0.35 mmol) in CH2Cl2 (5 mL) was added
NaHCO3 (0.29 g, 3.5 mmol) followed by the Dess-Martin periodinane
reagent (0.29 g, 0.69 mmol). The resultant mixture was stirred for 45
min. Ethyl acetate (5 mL), saturated aqueous NaHCO3 (5 mL), and
10% aqueous Na2S2O3 (5 mL) were added, and the mixture was stirred
until the organic layer became clear. The aqueous phase was extracted
with ethyl acetate (3 × 10 mL), and the combined organic phase was
washed with saturated aqueous NaCl (5 mL), dried over MgSO4,
filtered, and concentrated to give an oil. The residue was filtered through
a pad of silica gel with hexanes/ethyl acetate (8:2, v/v) to obtain the
corresponding aldehyde 47a and its cis-isomer in a 19:1 ratio (trans/
cis), respectively, as an oil (90 mg, 0.31 mmol, 88%): Rf 0.28 (hexanes/
1
ethyl acetate, 8:2, v/v); H NMR (CDCl3, 300 MHz) δ 9.68 (s, 1H),
5.04 (s, 1H), 4.18 (dd, J ) 6.6, 8 Hz, 1H), 2.20 (s, 3H), 2.00 (s, 3H),
1.40-2.00 (m, 4H), 1.49 (s, 3H), 1.47 (s, 3H), 1.28 (s, 3H). To a room
temperature mixture of CrCl2 (0.43 g, 3.5 mmol) in THF (4.5 mL)
was added dropwise a solution of the aldehyde 47a (19:1 mixture, 84
mg, 0.29 mmol) and CHI3 (0.46 g, 1.2 mmol) in THF (2 mL) in a
glovebox under nitrogen. After 16 h, ethyl acetate (5 mL) and H2O (5
mL) were added, and the resulting mixture was stirred for 20 min. The
aqueous phase was extracted with ethyl acetate (3 × 10 mL). The
organic layers were combined, washed with saturated aqueous NaCl
(5 mL), dried over MgSO4, filtered, and concentrated. Silica gel column
chromatography (hexanes/ethyl acetate, 93:7-90:10, v/v) of the residue
gave 5 and its cis-isomer in a 19:1 ratio (trans/cis), respectively, as a
colorless oil (88 mg, 0.21 mmol, 74%). Further purification by reverse-
phase HPLC (C-18, CH3CN-H2O, 96:4, v/v) afforded an analytical
Thyrsiferyl 18,23-Diacetate (1d). To a -78 °C solution of 49a (8
mg, 12 µmol) in THF (0.8 mL) was added methylmagnesium bromide
(47 µL of a 3 M solution in ether, 143 µmol). After the solution was
stirred at -78 °C for 5 h, saturated aqueous NH4Cl (3 mL) and ethyl
acetate (3 mL) were added. The mixture was allowed to warm to room
temperature, and the aqueous phase was extracted with ethyl acetate
(3 × 3 mL). The combined organic phase was washed with saturated
aqueous NaCl, dried over MgSO4, filtered, and concentrated. The
residue was purified by silica gel column chromatography (hexanes/
ethyl acetate/CHCl3, 75:20:5, v/v) to give 1d (7 mg, 10 µmol, 87%) as
a colorless oil. Further purification by reverse-phase HPLC (C-18,
CH3CN/H2O, 96:4, v/v) afforded an analytical sample: Rf 0.31 (hexanes/
1
ethyl acetate/CH2Cl2, 6.5:3:0.5, v/v); H NMR (CDCl3, 500 MHz) δ
sample: Rf 0.25 (hexanes/ethyl acetate, 9:1, v/v); [R]22 +21 (c 0.61,
4.90 (dd, J ) 4, 9.7 Hz, 1H), 4.03 (dd, J ) 5.5, 8.7 Hz, 1H), 3.90 (dd,
J ) 4, 12.2 Hz, 1H), 3.70 (dd, J ) 3, 12.7 Hz, 1H), 3.56 (dd, J ) 7.5,
11 Hz, 1H), 3.05 (dd, J ) 2.5, 11.5, 1H), 2.45 (bs, 1H), 2.25 (dddd, J
D
CHCl3); IR (neat) 2976, 2920, 1732, 1459, 1363, 1237; 1H NMR
(CDCl3, 300 MHz) δ 6.55 (dd, J ) 6.3, 14.6 Hz, 1H), 6.42 (dd, J )

9108 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
Gonza´lez and Forsyth
) 4, 13, 13, 13 Hz, 1H), 1.14-2.14 (m, 19 H), 2.08 (s, 3H), 1.98 (s,
3H), 1.46 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H), 1.27 (s, 3H), 1.21 (s, 3H),
1.20 (s, 3H), 1.16 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 170.83, 170.45, 86.51, 84.97, 84.39, 82.58, 78.32, 76.26, 75.86, 74.96,
74.36, 72.97, 71.89, 59.01, 38.56, 37.08, 34.25, 32.08, 31.01, 28.23,
26.47, 23.80, 23.68, 23.12, 22.98, 22.48, 22.40, 21.74, 21.41, 21.17,
21.08, 20.60, 20.04; HRMS (FAB) calcd for C34H58O979Br [M + H]+
689.3249, found 689.3231, calcd for C34H56O879Br [M - OH]+
671.3144, found 671.3148.
1.13 (s, 3H), 1.10 (s, 3H); HRMS (FI) found for C30H54O779Br [M +
H]+ 605.3097]. [Lit.63 1H NMR (CDCl3, 300 MHz) δ 3.89 (dd, J )
4.3, 12.2 Hz, 1H), 3.76 (dd, J ) 6.5, 9.3 Hz, 1H), 3.73 (dd, J ) 3.1,
12.3 Hz, 1H), 3.56 (dd, J ) 7.0, 11.3 Hz, 1H), 3.45 (dd, J ) 2.2, 9.8
Hz, 1H), 3.04 (dd, J ) 2.3, 9.6 Hz, 1H), 1.40 (s, 3H), 1.27 (s, 3H),
1.21 (s, 3H), 1.20 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H), 1.15 (s, 3H), 1.12
(s, 3H), 1.09 (s, 3H)].
Thyrsiferyl 18-Acetate (1c). To a room temperature solution of 1b
(1.2 mg, 2 µmol) in pyridine (80 µL, 1 mmol) was added acetic
anhydride (23 µL, 0.2 mmol). The mixture was stirred for 18 h before
it was concentrated. Silica gel column chromatography of the residue
gave 1c (0.8 mg, 1.3 µmol, 70%) as a colorless solid. Further
purification by reverse-phase HPLC (C-18, CH3CN/H2O, 96:4, v/v)
afforded an analytical sample: Rf 0.24 (chloroform/acetone, 9:1, v/v);
1H NMR (CDCl3, 500 MHz) δ 4.91 (dd, J ) 4, 9.5 Hz, 1H), 3.89 (dd,
J ) 4, 12.2 Hz, 1H), 3.69-3.73 (m, 2H), 3.56 (dd, J ) 7, 11 Hz, 1H),
3.66 (bs, 1H), 3.05 (dd, J ) 2, 12 Hz, 1H), 2.45 (bs, 1H), 2.25 (dddd,
J ) 4, 13, 13, 13 Hz, 1H), 1.20-2.14 (m, 19H), 2.08 (s, 3H), 1.40 (s,
3H), 1.27 (s, 3H), 1.20 (s, 9H), 1.16 (s, 3H), 1.19 (s, 3H), 1.09 (s, 3H);
HRMS (FAB) calcd for C32H56O879Br [M + H]+ 647.3144, found
647.3131, calcd for C32H54O779Br [M - OH]+ 629.3039, found
629.3096. Comparison spectra of synthetic 1c and 1c derived from
naturally occurring 1b are included in the Supporting Information.
Thyrsiferyl 23-Acetate (1a) and Thyrsiferol (1b). To a room
temperature solution of 1d (3.3 mg, 4.8 µmol) in methanol (360 µL)
was added K2CO3 (∼1.3 mg, 9.4 µmol). The mixture was stirred for
∼9 h before the pH was adjusted to ∼7 with a solution of acetic acid
in ethyl acetate. The resultant mixture was concentrated, and the residue
was purified by silica gel column chromatography (CHCl3/acetone, 95:
5-80:20, v/v) to obtain 1a (1.1 mg, 1.7 µmol, 35%) and 1b (1.2 mg,
2.0 µmol, 42%) as colorless oils. Further purification by reverse-phase
HPLC (C-18, CH3CN/H2O, 96:4, v/v) afforded analytical samples.
1
Data for 1a: Rf 0.26 (CHCl3/acetone, 9:1, v/v); H NMR (CDCl3,
500 MHz) δ 4.02 (dd, J ) 6.5, 9.5 Hz, 1H), 3.89 (dd, J ) 4, 12.2 Hz,
1H), 3.72 (dd, J ) 3, 13 Hz, 1H), 3.58 (dd, J ) 7.5, 11.2 Hz, 1H),
3.46 (dd, J ) 2, 10.5 Hz, 1H), 3.05 (dd, J ) 2.5, 12 Hz, 1H), 2.91 (bs,
1H), 2.81 (bs, 1H), 2.25 (dddd, J ) 4, 13, 13, 13 Hz, 1H), 1.34-2.10
(m, 19H), 2.00 (s, 3H), 1.49 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H), 1.27
(s, 3H), 1.20 (s, 3H), 1.19 (s, 3H), 1.17 (s, 3H), 1.10 (s, 3H); HRMS
(FAB) calcd for C32H56O879Br [M + H]+ 647.3144, found 647.3163,
calcd for C32H54O779Br [M - OH]+ 629.3039, found 629.3074. [Lit.14d
1H NMR (CDCl3, 400 MHz) δ 4.00 (dd, J ) 6.1, 9.5 Hz, 1H), 3.89
(dd, J ) 3.9, 12.2 Hz, 1H), 3.70 (dd, J ) 2.4, 12.7 Hz, 1H), 3.57 (dd,
J ) 7.6, 10.9 Hz, 1H), 3.45 (dd, J ) 2.0, 10.3 Hz, 1H), 3.04 (dd, J )
2.7, 11.5 Hz, 1H), 1.99 (s, 3H), 1.48 (s, 3H), 1.44 (s, 3H), 1.40 (s,
3H), 1.27 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H), 1.16 (s, 3H), 1.09 (s,
3H)].
Acknowledgment. We thank Prof. J. Blunt (University of
1
Canterbury) for generously providing a comparison H NMR
spectrum of 1c derived from naturally occurring 1b, and Dr. L.
Yao (NMR Lab, Department of Chemistry, University of
Minnesota) for assistance. We also gratefully acknowledge
postdoctoral fellowship support from the Ministerio de Educa-
cio´n y Cultura of Spain (I.C.G.) and thank Bristol-Myers Squibb
for a generous 1999 Unrestricted Grant in Synthetic Organic
Chemistry (C.J.F.).
1
Data for 1b. Rf 0.30 (CHCl3/acetone, 7:3, v/v); H NMR (CDCl3,
500 MHz) δ 3.90 (dd, J ) 4, 12.5 Hz, 1H), 3.76 (dd, J ) 6, 10 Hz,
1H), 3.72 (dd, J ) 3, 13 Hz, 1H), 3.57 (dd, J ) 7.5, 11 Hz, 1H), 3.46
(dd, J ) 2.5, 10.5 Hz, 1H), 3.05 (dd, J ) 2.5, 12 Hz, 1H), 2.96 (bs,
1H), 2.81 (bs, 1H), 2.25 (dddd, J ) 4, 13, 13, 13 Hz, 1H), 2.06-2.16
(m, 1H), 1.32-1.94 (m, 18H), 1.40 (s, 3H), 1.27 (s, 3H), 1.22 (s, 3H),
1.20 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H);
HRMS (FAB) calcd for C30H53O779BrNa [M + Na]+ 627.2811, found
627.2876, calcd for C30H54O779Br [M + H]+ 605.3039, found 605.3031.
[Lit.14d 1H NMR (CDCl3, 400 MHz) δ 3.89 (dd, J ) 3.9, 12.2 Hz,
1H), 3.76 (dd, J ) 6.3, 9.8 Hz, 1H), 3.72 (dd, J ) 2.9, 13.2 Hz, 1H),
3.57 (dd, J ) 7.3, 11.2 Hz, 1H), 3.46 (dd, J ) 2.0, 10.3 Hz, 1H), 3.05
(dd, J ) 2.4, 11.9 Hz, 1H), 2.25 (dq, J ) 3.4, 12.7 Hz, 1H), 1.40 (s,
3H), 1.27 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H), 1.16 (s, 3H),
Supporting Information Available: Experimental proce-
dures and characterization data for compounds 1a, 1b, 1c, 1d,
4, 5, 6, 6a, 7, 10, 11a, 11b, 12, 16, 17b, 23-28, 31-37, 40a,
40b, 41a, 41b, 42-49, and 49a; copies of 1H NMR spectra of
compounds 1a-d, 4-6, 6a, 7, 11a, 11b, 12, 16, 17b, 23-28,
31-37, 40a, 40b, 41a, 41b, 42-47, 47a, 48, 49, and 49a; NOE
data of compounds 12, 37, and 46; and an HMQC spectrum of
1a (PDF). This information is available free via the Internet at
http://pubs.acs.org.
JA000001R