Biomimetic enantioselective total synthesis of (-)-siccanin via the Pd-catalyzed asymmetric allylic alkylation (AAA) and sequential radical cyclizations

Article abstract of DOI:10.1021/ja048084p

(-)-Siccanin (1), a natural product possessing significant antifungal properties, was synthesized enantioselectively via a biomimetic route. This synthetic route features two sequential radical cyclizations: a Ti(III)-mediated radical cyclization of epoxy

Full text of DOI:10.1021/ja048084p

Published on Web 09/03/2004
Biomimetic Enantioselective Total Synthesis of (-)-Siccanin
via the Pd-Catalyzed Asymmetric Allylic Alkylation (AAA) and
Sequential Radical Cyclizations
Barry M. Trost,* Hong C. Shen, and Jean-Philippe Surivet
Contribution from the Department of Chemistry, Stanford UniVersity,
Stanford, California 94305-5080
Received April 2, 2004; E-mail: bmtrost@stanford.edu
Abstract: (-)-Siccanin (1), a natural product possessing significant antifungal properties, was synthesized
enantioselectively via a biomimetic route. This synthetic route features two sequential radical cyclizations:
a Ti(III)-mediated radical cyclization of epoxyolefin 48 to construct the B-ring, and a Suarez reaction to
establish the tetrahyrofuran ring. Chiral chroman moiety of siccanin was prepared based on our recent
development of the Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol trisubstituted allyl carbonates.
Several other members of the siccanin family were also synthesized including siccanochromenes A (2), B
(3), E (6), F (7), and the methyl ether of siccanochromene C (55). These studies may shed light on the
biosynthesis of this novel family of compounds.
1. Introduction
Siccanin (1) (Figure 1) is a mold metabolite first isolated from
the culture broth of Helminthosposium siccans by Ishibashi in
1962.1 The structure and absolute stereochemistry of siccanin
(1) were subsequently established by X-ray crystallographic
analysis of its p-bromosulfonate ester.2 As depicted, siccanin
(1) possesses an unusual cis, syn, cis-fused alicyclic ring system.
It can be regarded as derived from a cis-fused drimane
condensed with orcinol. This compound exhibits potent anti-
fungal activity, particularly against the pathogenic fungi Tri-
chophyton interdigitale and Trichophyton asteroids as well as
Epidermophyton and Mycosporum.3 Further studies have dem-
onstrated that siccanin shows a 50% growth inhibition of
Trichophyton menatgraphytes at a concentration of 0.3 µg/mL,
and that its biological activity is repression of respiration by
inhibition of succinate dehydrogenase.4 The clinical effectiveness
of siccanin against surface mycosis has also been established.5
After extensive scrutiny of the culture broth, siccano-
chromenes A-H (Figure 2), several congeners related to
siccanin, were also isolated by Hirai, et al.2 The drimanes are
an important terpenoid class whose members exhibit broad
biological activities including potent antifungal, antibacterial,
cytotoxic, insecticidal, etc.6
Figure 1. (-)-Siccanin (1).
The comparison of the structures of minor metabolites of H.
siccans, such as trans-γ-monocyclofarnesol, siccanochromene
A (2) and siccanochromene B (3) with siccanin (1) made it
possible to propose a biogenetic pathway leading to siccanin
(1). Experiments with both cell free and intact cell systems of
Helminthosporium siccans Drechsler have been used to support
this proposed biosynthetic pathway for the formation of siccanin,
which begins with farnesyl pyrophosphate 10 and consists of
at least six steps (Scheme 1).7
As depicted in Scheme 1, the biosynthesis is believed to
proceed by cyclization of trans,trans-farnesyl pyrophosphate
10 to trans-γ-monocyclofarnesyl pyrophoshate 11 (Step A)
which undergoes condensation with orsellinic acid 12 to yield
presiccanochromenic acid 13 (Step B). Oxidative cyclization
of presiccanochromenic acid forms siccanochromenic acid 14
(Step C) and the chromene functionality of siccanin. The
sequence then continues with decarboxylation to give siccano-
chromene A (2) (Step D). Epoxidation of the exocyclic
methylene group of siccanochromene A (2) provides siccano-
chromene B (3) (Step E). Epoxyolefin cyclization8 of siccano-
(1) Ishibashi, K. J. J. Antibiot. Ser. A. 1962, 15, 161-167.
(2) (a) Hirai, K.; Nozoe, S.; Tsuda, K.; Iitaka, Y.; Shirasawa, M. Tetrahedron
Lett. 1967, 8, 2177-2179. (b) Hirai, K.; Suzuki, K. T.; Nozoe, S.
Tetrahedron 1971, 27, 6057-6061. (c) Nozoe, S.; Suzuki, K. T. Tetrahe-
dron, 1971, 27, 6063-6071. (d) Nozoe, S.; Hirai, K.; Snatzke, F.; Snatzke,
G. Tetrahedron, 1974, 30, 2773-2776.
(3) Belloti, M. G.; Riviera, L. Chemioterapia 1985, 4, 431-433.
(4) Nose, K.; Endo, A. J. Bacteriology 1971, 105, 171-172.
(5) (a) Crippa, D.; Albanese, C. G.; Sala, G. P. G. Ital. Dermatol. Venereol.
1985, 120, LVII, and references therein. (b) Arai, M.; Ishibashi, K.; Okazaki,
H. Antimicrob. Agents Chemother. 1969, 9247-9252. c. Sugawara, S.
Antimicrob. Agents Chemother. 1969, 9253-9256.
(7) (a) Suzuki, K. T.; Nozoe, S. Bioorganic Chem. 1974, 3, 72-80. (b) Suzuki,
K. T.; Nozoe, S. J. Chem. Soc., Chem. Commun. 1971, 527-528.
(8) (a) Goldsmith, D. J.; Philips, C. F. J. Am. Chem. Soc. 1969, 91, 5862-
5870. (b) Goldsmith, D. J.; Clark, B. C. Tetrahedron Lett. 1967, 8, 1215-
1217.
(6) (a) Jansen, B. M. M.; de Groot, A. Nat. Prod. Rep. 1991, 8, 309-318. (b)
Jansen, B. M. M.; de Groot, A. Nat. Prod. Rep. 1991, 8, 319-337.
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A R T I C L E S
Trost et al.
Figure 2. Representative compounds of siccanochromene family.
Scheme 1. Proposed Biosynthesis of Sicannin (1)
chromene B (3) then completes the biosynthesic pathway to
afford siccanin (1) (Step F).
Herein we report the first biomimetic enantioselective total
synthesis of (-)-siccanin (1) via a highly convergent route,
featuring a Pd-catalyzed asymmetric allylic alkylation (AAA)
and two novel sequential stereoselective radical cyclizations.12
As a result of its biomimetic premise, the synthesis of siccano-
chromenes A, B, E, F, and the methyl ether of siccanochromene
C were also synthesized.
Due to its interesting biological activity, siccanin (1) has been
the subject of a number of synthetic efforts.9 Prior to this work,
two successful racemic total syntheses of this natural product
have been reported. The synthesis of siccanin (1) by the
Yoshikoshi group proceeded in a linear fashion,10 in which the
A, B, C, and D rings were introduced consecutively. The
highlight of our own previous racemic synthesis is the Pd-
catalyzed diyne reductive cycloisomerization to construct the
B-ring. 11
2. Enantioselective Total Synthesis of (-)-Siccanin
The retrosynthetic plan is illustrated in Scheme 2. The tetra-
hydrofuran ring and B-ring of siccanin (1) can presumably be
formed via an epoxyolefin cyclization reaction of siccanochro-
men B (3), the proposed biosynthetic precursor of siccanin (1).
Siccanochromen B (3) can be derived from 15, prepared from
the coupling of chiral sulfone 17 and chiral vinyl chroman 16a.
(9) (a) Nozoe, S.; Hirai, K. Tetrahedron 1971, 27, 6073-6081. (b) Oida, S.;
Ohashi, Y.; Yoshida, A.; Ohki, E. Chem. Pharm. Bull. 1972, 20, 2634-
2641. (c) Yoshida, A.; Oida, S.; Ohashi, Y.; Tamura, C.; Ohki, E. Chem.
Pharm. Bull. 1972, 20, 2642-2650. (d) Oida, S.; Ohashi, Y.; Ohki, E.
Chem. Pharm. Bull. 1973, 21, 528-537. (e) Liu, H.; Ramani, B.
Tetrahedron Lett. 1988, 29, 6721-6724. (f) Kato, M.; Matsuma, Y.; Heima,
K.; Yoshikoshi, A. Bull. Chem. Soc. Jpn 1988, 61, 1991-1998.
(10) (a) Kato, M.; Matsumura, Y.; Heima, K.; Fukamiya, N.; Kabuto, C.;
Yoshikoshi, A. Tetrahedron 1987, 43, 711-722. (b) Kato, M.; Heima, K.;
Matsumura, Y.; Yoshikoshi, A. J. Am. Chem. Soc. 1981, 103, 2434-2435.
(11) Trost, B. M.; Fleitz, F. J.; Watkins, W. J. J. Am. Chem. Soc. 1996, 118,
5146-5147.
(12) For the communication of this work, see: Trost, B. M.; Shen, H. C.; Surivet,
J. P. Angew. Chem., Int. Ed. 2003, 42, 3943-3947.
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Total Synthesis of (−)-Siccanin
A R T I C L E S
Scheme 2. Retrosynthetic Analysis of (-)-siccanin (1)
Scheme 3. Synthesis of Chiral Vinyl Chroman 16
Synthesis of Building Blocks. Chroman 16a is derived form
allyl carbonate 18 or 19 via a Pd-catalyzed asymmetric allylic
alkylation (AAA) reaction recently developed by our group.13
In the preceding paper, the syntheses and asymmetric cycliza-
tions of the Z and E allyl carbonates 18 and 19 (Scheme 3)
were described. The absolute configuration was established by
the phenylglycine methyl ester (PGME) derivative method
developed by Kusumi and Yabuuchi.14
tially oxidized sulfoxide, the later was resubjected to the oxi-
dation conditions to provide the desired sulfone in 98% overall
yield including the recycle. As shown in Scheme 5, chiral car-
boxylic acid 27, the precursor of pyridinyl sulfone 31, is avail-
able via a protocol developed by Kurth’s group.17 The Barton’s
decarboxylative rearrangement of O-acyl thiohydroxamate 2918
led to the formation of sulfide 30, which was further oxidized
to pyridinyl sulfone 31 following Charette’s procedure.19
Chiral alcohol 21 was readily available in large scale
following a literature protocol,15 which was then transformed
to the corresponding phenyl sulfide. The subsequent chemoselec-
tive oxidation by oxone gave phenyl sulfone 2216 (eq 1). To
test the modified Julia olefination, which could save steps com-
pared to the standard Julia reaction, phenyltetrazole sulfone 25
was prepared by the Mitsunobu reaction followed by oxidation,
as depicted in Scheme 4. Since the initial molybdenum catalyzed
oxidation gave a mixture of the fully oxidized sulfone and par-
Synthesis of Cyclization Substrates. Two strategies have
been examined for the C6-C7 bond formation in siccanin. To
(15) Tanimoto, H.; Oritani, T. Tetrahedron 1997, 53, 3527-3536.
(16) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287-1290.
(17) (a) Kurth, M. J.; Decker, O. H. W.; Hope, H.; Yanuck, M. D. J. Am. Chem.
Soc. 1985, 107, 443-448. (b) Kurth, M. J.; Soares, C. J. Tetrahedron Lett.
1987, 28, 1031-1034.
(13) Trost, B. M.; Shen, H. C.; Surivet, J.-P. J. Am. Chem. Soc. 2003, 125,
9276-9277.
(14) Yabuuchi, T.; Kusumi, T. J. Org. Chem. 2000, 65, 397-404.
9
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A R T I C L E S
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Scheme 4. Synthesis of Tetrazole Sulfone 25
Scheme 5. Synthesis of Pyridinyl Sulfone 31
Scheme 6. First Approach for the C6-C7 Bond Formation
reaction was very messy and the impurities were likely phenols
resulting from oxidation of the electron-rich aromatic ring of
34.
Observing no side reaction occurring with respect to the trans-
double bond, we envisioned that catalytic dihydroxylation might
avoid the undesired oxidation of the aromatic ring. It has been
widely demonstrated that the rate of the dihydroxylation of
isolated double bonds are much faster with trans-1,2-disubsti-
tuted and trisubstituted olefins than with cis-1,2-disubstituted
and terminal alkenes. On the other hand, steric effects may play
a decisive role in systems with electronically very similar double
bonds, and generally the sterically more accessible site is
osmylated preferentially.22 The chemo- and diastereoselective
dihydroxylation of diene 34 with AD-mix-â employing the
Sharpless protocol generated diol 36 with 10:1 diastereoselec-
tivity (eq 4). The NMR data showed that the terminal methylene
minimize chemoselectivity issues, the critical approach envi-
sioned an alkylation of a sulfone stabilized anion followed by
reductive desulfonylation. The electrophilic triflate 32 prepared
from reduction of aldehyde 16b followed by triflate formation,20
gave only low conversions to the alkylation product 33
presumably due to the neopentyl character of the electrophile
(Scheme 6).
To circumvent this problem, Julia olefination was utilized to
couple chiral sulfone 22 with chiral chroman aldehyde 16b.21
As shown in eq 2, reaction proceeded in high yield to form
diene 34. Unfortunately, the attempts for the modified Julia
olefination employing either 25 or 31 failed.
protons (δ 4.59 and 4.14 ppm as two singlets) present in
diene 34 have disappeared, and the two olefinic protons of
the 1,2-disubstituted double bond (d, 5.54 ppm and dd, 5.48
ppm) remained. The use of AD-mix-R gave similar results
in terms of yield and diastereoselectivity. The dihydroxyla-
tion protocol using osmium tetraoxide and NMO also gave
Epoxidation of diene 34 gave two diastereomers of epoxide
35 and oxidation products of the aromatic ring (eq 3). The
(18) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985, 41,
3901-3924.
(19) Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett. 2001, 42,
5149-5153.
(20) Surivet, J. P.; Vatele, J. M. Tetrahedron 1999, 55, 13 011-13 028.
(21) (a) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 14, 4833-4836. (b)
Kocienski, P. Phosphorus Sulfur 1985, 24, 97-127.
(22) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483-2547.
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Total Synthesis of (−)-Siccanin
A R T I C L E S
Scheme 7. Synthesis of Chromen Diol 38
Scheme 8. Demethylation of Chromen Methyl Ether
the desired diastereomer 36 with lower yield presumably
resulting from the dihydroxylation of the trans double bond as
a side reaction. Apparently, the less sterically hindered ter-
minal olefin is preferably dihydroxylated in the presence of a
1,2-disubstituted trans olefin which is adjacent to a quaternary
center. The chiral ligand is unnecessary for the diastereoselec-
tivity in the dihydroxylation reaction due to the substrate con-
trol, yet seems to be important to achieve a better chemoselec-
tivity. Presumably, the increased steric bulk of the ligand of
the osmium complex will favor the reaction to occur with the
sterically more accessible 1,1-disubstituted double bond. On
the basis of the lowest energy conformation of 34 calcu-
lated by MM2 (Chem 3D), presumably the osmium reagent
prefers to approach the 1,1-disubstituted olefin from the less
hindered bottom face to give diastereomer 36 (Figure 3). The
The hydrogenation of 36 smoothly afforded chroman diol 37,
which was oxidized by DDQ23 to generate chromen diol 38 in
91% yield (Scheme 7).
The subsequent demethylation of 38 was problematic. Typical
ethyl thiolate demethylation only led to degradation. By
protecting the diol as the acetonide, demethylation proceeded
smoothly to afford the corresponding phenol 41. However, under
the reaction conditions, a ring-opening and closure led to the
complete epimerization of the chromen moiety of phenol 41
(Scheme 8). This result suggests that the demethylation should
be executed prior to the oxidation of the chroman to the
chromen. As shown in Scheme 9, the acetonide chroman 42
was successfully demethylated to phenol 43a in good yield.
DDQ oxidation of chroman 43a as an unprotected phenol
only decomposed the starting material. Presumably, the phenol
Scheme 9. Synthesis of Chromen 44
Figure 3. Rationale for diastereoselectivity of dihydroxylation of 34.
top face is blocked by the chroman moiety as well as the axial
methyl group of the cyclohexane. The assigned stereochemistry
is later confirmed by the derivatization of 36 into siccano-
chromene B (3) and siccanin (1) over several steps. The
approximately 10:1 diastereomeric mixtures were inseparable
by flash chromatography and were carried on for the subse-
quent synthesis. Consequently, compounds 37-39, 47-48, and
3 were all accompanied by minor amounts of their diastereo-
mers. However, the stereochemical integrity of C-10 of these
intermediates was irrelevant to the synthesis of siccanin, due
to the nature of the epoxy-olefin radical cyclization as illustrated
later.
ring is oxidized by DDQ. The acetate derivative of 43a did not
react under the typical DDQ oxidation conditions, likely due
(23) (a) Starratt, A. N.; Stoesl, A. Can. J. Chem. 1977, 55, 2360-2362. (b)
Ahluwalia, V. K.; Jolly, R. S. Synthesis 1982, 74-75. (c) Buckle, D. R. In
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
Wiley: New York, 1995; Vol. 3, p 1699.
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A R T I C L E S
Trost et al.
to the electron withdrawing property of the acetate, thus
disfavoring the formation of the benzylic cation intermediate
initially generated. On the other hand, the TBS ether 43b was
smoothly oxidized to the desired chromen 44 in 84% yield. The
1H NMR spectrum of chromen 44 has two doublets at 6.61 and
5.46 ppm, both of which have a coupling constant of 10.0 Hz,
which corresponds to the two olefinic protons of the chromen
ring.
Tosylation of the primary alcohol of 45 was followed by
treatment with sodium hydride to give epoxide 47. Subsequent
desilylation yielded siccanochromene B (3), the proposed
biosynthetic precursor of siccanin (1) (Scheme 11). Similarly,
the methyl ether of chromen 38 was also converted to epoxide
48 over two steps in 93% yield (eq 6).
The subsequent deprotection of 44 using p-TsOH afforded
triol 7, known as siccanochromene F (7), in 15% yield and diol
45 in 60% yield (eq 5) after 3 recycles. By using a mixture of
water and methanol under reflux, p-TsOH removed both the
acetonide and TBDMS group to form siccanochromene F (7)
exclusively.
Biomimetic Cyclization and Completion. Now the synthesis
reached a pivotal point to test our biomimetic proposal. The
proposed cationic cyclization is shown in Scheme 12. A Lewis
acid will likely open epoxide 3 to generate a tertiary cation 49,
which is then trapped by an electron-rich olefin to form the
B-ring. The resulting oxygen nucleophile can undergo a Lewis
acid-promoted 1,4-addition to the pendant enone as in 50 to
construct the tetrahydrofuran ring. This novel proposal involves
one C-O bond cleavage, followed by a C-C and C-O bond
formation, to create the natural product in one step.
Scheme 12. Biomimetic Cationic Cyclization of Siccanochromene
B (3) to Form Sicannin (1)
In the natural product isolation paper2b, the authors reported
that siccanochromene F (7) existed as a mixture of two epimers
at the quaternary center C-10. They also described their diacetate
derivatives. Our recorded data for siccanochromene F (7) and
its diacetylated derivative (7′) matched those reported in the
literature for one epimeric series. Triol 7 underwent an oxidative
cleavage to afford ketone 46 (Scheme 10). It is known in the
Scheme 10. Synthesis of Siccanochromene A (2)
Scheme 13. Proposed Radical Cyclization of Siccanochromene B
Methyl Ether 48
literature that siccanochromene A (2) could be prepared from
46 by Wittig olefination.2b
Scheme 11. Synthesis of Siccanochromene B (3)
In the event, the treatment of siccanochromene B (3) or
siccanochromene B methyl ether 48 with a variety of Lewis
acids (BF3‚OEt, SnCl2, SnCl4, TiCl2(OiPr)2, Yb(OTf)3, FeCl3)
in various solvents (CH2Cl2, dioxanne, nitromethane) gave no
reaction, decomposition, or some evidence for aldehydes that
would arise by ring opening to an epoxide followed by hydride
shift.
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Total Synthesis of (−)-Siccanin
A R T I C L E S
Table 1. Ti-mediated Radical Cyclization of Epoxide 48a
a All reactions were performed in freshly distilled and degassed THF (THF has to be air and water free by distillation over sodium).
In contrast to cationic intermediate 49, tertiary radical 51
should not undergo the hydride shift or other cationic decom-
position pathways. Inspired by the work of RajanBabu and
Nugent,24 the opening of epoxide 48 may form tertiary radical
51 in the presence of Cp2Ti(III)Cl, and undergo a 6-exo-trig
cyclization to afford benzylic radical 52 (Scheme 13). The
stability of the benzylic radical potentially serves as a driving
force for the ring formation. Collapse to siccanin expels Ti(+3)
and the result is the reaction becomes catalytic in Ti(+3). At
this stage, 48 and its diastereomer were presumably both
converted to radical 51. The subsequent cyclization will then
establish the stereogenic center C-10.
Table 1 summarized the experimentations of the Ti-mediated
radical cyclization of epoxide 48. With 1 equiv of titanocene
dichloride and 2 equiv of manganese (entry 1), the reaction gave
about 40% yield of 53, with the desired stereochemistry, and
54, a pentacyclic compound, in 3:1 ratio. The pentacylic
compound is the methyl ether of 10-epi-siccanin. The rest of
the starting material was recovered. The addition of indium
trichloride led to no cyclization products (entry 2). Presumably,
the redox reaction between indium trichloride and Ti(III) and/
or manganese occurred. The addition of iodine was intended to
quench the benzylic radical 52, which could presumably lead
to a further cyclization. However, only 44% of tetracyclic
product 53 was obtained (entry 3) accompanied with trace
amount of 54 (∼5%) and decomposition. Gansa¨uer and co-
workers found that pyridinium chloride could protonate alkoxy
species to regenerate Ti(IV) species.25 Their reaction conditions
could potentially lead to a Ti-catalyzed radical cyclization of
epoxyolefin 48. However, under their conditions, only 10% yield
of tetracyclic product 53 was isolated with about 80% recovery
of the starting material (entry 4). The best result is shown in
entry 5. Using 3 equiv of titanocene and 6 equivalents of
manganese, the Ti(III)-mediated cyclization of 48 gave full
conversion of the starting material, to yield the tetracyclic
compound 53, accompanied with the methyl ether of 10-epi-
siccanin 54, in 3:1 ratio and 81% overall yield. Compared with
entry 1, the reason excessive amount of titanocene and
manganese is important for the completion of the reaction is
likely due to the Lewis basic sites present in the substrate, which
may coordinate with titanium or manganese species. Interest-
ingly, at elevated temperature or in the presence of iodine at
elevated temperature (entries 6 and 7), we observed no cycliza-
tion products. Instead, the elimination product allylic alcohol
55, which is the methyl ether of siccanochromene C (4), was
obtained in modest yield. It seems that temperature is a critical
factor in this reaction. Higher temperature favors the elimination
product 55, not the cyclization products, and low temperature
(0 °C) gave very slow reaction and low conversion (entry 8).
To understand the intriguing stereoselective formation of 53
and 54, a mechanism is proposed as shown in Scheme 14. The
green-colored Ti(III) species is generated by the reduction of
titanocene dichloride using manganese. The ring-opening of
epoxide 48 in the presence of Ti(III) species results in the
formation of tertiary radical 51, which then undergoes a 6-exo-
trig cyclization to form benzylic radical 56. The further reaction
(24) (a) RajanBabu, T. V.; Nugent, W. A.; Beattie, M. S. J. Am. Chem. Soc.
1990, 112, 6408-6409. (b) Gansa¨uer, A.; Pierobon, M.; Bluhm, H.
Synthesis, 2001, 2500-2520. (c) RajanBabu, T. V.; Nugent, W. A.; J. Am.
Chem. Soc. 1994, 116, 986-997. (d) Roy, S. C.; Rana, K. K.; Guin, C. J.
Org. Chem. 2002, 67, 3242-3248.
(25) Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998, 120,
12 849-12 859.
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Figure 4. Calculated energy for natural and 10-epi-tetracyclic/pentacyclic compounds.
Scheme 14. Proposed Mechanism for the Radical Cyclization
with another equivalent of Ti(III) species forms a C-Ti bond.
Subsequent hydrolysis leads to the formation of the desired
tetracyclic product 53. Alternatively, the diastereomeric benzylic
radical 58 can be formed. At this stage, it could be oxidized by
air during workup to give benzylic cation, which could then
react with the oxygen nucleophile intramolecularly to form the
tetrahydrofuran ring. However, carefully quenching the reaction
mixture under argon also gave the pentacyclic product in almost
the same yield, which indicates that the oxidation of benzylic
radical to cation is not the case. Another plausible mechanism
proposed that intermediate 59 could undergo a further tetrahy-
drofuran ring formation due to the proximity of the oxygen atom
with the benzylic carbon radical. Our original proposal is rather
bold and counterintuitive. It involves a homolytic cleavage of
a Ti-O bond, although it is well-known that Ti-O bond is
quite strong. This conceptually novel reaction can be deemed
as a homolytic substitution of Cp2TiCl radical with a benzylic
radical. Coincidentally, in a similar scenario reported very re-
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Total Synthesis of (−)-Siccanin
A R T I C L E S
Scheme 15. Formation of Tetrahydrofuran Ring in Pentacyclic Compound 60
Scheme 16. Proposed Mechanism for the Formation of 69-71
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A R T I C L E S
Trost et al.
cently by Gansa¨uer,26 the counterintuitive cleavage of a strong
Ti-O bond was justified both by experiments and DFT calcula-
tion. It is very likely that the transformation from 58 to 54 is
exothermic given that the Cp2TiCl species may still bind to
oxygen of the tetrahydro furan ring.
To understand why intermediate 58 is more prone to a further
cyclization than its diastereomer 56, we performed PM3 calcula-
tions in Spartan 2002 (Figure 4). The results show that the
energy difference between tetracyclic compound 53 and penta-
cyclic compound 60 is 16.1 kcal/mol, which is 5 kcal/mol higher
than the energy difference between 61 and 54. This calculation
suggests that it is much easier for intermediate 58 to cyclize
than 56.
The demethylation of 53 yielded diol 62 (eq 7), whose proton
NMR data matches siccanochroman diol, a known derivative
of siccanin (1),2b and therefore ensures our assignment of stereo-
chemistry of 53.
The availability of siccanin may also provide an access to
siccanochromene E (6) by a selective cleavage of the benzylic
C-O bond and a subsequent elimination. The attempt to convert
(-)-siccanin (1) to siccanochromene E (6) in one step by the
treatment of boron trifluoride etherate in dichloromethane, or 1
equivalent of BSA and catalytic amount of TMSOTf only
returned starting material. The treatment with excess BSA and
2 equiv of TMSOTf overnight only led to decomposition.
The end game of the synthesis is to form the tetrahydrofuran
ring of siccanin. The attempted cyclization of 53 to 60 by the
treatment with DDQ failed with the full recovery of starting
material, likely due to the steric hindrance of the benzylic
hydrogen atom. This strategy assumed that benzylic cation
generated in situ could be trapped by the alcohol nucleophile
to form the tetrahydrofuran ring.
Despite the failure of the reaction of (-)-siccanin with boron
trifluoride etherate in dichloromethane, the treatment of (-)-
siccanin with acetic anhydride and boron trifluoride etherate at
-78 °C, following a protocol developed by Hirai2b, gave three
separable products, siccanochromene E diacetate 69, triacetate
70 and monoacetate 71 (eq 10). The assignment of stereochem-
istry of the benzylic acetate 69 and the benzylic alcohol 71 was
based on the observation that the benzylic proton in the NMR
spectra of both compounds was a singlet. The computational
modeling (Spartan 2003, PM3) shows that the dihedral angle
H-C9-C11-H in the R-acetate is 94°, which is much closer to
90°, than the â-acetate with the corresponding dihedral angle
around -51°. Furthermore, 70 (-289.6 kcal/mol) is consider-
ably more stable than the corresponding â-acetate (-280.0 kcal/
mol). Therefore, 70 and 71 should most likely bear R-benzylic
acetate and hydroxyl group, respectively.
Successful realization of formation of the tetrahydrofuran ring
of siccanin employed a free-radical remote functionalization via
a Barton type reaction under the Suarez conditions.27 As shown
in Scheme 15, the use of iodobenzene diacetate generates
oxygen radical 63, which can abstract a benzylic hydrogen atom
to form benzylic radical 64. This radical is quenched by iodine
to form benzyl iodide 65. The electron-rich aromatic ring may
then promote the elimination of benzyl iodide to generate
oxonium 66, which is subsequently attacked by the pendant
oxygen nucleophile to form the tetrahydrofuran ring of 60.
Intuitively, the oxygen nucleophile should approach the benzylic
carbon in 66 from the top face to form 11-epi-siccanin methyl
ether 67. However, PM3 calculations in Spartan 2002 showed
that the natural siccanin methyl ether 60 is 16.5 kcal/mol more
stable than 11-epi-siccanin methyl ether 67. Presumably, the
energy of the transition states that lead to 60 or 67 should reflect
the strain energy of the product. Hence, the formation of the
product with significantly lower energy is preferred. Consistent
with these calculations is an examination of a model of 66 which
reveals that the all cis-fused ring junction only allows the
hydroxyl nucleophile to attack from the bottom face to form
the desired pentacyclic compound 60. Finally, the pentacyclic
compounds 60 and 54 were demethylated to afford (-)-siccanin
1 (eq 8) and (-)-10-epi-siccanin 68 (eq 9) to constitute the first
enantioselective total syntheses.
(26) Gansa¨uer, A.; Rinker, B.; Pierobon, M.; Gimme, S.; Gerenkamp, M.; Mu¨ck-
Lichtenfeld, C. Angew. Chem., Int. Ed. 2003, 42, 3687-3690.
(27) Concepcion, J. T.; Francisco, C. G.; Hernandez, R.; Salaza, J. A.; Suarez,
E. Tetrahedron Lett. 1984, 25, 1953-1956.
9
12574 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004

Total Synthesis of (−)-Siccanin
A R T I C L E S
Scheme 17. Synthesis of Siccanochromene E (6)
(R)-5-Methoxy-2,7-dimethyl-chroman-2-carboxyaldehyde (16b):
To a solution of (R)-5-methoxy-2.7-dimethyl-2-vinyl-chroman 16a (0.20
g, 0.92 mmol) in 3.5 mL of dichloromethane was added N-methyl-
morphonline-N-oxide (0.3 g, 2.56 mmol) and aqueous osmium tetra-
oxide (0.27 mL, 4% in water, 0.043 mmol). The solution was stirred
for 5 h at room temperature and diluted with water (10 mL) and
dichloromethane (20 mL). The organic layer was dried over magnesium
sulfate and evaporated to dryness. The residue was chromatographed
with 1:1 to 1:5 of petroleum ether in diethyl ether. The resulting brown
oil (contaminated with osmium residue) was resuspended in acetone
(4 mL) and a solution of sodium periodate (0.4 g, 1.87 mmol) in water
(1 mL) was added. After a white precipitate was formed the reaction
mixture was stirred at room temperature for additional 20 min. The
mixture was filtered through a pad of diatomaceous earth and the filtrate
was partitioned between water (5 mL) and dichloromethane (10 mL).
The aqueous layer was extracted with dichloromethane (2 × 10 mL).
The combined organic extracts were washed with brine (20 mL) and
dried over magnesium sulfate. The residue was separated by flash
chromatography eluting with 5% to 25% diethyl ether in petroleum
ether to afford aldehyde 16b as a colorless oil (0.19 g, 0.86 mmol,
94%).
As shown in Scheme 16, the benzylic C-O bond is
presumably selectively cleaved by the Lewis acid. The resulting
benzylic cation can either be trapped with acetic anhydride, or
undergo an E1 type of elimination, with the simultaneous
esterification of phenol and primary alcohol to afford 70 and
69, respectively. It is interesting to observe the formation of
monoacetate 71, which implies the formation of intermediate
72, followed by the trapping with acetic anhydride to form ortho
ester 74. The subsequent hydrolysis upon aqueous workup leads
to 71. The treatment of monoacetate 71 with acetic anhydride
and pyridine gave triacetate 70 in quantitative yield.
[R]D ) +16.3 (c 0.47, Et2O); IR (film): 2935, 1738, 1619, 1587,
1463, 1146, 1113 cm-1; 1H NMR (300 MHz, CDCl3): δ 9.65 (s, 1H),
6.44 (s, 1H), 6.27 (s, 1H), 3.78 (s, 3H), 2.64 (td, J ) 6.4, 17.3 Hz,
1H), 2.47 (ddd, J ) 6.6, 9.2, 16.1 Hz, 1H), 2.30 (s, 3H), 2.22 (m, 1H),
1.77 (ddd, J ) 6.6, 9.5, 15.8 Hz, 1H), 1.40 (s, 3H); 13C NMR (75
MHz, CDCl3): δ 203.5, 157.5, 153.5, 137.4, 110.0, 107.1, 103.4, 80.0,
55.3, 27.2, 21.5, 21.2, 16.1. HRMS: Calc’d for C13H16O3: 220.1099.
Found: 220.1093.
Diacetate 69 could be reduced by DIBAL-H to afford (-)-
siccanochromene E (6) (Scheme 17). The spectroscopic data
(1H NMR, IR, MS, mp, and optical rotation) are all in agreement
with the data disclosed by the isolation paper.2b Conversion of
triacetate 70 to siccanochromene E with base either DBU or
lithium trifluoroethoxide failed. The use of boron trifluoride
etherate, successfully triggered the elimination of benzyl acetate,
followed by a DIBAL-H reduction to give cleanly the desired
product, siccanochromene E (6), in 82% yield over two steps.
Therefore, all three products from siccanin, 69, 70, and 71, were
directly or indirectly converted to siccanonchromene E (6).
(1S)-(2,2-Dimethyl-6-methylene cyclohexylmethanesulfonyl)-
benzene (22): To a solution of alcohol 21 (230 mg, 1.49 mmol) in
THF (5 mL) were added triphenylphosphine (470 mg, 1.79 mmol) and
benzenethiol (197 mg, 0.18 mL, 1.79 mmol). To this solution at 0 °C
was added diisopropylazodicarboxylate (362 mg, 0.35 mL, 1.79 mmol).
The resulting yellow solution was warmed to room temperature and
stirred for 5h. The solution was concentrated in vacuo and the residue
was purified by flash chromatography eluting with 5% to 10% diethyl
ether in petroleum ether to afford sulfide as a colorless oil (369 mg,
1.50 mmol). The sulfide was dissolved in 5 mL of methanol. To this
solution was added a solution of oxone (0.7 g) in 5 mL of water at 0
°C, and the solution was stirred at room temperature overnight. The
mixture was then filtered through diatomaceous earth and washed with
diethyl ether. The filtrate was concentrated in vacuo. The residue was
diluted with 20 mL of dichloromethane and the aqueous layer was
extracted with dichloromethane (2 × 20 mL). The combined organic
extracts were dried over magnesium sulfate. After concentration under
reduced pressure, the residue was purified on silica gel eluting with
diethyl ether in petroleum ether (5%-10%) to afford sulfone 22 (369
mg, 1.33 mmol, 89%) as a colorless oil.
Experimental Section
(R)-5-Methoxy-2,7-dimethyl-2-vinyl-chroman (16a): To a solution
of Z-3-methyl-5′-(6′-hydroxy-2′-methoxyphenyl)-2-pentene (1.15 g, 4.92
mmol) in dichloromethane (20 mL) was added pyridine (1.23 mL, 15.2
mmol). The solution was cooled to 0 °C. To this solution was added
dropwise methyl chloroformate (0.45 mL, 5.81 mmol). After 15 min,
water (20 mL) and ethyl acetate (200 mL) were added. The organic
layer was washed with a saturated solution of CuSO4 (3 × 50 mL),
water (50 mL) and brine (50 mL). The organic layer was dried over
magnesium sulfate and concentrated to dryness to afford Z-carbonate
18 (1.45 g, 4.92 mmol, 100%). To a degassed mixture of Pd2(dba)3‚
CHCl3 (0.100 g, 0.1 mmol) and chiral ligand ent-20 (S, S) (0.200 g,
0.3 mmol), was added dichloromethane (20 mL). The solution was
stirred for 10 min, then acetic acid (0.210 mL, 5.57 mmol) was added.
After 5 min, a solution of Z-carbonate 18 (1.45 g, 4.92 mmol) in
dichloromethane (4 mL + 1 mL rinse) was added. The reaction mixture
was stirred at room temperature for 1h. The volatiles were removed
under reduced pressure and the residue was purified directly over silica
gel eluting with 1:11 of diethyl ether in petroleum ether to afford (R)-
5-methoxy-2.7-dimethyl-2-vinylchroman 16a (0.852 g, 3.90 mmol,
79%) as a colorless oil.
[R] ) +54.0 (c 2.18, CHCl3), 97% ee; IR (neat): 2936, 1618, 1586,
1139 cm-1; 1H NMR (300 MHz, CDCl3): δ 6.40 (s, 1H), 6.25 (s, 1H),
5.85 (dd, J ) 10.7, 17.3 Hz, 1H), 5.20 (dd, J ) 1.2, 17.3 Hz, 1H),
5.07 (dd, J ) 1.2, 10.7 Hz, 1H), 3.81 (s, 3H), 2.68 (td, J ) 5.6, 16.8
Hz, 1H), 2.47 (ddd, J ) 6.1, 9.8, 16.8 Hz, 1H), 2.31 (s, 3H), 1.93 (dd,
J ) 4.8, 5.8, 13.4 Hz, 1H), 1.79 (ddd, J ) 5.6, 9.8, 13.4 Hz, 1H), 1.43
(s, 3H); 13C NMR (75 MHz, CDCl3): δ 157.4, 154.3, 141.3, 136.9,
113.6, 110.0, 107.2, 102.6,76.1, 55.2, 31.0, 26.7, 21.6, 16.7. HRMS:
Calc’d for C14H18O2 [M+]: 218.1307. Found: 218.1303. Chromato-
graphic separation (GC, Cyclosil B): T oven ) 160 °C, tR (S, minor)
) 18.5 min, tR (R, major) ) 18.9 min.
[R]D ) +10.1 (c 1.06, CHCl3); IR (neat): 3069, 2934, 1470, 1447,
1
1306, 1140 cm-1; H NMR (500 MHz, CDCl3) δ: 7.88 (dd, J ) 1.2,
8.3 Hz, 2H), 7.63 (tt, J ) 1.2, 7.3 Hz, 1H), 7.53 (tdd, J ) 1.2, 7.3, 8.3
Hz, 2H), 4.74 (s, 1H), 4.56 (s, 1H), 3.36 (dd, J ) 9.2, 14.9 Hz, 1H),
3.24 (dd, J ) 2.2, 14.9 Hz, 1H), 2.44 (dd, J ) 2.2, 9.2 Hz, 1H), 1.99
(m, 2H), 1.49 (m, 2H), 1.30 (m, 2H), 0.89 (s, 3H), 0.78 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ: 145.4, 139.8, 133.3, 128.9, 128.0, 110.8,
54.3, 47.6, 37.0, 35.2, 32.8, 27.7, 24.8, 23.1. HRMS: Calc’d for
C16H23O2S [M + H+]: 279.1418. Found: 279.1414.
(1S)-2-[2-(2,2-Dimethyl-6-methylene-cyclohexyl)-vinyl]-(2R)-5-
methoxy-2,7-dimeth-yl-chroman (34): To a solution of phenyl sulfone
22 (0.880 g, 3.16 mmol) in THF (13 mL) was added at -78 °C
n-butyllthium (1.4 mL, 3.16 mmol, 2.25 M in hexanes, freshly titrated
with N-benzylbenzamide). The pale yellow solution was stirred at -78
°C for 40 min. To this solution was added a solution of aldehyde 16b
(0.536 g, 2.43 mmol) in THF (5 mL + 2 mL rinse). The reaction was
stirred for 2 h at -78 °C and warmed gradually to room temperature
9
J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12575

A R T I C L E S
Trost et al.
over 1 h. At this point, water (10 mL) was added. The aqueous layer
was extracted with diethyl ether (3 × 50 mL). The combined organic
extracts were washed with brine (50 mL) and dried over magnesium
sulfate. After concentration under reduced pressure, the residue was
chromatographed eluting with 20% diethyl ether in petroleum ether to
afford intermediate sulfone secondary alcohol. This material was taken
up in THF (18 mL), and 1,10-phenantroline (a few seeds) was added.
The mixture was cooled to -78 °C, and n-butyllithium (2.25 N in
hexanes) was added until an intense brown color appeared. At this point,
a few more drops were added, and the solution was stirred for 10 min.
Acetic anhydride (2 mL) was added dropwise, and the reaction mixture
turned yellow. The reaction was stirred 10 h at room temperature,
diluted with water (10 mL) and diethyl ether (20 mL). The aqueous
layer was then extracted with dichloromethane (3 × 30 mL). The
combined organic layers were washed with brine (30 mL) and dried
over magnesium sulfate. After evaporation to dryness, the residue was
diluted in methanol (30 mL) and sodium phosphate dibasic Na2HPO4
(3 g, 21.1 mmol) were added. The reaction was cooled to 0 °C, and to
the reaction mixture was added the freshly prepared sodium amalgam
(5 g, 13 mmol) in one portion. The reaction was stirred at 0 °C for 30
min, and more sodium amalgan was added (3 g, 8 mmol). After 20
min, the reaction mixture was filtered through a pad of diatomaceous
earth washing with diethyl ether. The remaining amalgam was destroyed
with 2N of HCl, and disposed in an appropriate way. The filtrate was
evaporated under reduced pressure and diluted with 1N HCl (10 mL),
water (20 mL) and dichloromethane (30 mL). The aqueous laayer was
extracted with dichloromethane (3 × 30 mL), and the combined organic
layer were washed with brine (50 mL) and dried over magnesium
sulfate. After concentration in vacuo, the residue was purified on silica
gel eluting with 10% diethyl ether in petroleum ether to afford 1,4-
diene 34 (0.775 g, 2.27 mmol) as a colorless oil.
21.6, 18.5, 17.2; HMRS: Calc’d for C23H34O4 [M+]: 374.2457.
Found: 374.2454.
(1S,2S)-1-Hydroxymethyl-2-[(2S)-2-(5-methoxy-2,7-dimethyl-chro-
man-2-yl)-ethyl]-3,3-dimethyl-cyclohexanol (37): A solution of diol
36 (0.5 g, 1.33 mmol) and platinum oxide (0.06 g, 0.266 mmol) in
ethyl acetate (HPLC grade, 15 mL) was purged thoroughly with argon
and the mixture was heated to 70 °C. The reaction flask was then purged
with hydrogen (balloon), and the reaction was stirred under H2
atmosphere at 70 °C for 5 h. The reaction flask was then purged with
argon, and the reaction mixture was filtered through a pad of silica gel
washing with ethyl acetate. The filtrate was concentrated in vacuo, and
the residue was purified over silica gel (1/1 to 3/1 diethyl ether in
petroleum ether) to afford 37 (0.415 g, 1.10 mmol) as a colorless oil
containing an inseparable mixture of two diastereomers and starting
material 36 (0.042 g, 0.112 mmol).
1
IR (neat): 3426, 2934, 16117, 1585, 1462, 1109 cm-1; H NMR
(500 MHz, CDCl3) δ: 6.32 (s, 1H), 6.25 (s, 1H), 3.82 (s, 3H), 3.63
(dd, J ) 6.6, 10.5 Hz, 1H), 3.58 (d, J ) 10.5 Hz, 1H), 2.66 (td, J )
6.1, 17.3 Hz, 1H), 2.59 (td, J ) 6.9, 17.3 Hz, 1H), 2.49 (s, 1H), 2.45
(m, 1H), 2.30 (s, 3H), 2.04 (m, 1H), 1.91-1.56 (m, 6H), 1.49-1.38
(m, 3H), 1.31 (app t, J ) 4.4 Hz, 1H), 1.28 (s, 3H), 1.22 (m, 1H), 1.15
(td, J ) 3.4, 12.9 Hz, 1H), 1.00 (s, 3H), 0.80 (s, 3H); 13C NMR (125
MHz, CDCl3) δ: 157.5, 154.0, 136.9, 110.2, 107.1, 102.5, 76.2, 75.6,
63.5, 55.7, 55.2, 42.5, 40.5, 35.7, 35.3, 32.3, 30.4, 23.2, 22.8, 21.5,
19.6, 19.0, 16.4. HMRS: Calc’d for C23H36O4 [M+]: 376.2613.
Found: 376.2607.
(1S,2S)-1-Hydroxymethyl-2-[(2S)-2-(5-methoxy-2,7-dimethyl-2H-
chromen-2-yl)-ethyl]-3,3-dimethyl-cyclohexanol (38): To a solution
of diol 37 (0.243 g, 0.645 mmol) in benzene (20 mL) was added DDQ
(0.250 g, 1.1 mmol). The solution was heated at 80 °C for 45 min and
then cooled to room temperature. The reaction mixture was filtered
through a pad of silica washing with diethyl ether, and thoroughly
washed with diethyl ether. The filtrate was concentrated in vacuo, and
the residue was chromatographed eluting with 1/1 to 3/1 diethyl ether
in petroleum ether to afford chromene 38 (0.220 g, 0.587 mmol) as a
sticky pale yellow oil.
IR (neat): 3418, 2932, 1614, 1573, 1463, 1115 cm-1; 1H NMR (500
MHz, CDCl3) δ: 6.67 (d, J ) 10.0 Hz, 1H), 6.30 (s, 1H), 6.24 (s, 1H),
5.49 (d, J ) 10.0 Hz, 1H), 3.81 (s, 3H), 3.63 (d, J ) 10.7 Hz, 1H),
3.56 (d, J ) 10.7 Hz, 1H), 2.29 (s, 3H), 2.27 (br s, 1H), 2.17 (br s,
1H), 2.04 (br d, J ) 12.9 Hz, 1H), 1.90 (ddd, J ) 5.4, 11.7, 13.9 Hz,
1H), 1.81 (ddd, J ) 5.4, 11.4, 13.9 Hz, 1H), 1.58 (m, 2H), 1.50-1.38
(m, 3H), 1.36 (s, 3H), 1.30 (t, J ) 4.7 Hz, 1H), 1.22 (td, J ) 3.4, 12.9
Hz, 1H), 1.13 (td, J ) 3.2, 12.9 Hz, 1H), 0.98 (s, 3H), 0.76 (s, 3H);
13C NMR (125 MHz, CDCl3) δ: 155.0, 153.5, 139.3, 126.9, 117.2,
109.7, 107.8, 103.8, 78.6, 75.7, 63.4, 55.6, 55.5, 43.7, 40.6, 36.0, 35.4,
32.3, 26.0, 22.7, 21.9, 19.9, 19.6. HMRS: Calc’d for C23H34O4 [M+]:
374.2457. Found: 374.2458.
(3S,4S)-2-[2-(5,5-Dimethyl-1-oxa-spiro[2.5]oct-4-yl)-ethyl]-(2S)-
5-methoxy-2,7-dimeth-yl-2H-chroman (48): To a solution of diol 38
(0.220 g, 0.588 mmol) in 5 mL of dichloromethane was added
successively at room temperature triethylamine (0.170 mL, 1.21 mmol),
DMAP (0.15 g, 1.22 mmol) and p-TsCl(0.168 g, 0.88 mmol). The
reaction was stirred at room temperature for 3 h. Without workup, the
mixture was directly purified by preparative TLC (first eluting with
diethyl ether in petroleum ether (1:1), second elution if necessary using
diethyl ether in petroleum ether (2:1)) to afford pure tosylate (0.277 g,
0.524 mmol). The material was dissolved in THF (10 mL) and DMSO
(15 drops). Sodium hydride (excess) was added, and the reaction
mixture was stirred at room temperature for 10 min. The mixture was
directly filtered through a pad of silica gel washing with diethyl ether.
The filtrate was concentracted in vacuo, and the oil material was purified
on silica gel eluting with diethyl ether in petroleum ether (1/9 to 2/3)
to afford epoxide 48 (0.195 g, 0.546 mmol, 93%) as a colorless oil.
IR (neat): 2937, 1614, 1573, 1463, 1119 cm-1; 1H NMR (500 MHz,
CDCl3): δ 6.67 (d, J ) 10.0 Hz, 1H), 6.29 (s, 1H), 6.24 (s, 1H), 5.45
[R]D ) +14.8 (c 1.08, CDCl3); IR (neat): 3076, 2928, 1619, 1586,
1
1352, 1112 cm-1; H NMR (500 MHz, CDCl3) δ: 6.37 (s, 1H), 6.23
(s, 1H), 5.67 (dd, J ) 9.8, 15.6 Hz, 1H), 5.47 (d, J ) 15.6 Hz, 1H),
4.57 (s, 1H), 4.14 (s, 1H), 3.78 (s, 3H), 2.63 (td, J ) 5.3, 16.8 Hz,
1H), 2.45 (ddd, J ) 6.3, 10.2, 16.6 Hz, 1H), 2.35 (d, J ) 9.8 Hz, 1H),
2.29 (s, 3H), 2.19 (td, J ) 4.6, 13.4 Hz, 1H), 1.98-1.88 (m, 2H), 1.78
(ddd, J ) 5.8, 10.0, 13.4 Hz, 1H), 1.58-1.46 (m, 2H), 1.44 (s, 3H),
1.42 (m, 1H), 1.29 (m, 1H), 0.87 (s, 3H), 0.78 (s, 3H); 13C NMR (125
MHz, CDCl3) δ: 157.5, 154.4, 150.0, 136.8, 135.0, 128.3, 110.1, 108.1,
107.5, 102.6, 76.0, 56.9, 55.3, 39.8, 35.2, 35.0, 32.0, 29.7, 27.2, 23.3,
22.2, 21.6, 17.0. HMRS: Calc’d for C23H32O2 [M+]: 340.2402.
Found: 340.2402.
(1S,2S)-1-Hydroxymethyl-2-[(2R)-2-(5-methoxy-2,7-dimethyl-
chroman-2-yl)-vinyl]-3,3-dimethyl-cyclohexanol (36): To a solution
of 1,4-diene 34 (0.5 g, 1.4 mmol) in tert-butyl alcohol (7 mL) was
added water (7 mL), AD-mix â (3.5 g) and methanesulfonamide (0.3
g, 3.15 mmol). After 5 min, the solution turned clear, and the reaction
was stirred under vigorous stirring for 20 h. Sodium metabisulfite (4
g) was added carefully. After the reaction mixture was stirred for 10
min, to this mixture was added water (10 mL) and diethyl ether (20
mL). The aqueous phase was extracted with dichloromethane (3 × 30
mL). The combined organic extracts were dried over magnesium sulfate.
After concentration in vacuo, the residue was chromatographed eluting
with a mixture of diethyl ether and petroleum ether (3:2) to afford diol
36 (0.494 g, 1.31 mmol) as a sticky slightly brown oil.
[R]D ) +38.5 (c 1.08, CDCl3); IR (neat): 3440, 2932, 1618, 1585,
1
1462, 1113 cm-1; H NMR (500 MHz, CDCl3) δ: 6.37 (s, 1H), 6.24
(s, 1H), 5.54 (d, J ) 15.4 Hz, 1H), 5.48 (dd, J ) 10.2, 15.4 Hz, 1H),
3.79 (s, 3H), 3.11 (m, 1H), 2.81 (d, J ) 11.3 Hz, 1H), 2.68 (ddd, J )
3.4, 5.8, 17.3 Hz, 1H), 2.39 (ddd, J ) 6.6, 11.0, 17.5 Hz, 1H), 2.30 (s,
3H), 1.91 (ddd, J ) 3.1, 6.3, 13.4 Hz, 1H), 1.86 (m, 1H), 1.79 (ddd,
J ) 5.8, 11.0, 13.4 Hz, 1H), 1.64 (m, 2H), 1.56 (m, 1H), 1.45 (s, 3H),
1.40 (m, 1H), 1.22 (m, 4H), 1.01 (m, 3H), 0.79 (s, 3H); 13C NMR (125
MHz, CDCl3) δ: 157.6, 154.4, 137.3, 136.5, 127.6, 110.0, 107.3, 102.8,
75.9, 73.9, 66.9, 58.0, 55.4, 38.2, 33.4, 31.9, 31.7, 31.1, 30.2, 27.6,
9
12576 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004

Total Synthesis of (−)-Siccanin
A R T I C L E S
(d, J ) 10.0 Hz, 1H), 3.82 (s, 3H), 2.63 (d, J ) 4.7 Hz, 1H), 2.49 (dd,
J ) 1.2, 4.6 Hz, 1H), 2.29 (s, 3H), 1.78-1.56 (m, 6H), 1.46 (m, 1H),
1.34 (s, 3H), 1.34 (m, overlapped, 1H), 1.24 (m, 2H), 1.09 (m, 1H),
1.01 (s, 3H), 0.84 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 155.7,
154.4, 140.1, 127.3, 118.1, 110.6, 108.5, 104.5, 79.0, 60.0, 55.5, 51.3,
50.2, 41.4, 36.9, 35.7, 31.9, 30.3, 28.8, 26.3, 22.0, 21.0, 20.6. HRMS:
Calc’d for C23H32O3: 356.2351. Found: 356.2360.
IR (neat): 2934, 1615, 1574, 1455, 1417, 1367, 1252 cm-1; 1H NMR
(500 MHz, CDCl3) δ: 6.28 (s, 1H), 6.17 (s, 1H), 3.83 (d, J ) 8.3 Hz,
1H), 3.71 (d, J ) 8.3 Hz, 1H), 2.66 (td, J ) 6.1, 17.1 Hz, 1H), 2.58
(td, J ) 8.5, 17.1 Hz, 1H), 2.22 (s, 3H), 1.96 (m, 2H); 1.84 (td, J )
7.6, 13.4 Hz, 1H), 1.73 (td, J ) 6.4, 13.4 Hz, 1H), 1.60 (m, 3H), 1.48-
1.26 (m, 3H), 1.43 (s, 3H), 1.29 (s, 6H), 1.04 (s, 9H), 1.01 (s, 3H),
0.74 (s, 3H), 0.25 (s, 3H), 0.24 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ: 154.7, 153.6, 136.5, 110.6, 1110.3, 109.6, 106.9, 85.3, 75.6, 68.4,
53.1, 43.2, 38.1, 35.9, 31.3, 30.4, 28.68, 28.63, 26.8, 26.6, 25.7, 23.8,
21.2, 20.3, 19.7, 18.1, 17.4, -4.1, -4.2. HRMS: Calc’d for C31H52O4-
Si: 516.3635. Found: 516.3637.
tert-Butyl-{(2S)-2,7-dimethyl-2-[(5S,6S)-2-(2,2,7,7-tetramethyl-
1,3-dioxa-spiro[4.5] dec-6-yl)-ethyl]-2H-chromen-5-yloxy}-dimeth-
ylsilane (44): To a solution of chromane 43c (0.5 g, 0.967 mmol) in
benzene (55 mL) was added at 80 °C in one portion DDQ (0.55 g,
2.42 mmol). The mixture was refluxed for 8 h. Without workup, the
reaction mixture was directly purified by chromatography over silica
gel eluting with 1/8 diethyl ether in petroleum ether to afford chromene
44 (0.42 g, 0.815 mmol) as a colorless oil.
(2S)-5-Methoxy-2,7-dimethyl-2-[(5S,6S)-2-(2,2,7,7-tetramethyl-
1,3-dioxa-spiro[4.5] dec-6-yl)-ethyl]-chroman (42): To a solution of
diol 37 (0.577 g, 1.54 mmol) and CSA (0.005 g) in dichloromethane
(12 mL) was added dropwise 2-methoxypropene (0.3 mL) (CAUTION:
the end of the needle has to be immersed in the solution during the
addition). The solution was stirred for 5 min and to this solution was
added a saturated aqueous solution of sodium bicarbonate (5 mL). After
separation, the aqueous phase was extracted with dichloromethane (3
× 20 mL). The combined organic extracts were dried over magnesium
sulfate and then concentrated in vacuo. The residue was purified over
silica gel eluting with 1/10 diethyl ether in petroleum ether to afford
acetonide 42 (0.629 g, 1.51 mmol, 98%) as a colorless oil.
IR (neat): 2931, 1614, 1566, 1461, 1387, 1214 cm-1; 1H NMR (500
MHz, CDCl3) δ: 6.61 (d, J ) 10.0 Hz, 1H), 6.27 (s, 1H), 6.15 (s, 1H),
5.46 (d, J ) 10.0 Hz, 1H), 3.80 (d, J ) 8.5 Hz, 1H), 3.65 (d, J ) 8.2
Hz, 1H), 2.22 (s, 3H), 1.99 (m, 1H), 1.88 (dd, J ) 5.4, 13.4 Hz, 1H),
1.78 (td, J ) 4.4, 13.4 Hz, 1H), 1.62-1.20 (m, 8H), 1.44 (s, 3H), 11.36
(s, 6H), 1.02 (s, 9H), 0.98 (s, 3H), 0.67 (s, 3H), 0.22 (s, 6H); 13C NMR
(125 MHz, CDCl3) δ: 154.2, 151.2, 138.9, 126.8, 118.1, 112.1, 110.5,
110.3, 106.9, 85.5, 78.4, 68.4, 53.2, 45.0, 38.1, 36.0, 31.4, 30.3, 28.8,
26.9, 26.8, 26.7, 25.8, 21.7, 20.5, 20.4, 18.3, -4.2, -4.3. HRMS:
Calc’d for C31H50O4Si: 514.3478. Found: 514.3468.
IR (neat): 2936, 1618, 1585, 1462, 1231 cm-1; 1H NMR (500 MHz,
CDCl3) δ: 6.29 (s, 1H), 6.22 (s, 1H), 3.83 (d, J ) 8.3 Hz, 1H), 3.81
(s, 3H), 3.71 (d, J ) 8.3 Hz, 1H), 2.66 (td, J ) 6.1, 17.1 Hz, 1H), 2.55
(td, J ) 8.5, 17.1 Hz, 1H), 2.28 (s, 3H), 1.95 (m, 2H), 1.84 (ddd, J )
6.3, 8.5, 13.4 Hz, 1H), 1.74 (td, J ) 6.1, 13.4 Hz, 1H), 1.60 (m, 3H),
1.48-1.22 (m, 6H), 1.43 (s, 3H), 1.29 (s, 6H), 1.01 (s, 3H), 0.73 (s,
3H); 13C NMR (125 MHz, CDCl3) δ: 157.5, 154.3, 136.7, 110.4,
106.98, 106.91, 102.2, 85.4, 75.7, 68.4, 55.2, 53.1, 43.3, 38.1, 35.9,
31.3, 30.4, 28.7, 28.6, 26.6, 23.67, 23.62, 21.5, 20.3, 19.6, 16.4.
HRMS: Calc’d for C26H40O4: 416.2926. Found: 416.2926.
2-{2-[5-(tert-Butyldimethylsilanyloxy)-(2S)-2,7-dimethyl-2H-
chromen-2-yl]-ethyl}-(1S,2S)-1-hydroxymethyl-3,3-dimethyl-cyclo-
hexanol (45) and (+)-siccanochromene F (7): Method A: A solution
of chromene 44 (0.400 g, 0.777 mmol) and p-TsOH (0.035 g, 0.183
mmol) in MeOH (40 mL) was refluxed for 1h. To this mixture was
then added a saturated solution of sodium bicarbonate (10 mL), and
the mixture was evaporated to dryness in vacuo. The solid residue was
diluted with dichloromethane (30 mL) and water (30 mL). The aqueous
layer was extracted with dichloromethane (3 × 30 mL). The combined
organic layers were dried over magnesium sulfate and evaporated in
vacuo. The residue was purified by preparative TLC (petroleum ether/
diethyl ether 4/1 v/v double elution) to afford first starting material
(0.310 g, 0.602 mmol), then diol 45 and siccanochromene F (7). The
remaining starting material has been submitted again three times,
adjusting the relative amount of reagent and solvent for each run. In
total, we have obtained diol 45 (0.221 g, 0.465 mmol), siccanochromene
F (7) (0.043 g, 0.119 mmol) and starting chromene 44 (0.021 g, 0.04
mmol) has been discarded.
(2S)-2,7-Dimethyl-2-[(5S,6S)-2-(2,2,7,7-tetramethyl-1,3-dioxa-
spiro[4.5]dec-6-yl)-ethyl]-chroman-5-ol (43a): To a solution of
acetonide 42 (0.652 g, 1.56 mmol) in DMF (10 mL) were added at
room temperature sodium hydride (0.5 g, 12.5 mmol, 60% dispersion
in oil, unwashed) and dropwise ethanethiol (1 mL, 13.5 mmol). After
10 min, the mixture was heated at 120 °C for 24 h. After cooling to
room temperature, to the reaction mixture was added water (20 mL).
The mixture was extracted with diethyl ether (4 × 50 mL). The
combined ethereal extracts were washed with brine (20 mL) and dried
over magnesium sulfate. After concentration in vacuo, the residue was
purified by flash chromatography eluting with 1/5 diethyl ether in
petroleum ether to afford first remaining 42 (0.051 g, 0.123 mmol),
and desired phenol 43a (0.540 g, 1.34 mmol) as a colorless oil.
IR (neat): 3388, 2935, 1626, 1586, 1456, 1368, 1215 cm-1; 1H NMR
(500 MHz, CDCl3) δ: 6.24 (s, 1H), 6.15 (s, 1H), 5.29 (br s, 1H), 3.84
(d, J ) 8.3 Hz, 1H), 3.71 (d, J ) 8.3 Hz, 1H), 2.66 (td, J ) 6.1, 16.6
Hz, 1H), 2.57 (td, 6.1, 16.6 Hz, 1H), 2.20 (s, 3H), 1.97 (m, 2H), 1.86
(ddd, J ) 6.6, 8.3, 13.1 Hz, 1H), 1.76 (dt, J ) 6.1, 13.4 Hz, 1H), 1.60
(m, 3H), 1.48-1.26 (m, 6H), 1.43 (s, 3H), 1.29 (s, 6H), 1.00 (s, 3H),
0.73 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 154.7, 153.7, 137.1,
110.1, 107.1, 106.7, 105.4, 85.5, 75.8, 68.4, 53.1, 43.2, 38.1, 35.9, 31.3,
30.3, 28.67, 28.62, 26.6, 23.7, 23.6, 21.1, 20.3, 19.6, 16.3. HRMS:
Calc’d for C25H38O4: 402.2770. Found: 402.2774.
Method B: To a solution of compound 44 (25 mg, 0.049 mmol) in
2 mL of aqueous methanol (MeOH:water ) 4:1) was added toluene-
sulfonic acid monohydrate (5 mg, 0.026 mmol). The resulting mixture
was under reflux for 4 h. The mixture was directly purified by flash
chromatography eluting with 50% ethyl acetate in petroleum ether to
afford siccanochromene F (7) (21 mg, 0.044 mmol, 90%) as a colorless
oil.
tert-Butyl-{(2S)-2,7-dimethyl-2-[(5S,6S)-2-(2,2,7,7-tetramethyl-
1,3-dioxa-spiro[4.5] dec-6-yl)-ethyl]-chroman-5-yloxy}-dimethylsi-
lane (43b): To a solution of phenol 43a (0.390 g, 0.968 mmol) in
dichloromethane (5 mL) were added successively triethylamine (0.200
mL, 1.43 mmol), DMAP (0.190 g, 1.55 mmol) and tert-butyldimeth-
ylsilyl chloride (0.190 g, 1.25 mmol). The resulting mixture was stirred
for 24 h art room temperature. The reaction mixture was then partitioned
between water (20 mL) and dichloromethane (20 mL). The aqueous
layer was then extracted with dichloromethane (2 × 20 mL). The
combined organic extracts were dired over magnesium sulfate and
concentrated under reduced pressure. The residue was then purified
by chromatography over silica gel eluting with 1/10 diethyl ether in
petroleum ether to afford silyl ether 43b (0.430 g, 0.832 mmol) as a
clear oil.
45: IR (neat): 2931, 1614, 1566, 1461, 1387, 1214 cm-1; 1H NMR
(500 MHz, CDCl3) δ: 6.62 (d, J ) 10.0 Hz, 1H), 6.29 (s, 1H), 6.17 (s,
1H), 5.49 (d, J ) 10.0 Hz, 1H), 3.64 (d, J ) 10.8 Hz, 1H), 3.57 (d, J
) 10.8 Hz, 1H), 2.23 (s, 3H), 2.23 (m, overlapped, 1H), 2.10 (br s,
1H), 2.05 (m, 1H), 1.90 (m, 2H), 1.60 (m, 2H), 1.50-1.38 (m, 3H),
1.36 (s, 3H), 1.31 (m, 1H), 1.23 (m, 1H), 1.11 (m, 1H), 1.02 (s, 9H),
0.97 (s, 3H), 0.76 (s, 3H), 0.22 (s, 6H); 13C NMR (125 MHz, CDCl3)
δ: 153.8, 151.2, 139.0, 127.0, 118.1, 112.3, 110.7, 110.2, 78.5, 75.7,
63.5, 55.5, 43.7, 40.6, 36.0, 35.4, 32.3, 26.1, 25.7, 22.7, 21.6, 19.9,
19.7, 18.2, -4.2, -4.3. HRMS: Calc’d for C28H46O4Si: 474.3165.
Found: 474.3159.
1
7: IR (neat): 3381, 2931, 1624, 1579, 1454, 1062 cm-1; H NMR
(500 MHz, CDCl3) δ: 6.64 (d, J ) 10.0 Hz, 1H), 6.25 (s, 1H), 6.14 (s,
9
J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12577

A R T I C L E S
Trost et al.
1H), 5.66 (br s, 1H), 5.51 (d, J ) 10.0 Hz, 1H), 3.65 (d, J ) 10.7 Hz,
1H), 3.57 (d, J ) 10.7 Hz, 1H), 2.35 (br s, 1H), 2.29 (br s, 1H), 2.21
(s, 3H), 2.05 (br d, J ) 12.9 Hz, 1H), 1.90 (ddd, J ) 5.1, 11.4, 13.6
Hz, 1H), 1.80 (m, 2H), 1.60 (m, 2H), 1.50-1.38 (m, 3H), 1.30 (m,
1H), 1.24 (m, 1H), 1.15 (td, J ) 4.1, 12.7 Hz, 1H), 0.98 (s, 3H), 0.76
(s, 3H); 13C NMR (125 MHz, CDCl3) δ: 153.9, 151.3, 139.5, 127.2,
117.0, 109.5, 108.5, 106.9, 78.7, 75.9, 63.5, 55.6, 43.7, 40.7, 36.0, 35.5,
32.4, 26.1, 22.7, 21.6, 19.9, 19.7. HRMS: Calc’d for C22H32O4:
360.2301. Found: 360.2302.
was then added a solution of epoxide 48 (20 mg, 0.056 mmol) in 0.5
mL of distilled THF under argon. The resulting solution was still green
and this solution was stirred at room temperature for 12 h. The solution
was filtered through diatomaceous earth, washed with ethyl acetate and
the mixture was concentrated to 2 mL. The residue was chromato-
graphed eluting with 5% to 30% diethyl ether in petroleum ether to
afford the tetracyclic compound 53 (12 mg, 0.034 mmol, 61%) and
pentacyclic compound 54 (4 mg, 0.011 mmol, 20%) as a colorless oil.
53: [R]D ) -83.8 (c 1.8, CDCl3); IR (neat): 3453b, 2922s, 2872m,
1618m, 1587s, 1462m, 1352m, 1224m, 1166m, 1112s, 1040m, 900w,
2-[2-(5-Hydroxy-2,7-dimethyl-2H-chromen-2-yl)-ethyl]-3,3-di-
methylcyclohexanone (46): To diol 7 (19 mg, 0.039 mmol) in 1 mL
of acetone was added sodium periodate (33 mg, 0.156 mmol) at room
temperature. After 5 h, the reaction mixture was directly purified by
flash chromatography eluting with 50% diethyl ether in petroleum ether
to afford ketone 46 (11 mg, 0.034 mmol, 86%) as a colorless oil.
[R]D ) +42 (c 1.1, CDCl3); IR (neat): 3620, 3385, 1710, 1638,
1
812w cm-1; H NMR (500 MHz, CDCl3): δ 6.23 (s, 1H), 6.21 (s,
1H), 4.05 (d, J ) 12.0 Hz, 1H), 3.79 (s, 3H), 3.63 (d, J ) 12.0 Hz,
1H), 2.79 (d, J ) 18.5 Hz, 1H), 2.59 (dd, J ) 8.5, 18.0 Hz, 1H), 2.27
(s, 3H), 2.00 (dt, J ) 3.0, 14.0 Hz, 1H), 1.92 (d, J ) 8.5 Hz, 1H), 1.80
(td, J ) 3.0, 13.5 Hz, 1H), 1.64 (m, 1H), 1.49 (dd, J ) 3.0, 13.5 Hz,
1H), 1.22-1.43 (m, 5H), 1.19 (s, 3H), 1.18 (s, 3H), 0.93 (s, 3H), 1.10
(d, J ) 9.5 Hz, 1H), 0.72 (d, J ) 7.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ 159.9, 154.8, 136.3, 110.2, 107.8, 102.6, 75.2, 64.5, 55.3,
43.4, 42.9, 39.1, 38.3, 34.7, 33.8, 33.6, 30.0, 27.1, 23.9, 21.6, 19.7,
18.6, 17.5. HRMS: Calc’d for C23H34O3: 358.2508. Found: 358.2490.
54: [R]D ) -118.6 (c 1.4, Et2O); IR (neat): 2925s, 2850m, 1618m,
1592m, 1463m, 1356w, 1230w, 1209w, 1163w, 1134w, 1110s, 1053w,
1102w, 950w, 895w, 817w, 733w cm-1; 1H NMR (500 MHz, CDCl3):
δ 6.36 (s, 1H), 6.33 (s, 1H), 5.48 (d, J ) 8.5 Hz, 1H), 3.86 (s, 3H),
3.85 (d, J ) 8.5 Hz, 1H), 3.76 (d, J ) 8.5 Hz, 1H), 2.30 (s, 3H), 2.27
(m, 1H), 2.13 (d, J ) 12.5 Hz, 1H), 2.05 (d, J ) 8.0 Hz, 1H), 1.43-
1.64 (m, 6H), 1.20-1.34 (m, 3H), 1.08 (s, 3H), 1.01 (s, 3H), 0.73 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 157.5, 156.0, 139.4, 112.5, 111.8,
104.8, 68.8, 65.6, 56.3, 55.5, 51.7, 48.7, 41.9, 40.7, 38.0, 33.7, 32.4,
29.7, 29.0, 21.9, 21.2, 19.4, 17.0. HRMS: Calc’d for C23H32O3:
356.2351. Found: 356.2352.
(-)-Siccanochromene C methyl ether (55): To manganese (25 mg,
0.45 mmol) and titanocene dichloride (58 mg, 0.22 mmol) was added
THF under argon. The resulting red mixture was stirred for 30 min to
give a green solution. To the solution was added a solution of epoxide
48 (20 mg, 0.056 mmol) in 0.5 mL of THF followed by iodine (30
mg, 0.11 mmol) in 0.5 mL of THF. The red solution was heated for 1
h before the addition of aqueous sodium thiosulfate (10%). The mixture
was chromatographed eluting with 5% to 40% diethyl ether in petroleum
ether to afford the allylic alcohol 55 (13.5 mg, 0.038 mmol, 68%) as
pale yellow oil.
1
1580, 1260 cm-1; H NMR (300 MHz, CDCl3): δ 6.64 (d, J ) 11.1
Hz, 1H), 6.08 (s, 1H), 6.03 (s, 1H), 5.45 (d, J ) 11.1 Hz, 1H), 2.16 (s,
3H), 2.15-2.05 (m, 3H), 1.80-1.55 (m, 4H), 1.50-1.25 (m, 4H), 1.27
(s, 3H), 1.01 (s, 3H), 0.75 (s, 3H); HRMS: Calc’d for C21H28O3:
328.2038. Found: 328.2040.
tert-Butyl-{2-[(1S,2S)-2-(5,5-dimethyl-1-oxa-spiro[2.5]oct-4-yl)-
ethyl]-(2S)-2,7-dimethyl-2H-chromen-5-yloxy}-dimethylsilane (47):
To a solution of diol 45 (0.180 g, 0.379 mmol) in dichloromethane (4
mL) at room temperature were added DMAP (0.110 g, 0.9 mmol) and
p-TsCl (0.121 g, 0.633 mmol). The solution was stirred for 4 h. Without
workup, the mixture was then directly purified by preparative TLC
(one elution, petroleum ether/diethyl ether ) 4/1) to afford intermediate
tosylate (0.230 g). This material was resuspended in 5 mL of THF and
sodium hydride (48 mg, 1.2 mmol, 60%) was added in one portion.
After gas evolution ceased, the solution was stirred for 5 more min
and the solution directly filtered through silica gel washing with diethyl
ether. The filtrate was concentrated in vacuo and the residue was
purified by preparative TLC (one elution, petroleum ether/diethyl ether
) 10/1) to afford epoxide 47 (0.141 g, 0.308 mmol) as a colorless oil.
IR (neat): 2930, 1614, 1565, 1461, 1387, 1099 cm-1; 1H NMR (500
MHz, CDCl3) δ: 6.62 (d, J ) 10.0 Hz, 1H), 6.28 (s, 1H), 6.17 (s, 1H),
5.45 (d, J ) 10.0 Hz, 1H), 2.62 (d, J ) 4.7 Hz, 1H), 2.48 (d, J ) 4.7
Hz, 1H), 2.23 (s, 3H), 1.78-1.59 (m, 6H), 1.44 (ddd, J ) 3.9, 8.8,
13.1 Hz, 1H), 1.34 (s, 3H), 1.34 (m, overlapped, 1H), 1.29-1.24 (m,
2H), 1.09 (m, 1H), 1.06 (s, 3H), 1.02 (s, 9H), 0.83 (s, 3H), 0.22 (s,
6H); 13C NMR (125 MHz, CDCl3) δ: 153.9, 151.1, 139.0, 126.8, 118.2,
112.3, 110.6, 110.2, 78.1, 59.9, 51.2, 50.1, 41.3, 36.9, 35.7, 31.9, 28.8,
26.3, 26.1, 25.7, 21.6, 20.8, 20.6, 18.2, -4.2. HRMS: Calc’d for
C28H44O3Si: 456.3060. Found: 456.3065.
(+)-Siccanochromene B (3): To a solution of epoxide 47 (130 mg,
0.285 mmol) in THF (5 mL) at 0 °C was added TBAF (0.5 mL, 0.5
mmol, 1M in THF). The solution was stirred for 10 min at 0 °C, and
was then filtrate through silica gel washing with diethyl ether. The
residue was purified by preparative TLC (one elution, petroleum ether/
diethyl ether ) 5/1) to afford siccanochromene B (3) (81 mg, 0.236
mmol) as a colorless oil.
IR (neat): 3375, 2939, 1624, 1579, 1453, 1065 cm-1; 1H NMR (500
MHz, CDCl3) δ: 6.63 (d, J ) 10.0 Hz, 1H), 6.21 (s, 1H), 6.12 (s, 1H),
5.44 (d, J ) 10.0 Hz, 1H), 5.02 (br s, 1H), 2.65 (d, J ) 4.4 Hz, 1H),
2.50 (d, J ) 4.4 Hz, 1H), 2.18 (s, 3H), 1.76-1.50 (m, 6H), 1.42 (ddd,
J ) 4.2, 8.8, 13.4 Hz, 1H), 1.38-1.16 (m, 4H), 1.32 (s, 3H), 1.04 (s,
3H), 0.81 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 153.9, 151.4, 139.3,
126.7, 117.2, 117.1, 109.4, 108.4, 106.7, 78.3, 60.6, 51.4, 50.1, 41.3,
35.7, 28.7, 26.2, 25.9, 21.5, 20.7, 20.5, 20.4. HRMS: Calc’d for
C22H30O3: 342.2195. Found: 342.2198.
[R]D ) -16.7 (c 0.8, Et2O); IR (neat): 3418b, 2983s, 2853s, 1614m,
1574m, 1456m, 1386w, 1230w, 1211w, 1115s, 1017m, 814m, 772w
cm-1; 1H NMR (500 MHz, CDCl3): δ 6.66 (d, J ) 9.5 Hz, 1H), 6.28
(s, 1H), 6.23 (s, 1H), 5.65 (s, 1H), 5.44 (d, J ) 9.5 Hz, 1H), 4.03 (bs,
2H), 3.82 (s, 3H), 2.29 (s, 3H), 2.03 (d, J ) 4.0 Hz, 2H), 1.70-1.26
(m, 11H), 1.26 (s, 3H); 0.93 (s, 3H), 0.86 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 155.0, 140.3, 139.4, 126.6, 122.5, 117.3, 109.8, 103.8, 78.4,
66.6, 55.5, 45.0, 41.0, 32.3, 31.5, 29.7, 27.7, 27.4, 26.3, 25.2, 22.7,
22.0, 14.1. HRMS: Calc’d for C23H32O3: 356.2352. Found: 356.2350.
(-)-Siccanin Methyl Ether (60): To a solution of alcohol 53 (28
mg, 0.078 mmol) in 1.0 mL of cyclohexane was added iodobenzene
diacetate (28 mg, 0.088 mmol) and iodine (5.0 mg, 0.02 mmol) at room
temperature. The red mixture was irradiated with 150 w filament
tungsten lamp for 1.5 h. To the mixture was added saturated sodium
thiosulfate (1.0 mL). After this mixture turned colorless, the mixture
was chromatographed eluting with 5% to 20% diethyl ether in petroleum
ether to afford 60 (18 mg, 0.051 mmol, 65%) as a pale yellow oil.
[R]D ) -107 (c 1.8, Et2O); IR (neat): 2930s, 2866s, 1617s, 1578s,
1463s, 1416m, 1361s, 1308w, 1287w, 1273w, 1232m, 1219m, 1188m,
1170s, 1138m, 1106s, 1055w, 1022m, 990w, 972w, 954w, 926m, 905w,
1
(-)-Siccanochromene Methyl Ether (53) and (-)-5-epi-Siccanin
Methyl Ether (54): To titanocene dichloride (58 mg, 0.224 mmol)
and manganese (25 mg, 0.448 mmol) under argon was added 1 mL of
distilled THF. The resulting red mixture was stirred for 30 min at room
temperature and the color of the solution turned green. To this solution
876w, 855w, 817w, 805w, 732s, 670w, 644w cm-1; H NMR (400
MHz, CDCl3): δ 6.26 (s, 1H), 6.20 (s, 1H), 5.12 (d, J ) 9.2 Hz, 1H),
4.24 (d, J ) 7.6 Hz, 1H), 3.86 (s, 3H), 3.40 (dd, J ) 2.0, 7.6 Hz, 1H),
2.25 (s, 3H), 2.13 (dd, J ) 4.0, 14.8 Hz, 1H), 1.95 (d, J ) 9.2 Hz,
1H), 1.90 (m, 2H), 1.65 (m, 1H), 1.54 (dd, J ) 6.4, 14.4 Hz, 1H), 1.46
9
12578 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004

Total Synthesis of (−)-Siccanin
A R T I C L E S
(m, 2H), 1.33 (m, 2H), 1.20 (s, 3H), 1.14 (dd, J ) 2.8, 12.0 Hz, 1H),
1.08 (d, J ) 8.8 Hz, 1H), 0.85 (s, 3H), 0.83 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 158.6, 154.7, 139.1, 110.6, 110.2, 104.2, 78.5, 75.2,
66.9, 55.9, 54.2, 50.3, 46.0, 37.4, 33.9, 33.7, 30.3, 28.2, 26.1, 23.2,
21.7, 21.2, 20.0. HRMS: Calc’d for C23H32O3: 356.2351. Found:
356.2351.
(-)-Siccanin (1): To a slurry of sodium hydride (12 mg, 0.46 mmol)
in 1 mL of DMF was added ethanethiol (26 mg, 31 uL, 0.42 mmol) at
0 °C. The mixture was warmed to room temperature and stirred for 40
min before the addition of methyl ether 60 (15 mg, 0.042 mmol) in 1
mL of DMF. The mixture was heated at 120 °C for 12 h. Without
workup, the mixture was directly chromatographed eluting with 10%
to 30% diethyl ether in petroleum ether to afford sicannin (1) as a white
solid (12.4 mg, 0.036 mmol, 86%).
12b-Hydroxymethyl-4,4,6a,9-tetramethyl-1,3,4,4a,5,6,6a,12,12a,
12b-decahydro-2H-ben-zo[a]xanthen-11-ol (62): To a slurry of
sodium hydride (40 mg, 60% in mineral oil, 1.01 mmol) in 0.5 mL of
DMF at 0 °C was added ethanethiol (58 mg, 69 uL, 0.94 mmol). After
10 min, the mixture was warmed to room temperature and stirred for
half an hour. To the mixture was added a solution of 53 (28 mg, 0.078
mmol) in 1.5 mL of DMF. The mixture was heated at 120 °C for 48
h. The mixture was purified by flash chromatography eluting with 10%
to 50% ethyl acetate in petroleum ether to afford phenol 62 as a dark
brown oil without any contamination of DMF (22 mg, 0.064 mmol,
82%).
[R]D ) -68.1 (c 1.8, CDCl3); IR (neat): 3419b, 2924s, 2855s,
1716w, 1623m, 1589s, 1456s, 1415m, 1349m, 1320m, 1261w, 1167s,
1
1075m, 1037m, 903w, 821w cm-1; H NMR (500 MHz, CDCl3): δ
[R]D ) -132.3 (c 1.28, CDCl3); mp ) 125-130 °C; [R]D2a ) -150
(c 7.75, CDCl3); mp2a ) 138 °C; IR (neat): 3465b, 2960s, 2929s, 2866s,
1634s, 1576s, 1456m, 1361s, 1304w, 1279w, 1197m, 1175s, 1134m,
1064s, 1012s, 985m, 971w, 953w, 906m, 806w, 766w, 734m, 702w
cm-1; 1H NMR (400 MHz, CDCl3): δ 6.58 (s, 1H), 6.31 (s, 1H), 6.14
(s, 1H), 5.16 (d, J ) 8.8 Hz, 1H), 4.24 (d, J ) 7.6 Hz, 1H), 3.48 (dd,
J ) 2.0, 7.6 Hz), 2.21 (s, 3H), 2.18 (dd, J ) 1.6, 5.2 Hz, 1H), 1.96 (d,
J ) 8.4 Hz, 1H), 1.90 (td, J ) 5.2, 13.6 Hz, 1H), 1.77 (m, 1H), 1.68
(m, 1H), 1.54 (ddd, J ) 6.0, 7.1, 12.2 Hz, 1H), 1.37 (m, 3H), 1.26 (s,
3H), 1.18-1.07 (m, 3H), 0.86 (s, 3H), 0.83 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 155.6, 154.7, 139.6, 109.9, 109.5, 108.3, 79.4, 74.8,
68.1, 53.5, 50.5, 45.9, 37.3, 33.6, 30.2, 28.1, 27.1, 23.5, 21.4, 21.2,
19.9. 1H NMR (400 MHz, CDCl3): δ 6.58 (s, 1H), 6.31 (s, 1H), 6.14
(s, 1H), 5.16 (d, J ) 8.8 Hz, 1H), 4.24 (d, J ) 7.6 Hz, 1H), 3.48 (dd,
J ) 2.0, 7.6 Hz), 2.21 (s, 3H), 2.18 (ddd, J ) 1.6, 5.2, 14.8 Hz, 1H),
1.96 (d, J ) 8.4 Hz, 1H), 1.90 (td, J ) 5.2, 13.6 Hz, 1H), 1.77 (m,
1H), 1.68 (m, 1H), 1.54 (ddd, J ) 6.0, 7.1, 12.2 Hz, 1H), 1.37 (m,
3H), 1.26 (s, 3H), 1.18-1.07 (m, 3H), 0.86 (s, 3H), 0.83 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 155.6, 154.7, 139.6, 109.9, 109.5, 108.3,
79.4, 74.8, 68.1, 53.5, 50.5, 45.9, 37.3, 33.6, 33.5, 30.2, 28.1, 27.1,
23.5, 21.4, 21.2, 19.9. (1H NMR (300 MHz, CDCl3) in the literature:11
δ 6.58 (s, 1H), 6.31 (s, 1H), 6.15 (s, 1H), 5.16 (d, J ) 8.8 Hz, 1H),
4.24 (d, J ) 7.6 Hz, 1H), 3.48 (dd, J ) 2.4, 7.6 Hz), 2.21 (s, 3H), 2.16
(ddd, J ) 1.5, 5.1, 14.7 Hz, 1H), 1.96 (d, J ) 8.7 Hz, 1H), 1.94-1.62
(m, 3H), 1.60-1.46 (m, 1H), 1.45-1.29 (m, 3H), 1.26 (s, 3H), 1.20-
1.02 (m, 3H), 0.86 (s, 3H), 0.83 (s, 3H); 13C NMR (100 MHz, CDCl3)
in the literature:11 δ 155.8, 153.8, 139.7, 109.9, 109.5, 108.4, 79.4,
74.8, 68.1, 53.5, 50.5, 45.8, 37.2, 33.6, 33.5, 30.1, 28.0, 27.0, 23.4,
21.3, 21.1, 19.8.) HRMS: Calc’d for C22H30O3: 342.2195. Found:
342.2212.
5-epi-(-)-Siccanin (68): To a slurry of sodium hydride (20 mg, 60%
in mineral oil, 0.51 mmol) in 1.0 mL of DMF at 0 °C was added ethane
thiol (29 mg, 35 uL, 0.47 mmol). After 10 min, the mixture was warmed
to room temperature and stirred for 0.5 h. To the mixture was added
epi-siccanin methyl ether 54 (14 mg, 0.039 mmol) in 1 mL of DMF.
The mixture was heated at 120 °C for 28 h. Without workup, the
mixture was purified by flash chromatography twice eluting with 10%
to 50% ethyl ether in petroleum ether to afford phenol 68 as a pale
yellow oil (11 mg, 0.032 mmol, 82%).
[R]D ) -76.8 (c 0.7, CDCl3); IR (neat): 3283b, 2925s, 2853s, 1626m,
1597m, 1466m, 1366m, 1268w, 1208w, 1165w, 1133m, 1066m, 1048m,
1010m, 896w, 826w, 757w, 724w cm-1; 1H NMR (500 MHz, CDCl3):
δ 6.21 (s, 1H), 6.16 (s, 1H), 5.29 (d, J ) 8.5 Hz, 1H), 3.88 (d, J ) 9.0
Hz, 1H), 3.66 (d, J ) 9.0 Hz, 1H), 2.17 (s, 3H), 2.02 (m, 3H), 1.45-
1.70 (m, 9H), 1.35 (s, 3H), 0.90 (s, 3H), 0.72 (s, 3H); 13C NMR (75
MHz, CDCl3): δ 155.5, 154.0, 139.7, 110.5, 109.9, 109.1, 75.9, 69.6,
69.2, 56.5, 49.1, 46.6, 42.0, 39.3, 33.8, 33.0, 31.9, 29.7, 21.4, 20.7,
19.6, 17.5. HRMS: Calc’d for C22H30O3: 342.2195. Found: 342.2182.
6.23 (s, 1H), 6.17 (s, 1H), 4.10 (d, J ) 12.0 Hz, 1H), 3.66 (d, J ) 12.0
Hz, 1H), 2.78 (d, J ) 18.0 Hz, 1H), 2.67 (dd, J ) 8.0, 18.0 Hz, 1H),
2.22 (s, 3H), 2.02 (dt, J ) 3.5, 14.0 Hz, 1H), 1.98 (d, J ) 8.0 Hz, 1H),
1.85 (dd, J ) 3.0, 13.0 Hz, 1H), 1.80 (dd, J ) 3.0, 13.5 Hz, 1H), 1.68
(m, 2H), 1.32-1.53 (m, 6H), 1.21 (s, 3H), 1.20 (s, 3H), 0.95 (s, 3H);
13C NMR (75 MHz, CDCl3): δ 155.2, 153.1, 136.7, 110.0, 107.2, 106.4,
75.3, 64.6, 43.4, 42.9, 39.1, 38.3, 34.6, 33.8, 33.6, 30.0, 27.1, 24.0,
21.2, 19.7, 18.6, 17.3. HRMS: Calc’d for C22H32O3 [M+]: 344.2351.
Found: 344.2352.
Conclusion
In conclusion, we have achieved the first enantioselective total
synthesis of (-)-siccanin (1) based on the development of the
Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol
allyl carbonate 18 and two sequential radical cyclizations. The
failure of siccanochromene B to cyclize under acid conditions
may provide insight into the biosynthesis. Presuming it is indeed
an enzyme catalyzed event, the enzyme must suppress the
intrinsic bias of the system to undergo a 1,2-hydride shift faster
than cyclization. Alternatively, the success of a radical based
cyclization opens the question of whether a similar mechanism
may be involved. This reaction is by far the most complicated
application of the Ti(III)-mediated epoxyolefin cyclization
reported to date and poses interesting mechanistic questions.
The second stereoselective radical cyclization to form the tetra-
hydrofuran moiety is quite efficient and involves multiple steps
including oxygen radical formation, selective hydrogen atom
abstraction, benzyl iodide formation, elimination and oxygen
nucleophile cyclization. During the course of the synthesis, other
members of the siccanin family were also prepared including
siccanochromenes A, B, E, F, and the methyl ether of siccano-
chromene C.
Acknowledgment. We thank the National Institutes of Health
(GM-13598) and the National Science Foundation for their
generous support of our programs. We thank Professor Dan
Yang for helpful discussions. H.C.S. was a Stanford Graduate
Fellow. Mass spectra were provided by the Mass Spectrometry
Regional Center of the University of CaliforniasSan Francisco
supported by the NIH Division of Research Resources.
Supporting Information Available: Experimental procedures
for the preparation of 24-26, 29-32, 39, 48, 69-71, and 6.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA048084P
9
J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12579