Total synthesis of (±)-methyl atis-16-en-19-oate via homoallyl- homoallyl radical rearrangement

Article abstract of DOI:10.1021/ja9739042

Total synthesis of (±)-methyl atis-16-en-19-oate (5c), a tetracyclic diterpenoid possessing a bicyclo [2.2.2] octane ring sytem, was accomplished. Intramolecular Diels-Alder reaction of tetraene 14 was employed in a construction of kaurene skeleton 13. Th

Full text of DOI:10.1021/ja9739042

4916
J. Am. Chem. Soc. 1998, 120, 4916-4925
Total Synthesis of (()-Methyl Atis-16-en-19-oate via
Homoallyl-Homoallyl Radical Rearrangement
Masahiro Toyota,* Toshihiro Wada, Keiichiro Fukumoto, and Masataka Ihara*
Contribution from the Pharmaceutical Institute, Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
ReceiVed NoVember 14, 1997
Abstract: Total synthesis of (()-methyl atis-16-en-19-oate (5c), a tetracyclic diterpenoid possessing a bicyclo-
[2.2.2]octane ring system, was accomplished. Intramolecular Diels-Alder reaction of tetraene 14 was employed
in a construction of kaurene skeleton 13. The pivotal step involved a homoallyl-homoallyl radical
rearrangement process of (()-methyl 12-hydroxykaur-16-en-19-oate monothioimidazolide 12, which led to
5c in good yield. Interestingly, treatment of methyl 12-oxo-kaur-16-en-19-oate 30 with hydrazine monohydrate
in the presence of KOH in bis(ethylene glycol) at 200 °C resulted in cyclopropanation to furnish, directly,
trachyloban-19-oic acid (4b), together with kaur-16-en-19-oic acid (6b).
Introduction
isomer 3 as common intermediates (Scheme 1).11 Based on
this scheme, interconversions and rearrangements of the bicy-
clooctane subunit of these diterpenes have been extensively
studied.12 In most cases, however, reactions proceed via
Wagner-Meerwein rearrangements of carbocations, analogous
to 2/3, which is generated under acid-catalyzed conditions.
Therefore, mixtures of products are frequently obtained.
To achieve such a transformation under mild conditions with
satisfactory selectivity, we designed cyclopropylcarbinyl radical
9 as an alternative to 2/3 because it can rearrange to homoallyl
radicals 10 and 11, and furthermore, the introduction of
hydrogen at C17, if possible, affords 4a.13 Rearrangement of
a cyclopropylcarbinyl radical via 3-exo fragmentation14 usually
results in the predominant formation of a thermodynamically
more stable homoallyl radical if the concentration of the
hydrogen source is sufficiently low.15 Thus, we expected that
homoallyl radical 10, which possesses a relatively strained five-
membered ring moiety, would undergo homoallyl-homoallyl
radical rearrangement via 9 to produce 11 (Scheme 2).
Atisirenoic acid (5b) was first isolated from Helichrysum
chionosphaerum as the corresponding methyl ester 5c by
Bohlmann in 1980;1 however, partial synthesis of 5c from
isosteviol was reported by Coates as early as 1969.2 Although
some kaurene- and trachylobane-type diterpenoids display a
wide range of interesting biological activities, including anti-
microbial,3 antitumor,4 antifeedant,5 gibberellin-like,6 and anti-
HIV (neotripterifordin 8)7 properties, relatively little is known
about the substantial biological activities of 5c and its relatives
(5a,b).8 However, the unique bicyclo[2.2.2]octane subunit of
5, constituting its CD ring system, has provided considerable
impetus for the development of new synthetic strategies in the
elaboration of the atisirene family.9
According to the hypothesis of diterpene biogenesis, originally
proposed by Wenkert in 1955,10 diterpenes belonging to hibaene
(7), kaurene (6a), trachylobane (4a), and atisirene (5a) families
all might arise from (-)-copalyl pyrophosphate (1) via nonclas-
sical carbocations such as 2 and its hydrogen shift (C12 to C16)
Synthetic Plan
(1) Bohlman, F.; Abraham, W.; Sherdlick, W. S. Phytochemistry 1980,
19, 869-871.
Our synthetic strategy for 5c is outlined in Scheme 3 in which
the Pd(II)-promoted cycloalkenylation reaction16 of silyl enol
ether 16 and the intramolecular Diels-Alder reaction of 14 were
employed for the construction of the kaurene skeleton. Herein,
we describe our investigation of novel skeletal rearrangements
(2) (a) Coates, R. M.; Bertram, E. F. J. Chem. Soc., Chem. Commun.
1969, 797-798. (b) Idem. J. Org. Chem. 1971, 36, 2625-2631.
(3) Mitscher, L. A.; Rao, G. S. R.; Veysoglu, T.; Drake, S.; Hass, T. J.
Nat. Prod. 1983, 46, 745-746.
(4) Ryu, S. Y.; Ahn, J. W.; Han, Y. N.; Han, B. H.; Kim, S. H. Arch.
Pharm. Res. 1996, 19, 77-78.
(5) Daniewski, W. M.; Skibicki, P.; Bloszyk, E.; Budesinsky, M.; Holub,
M. Polish J. Chem. 1993, 67, 1255-1259.
(6) Katsumi, M.; Phinney, B. O.; Jefferies, P. R.; Henrick, C. A. Science
1964, 144, 849-850.
(11) Although a face-protonated, trachlobane-type intermediate is em-
ployed in ref 10, we prefer the bridged ions 2 and 3 that are now widely
accepted, see: Coates, R. M.; Bertram, E. F. J. Org. Chem. 1971, 36, 3722-
3729 and references therein.
(12) Recent examples: Garcia-Granados, A.; Duenas, J.; Guerrero, A.;
Martinez, A.; Parra, A. J. Nat. Prod. 1996, 59, 124-130 and references
therein.
(13) In some cases, the cyclopropylcarbinyl radical can be trapped to
give the cyclopropane derivative. For example, see: Srikrishna, A.; Sharma,
V. R. J. Chem. Soc., Perkin Trans. 1 1997, 177-181 and references therein.
(14) For reviews, see: (a) Nonhebel, D. C. Chem. Soc. ReV. 1993, 347-
359. (b) Dowd, P.; Zhang, W. Chem. ReV. 1993, 93, 2091-2115.
(15) (a) Beckwith, A. L. J.; O’Shea, D. M. Tetrahedron Lett. 1986, 38,
4525-4528. (b) Stork, G.; Mook, R., Jr. Ibid. 1986, 38, 4529-4532.
(16) (a) Ito, Y.; Aoyama, H.; Hirao, T.; Machizuki, A.; Saegusa, T. J.
Am. Chem. Soc. 1979, 101, 494-496. (b) Kende, A. S.; Roth, B.; Sanfilippo,
P. J. Ibid. 1982, 104, 1784-1785.
(7) (a) Chen, K.; Shi, Q.; Fujioka, T.; Zhang, D.-C.; Hu, C.-Q.; Jin, J.-
Q.; Kilkuskie, R. E.; Lee, K.-H. J. Nat. Prod. 1992, 55, 88-92. (b) Chen,
K.; Shi, Q.; Fujioka, T.; Nakano, T.; Hu, C.-Q.; Jim, J.-Q.; Kilkuskie, R.
E.; Lee, K.-H. Bioorg. Med. Chem. 1995, 3, 1345-1348. Total synthesis:
Corey, E. J.; Liu, K. J. Am. Chem. Soc. 1997, 119, 9929-9930.
(8) Villalobos, N.; Martin, L.; Macias, M. J.; Mancheno, B.; Grande,
M. Phytochemistry 1994, 37, 635-639.
(9) (a) Recent synthesis: Berettoni, M.; Chiara, G. D.; Iacoangeli, T.;
Surdo, P. L.; Bettolo, R. M.; di Mirabello, L. M.; Nicolini, L.; Scarpelli, R.
HelV. Chim. Acta 1996, 79, 2035-2041 and references therein. (b) Our
own synthetic study: Ihara, M.; Toyota, M.; Fukumoto, K.; Kamitani, T.
J. Chem. Soc., Perkin Trans. 1 1986, 2151-2161 and references therein.
(10) Wenkert, E. Chem. Ind. (London) 1955, 282-284.
S0002-7863(97)03904-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/07/1998

Total Synthesis of (()-Methyl Atis-16-en-19-oate
J. Am. Chem. Soc., Vol. 120, No. 20, 1998 4917
Scheme 1
Scheme 2
A stoichiometric amount of Pd(OAc)2 allows the aforesaid
cycloalkenylation reaction to proceed under mild conditions;
however, this process suffers from low yield on a large scale
probably due to tarry Pd(0) species produced by reductive
elimination. This is a serious limitation in the application of
cycloalkenylation reaction involving Pd(II).
To address this issue, reproducible catalytic processes become
highly desirable. We demonstrate the viability of such a process
as exemplified by the conversion of cross-conjugated silyl enol
ethers 16 to bicyclo[3.2.1]octenone 15. Substrates 16 were
synthesized by the basic treatment of 1717 followed by silylation.
A number of different reaction parameters, such as silyl groups,
amount of Pd(OAc)2, concentrations, and solvents were evalu-
ated in order to optimize the reaction (Table 1). Since DMSO
has been recently reported to be an excellent solvent for Pd-
(II)-catalyzed dehydrosilylation of silyl enol ethers,18 the first
attempt to perform cycloalkenylation reaction was made by
employing 16a in the presence of 10 mol % of Pd(OAc)2 under
O2 (1 atm) in DMSO and resulted in the formation of the desired
compound 15 in 62% yield along with dienone 19 (21%) (run
1). For evaluation of the effect of the silyl protecting group,
we performed the same reaction using 16b, in which adduct 15
was isolated in 76% yield (run 2). Switching to TBDMS further
enhanced the yield to 81% (run 3). The dependence of the
of a kaurene derivative 12, leading to the first total synthesis
of (()-methyl atis-16-en-19-oate (5c).
Pd(II)-Catalyzed Cycloalkenylation Reaction
During the course of investigations directed toward a total
synthesis of gibberellin A12, we recently reported a route to the
bicyclo[3.2.1]octane derivative 1517b which utilized a Pd(II)-
promoted cyclization reaction of silyl enol ether 16a (Table 1).
(17) (a) Toyota, M.; Wada, T.; Nishikawa, Y.; Yanai, K.; Fukumoto, K.
Synlett 1994, 597-598. (b) Toyota, M.; Wada, T.; Nishikawa, Y.; Yanai,
K.; Fukumoto, K.; Kabuto, C. Tetrahedron 1995, 51, 6927-6940. (c)
Toyota, M.; Wada, T.; Fukumoto, K. Heterocycles 1995, 41, 1135-1138.
(18) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng,
D. Tetrahedron Lett. 1995, 36, 2423-2426. For mechanistic studies,
see: Larock, R. C.; Lee, N. H. Ibid. 1991, 42, 5911-5914 and references
therein.

4918 J. Am. Chem. Soc., Vol. 120, No. 20, 1998
Toyota et al.
Scheme 3
Table 1. Pd-Catalyzed Cycloalkenylation Reaction of Cross-Conjugated Silyl Enol Ethers (16)a
yield (%)
run
X
Pd(OAc)2 (mol %)
solvent (mol/L)
time (h)
15
18
19
16
1
2
3
4
5
6
7
8
9
TMS
TES
10
10
10
5
3
1
10
10
10
10
DMSO (0.05)
DMSO (0.05)
DMSO (0.05)
DMSO (0.05)
DMSO (0.05)
DMSO (0.05)
DMSO (0.1)
17
11
19
4
22
26
5
15
4.5
13
62
76
81
82
81
18
89
78
63
37
trace
trace
4
3
5
trace
2
3
trace
trace
21
14
5
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
3
trace
trace
3
5
trace
trace
64
57
DMSO (0.3)
DMSO-H2Ob (0.05)
MeCN (0.05)
10
a All reactions were carried out at 45 °C under O2 (1 atm). b DMSO:H2O (10:1 v/v).
Scheme 4a
amount of Pd(OAc)2 on the reaction was next investigated. As
a result, cycloalkenylation reactions were conveniently carried
out by heating a mixture of 16c with a catalytic amount (3∼10
mol %) of Pd(OAc)2 at 45 °C for 4-22 h (runs 3-5). In
contrast to the dehydrosilylation,18 even at a higher concentration
(0.3 M), the hydrolysis of silyl enol ether was not observed and
the major product was still 15 (runs 7 and 8). The cycloalk-
enylation reaction also tolerated the presence of water (run 9).
The effects of solvents were briefly examined. Unfortunately,
MeCN was not suitable for this catalytic system (run 10)
(Scheme 4).19
Homoallyl-Homoallyl Radical Rearrangement Reaction
Leading to Bicyclo[2.2.2]octane
To explore the feasibility of the designed synthetic strategy,
the novel homoallyl-homoallyl radical rearrangement reaction
of the corresponding R- and â-thioimidazolides of 20 was first
a (a) LDA, THF, -78 °C, then R3SiCl, HMPA, -78 to 0 °C. (b)
See Table 1.
examined. The requisite substrates 20 were readily prepared
(19) To prove the effect of the solvent, we used HMPA (to give 15,
36%) and DMPU (to give 15, 45%) as polar solvents.
by sequential stereoselective 1,4-conjugate addition20 of the

Total Synthesis of (()-Methyl Atis-16-en-19-oate
J. Am. Chem. Soc., Vol. 120, No. 20, 1998 4919
Scheme 5
To circumvent the above problem, we planned to construct
the bicyclo[2.2.2]octane ring system of 5c by the homoallyl-
homoallyl radical rearrangement process after intramolecular
Diels-Alder reaction.
Intramolecular Diels-Alder Reaction Oriented toward
Perhydrophenanthrene Construction
Tosylation of alcohol 25,17 followed by cyanation, gave
cyanide 26 in 97% overall yield in two steps, which was then
subjected to successive partial reduction with DIBALH (91%)
and Wittig olefination (92%) to afford 27 as mixture of
geometrical isomers (Z:E ) 5:1). Reduction of 27 with
DIBALH enabled the separation of each isomer as the corre-
sponding alcohol, and the desired Z-isomer obtained (74%) was
oxidized with MnO2, followed by methylenation, to give rise
to tetraene 14 in 83% overall yield in two steps. An intramo-
lecular Diels-Alder reaction24 of 14 was conducted in toluene
at 200 °C for 45 h in a sealed tube to afford the desired
perhydrophenanthrene derivative 13 and its stereoisomer 28 in
74% yield as a 5.7:1 mixture. Although recrystallization of the
above mixture from Et2O-hexane gave pure 13, the separation
of stereoisomers 13 and 28 was tedious at this stage. However,
it was found that the desired major isomer was easily separated
as the corresponding saturated ester 29. Accordingly, the above
cycloadducts were subjected to carbomethoxylation (70%)
followed by conjugate reduction (94%) with Mg in MeOH25
without further purification.
The stereoselectivity observed for the above cycloaddition
can be rationalized by considering two conformers (14A,B). The
major product 13 arises via conformer 14A. In the alternative
conformer 14B, the diene unit suffers from unfavorable steric
interactions with the axial hydrogen as shown in Figure 2.
Finally, the stereochemistry of the major isomer was established
by transformation into 5c.
(22) Deoxygenated compound II was synthesized by the Wolff-Kishner
reduction of I (ref 17b) to make sure that the structure of 21 is correct. It
is worth while to note that a small amount of tricyclo[3.2.1.02,7]octane
derivative IV and endo-olefin III was produced under these reaction
conditions.
isopropenyl group followed by NaBH4 reduction. Column
chromatography of 20 on silica gel (hexanes-EtOAc ) 5:1)
provided two fractions. The first fraction gave 20a (R-OH),
and on the other hand, the second one afforded 20b (â-OH).
The structure assigned to 20b is supported by its IR spectrum
which shows a band at 3450 cm-1 (hydroxyl) and the phase-
sensitive NOESY experiment in the NMR spectrum (Scheme
5). The radical deoxygenation reaction21 of 20b via the
corresponding thioimidazolide proceeded smoothly, giving
rearranged product 21 as a sole product. The spectral properties
of the rearranged product were consistent with structure 21.22
When 20a was subjected to the same conditions, however, 21
was obtained together with 22 (Chugaev-type elimination
product) (21:22 ) 5:1). The generation of 22 could be due to
the nonbonded interaction between the isopropenyl group in 23
and Bu3Sn• as shown in Scheme 5.
To provide some understanding of the previous results, the
calculations were performed on a system involving radical
species 24 by means of the semiempirical Hamiltonian PM3 in
MOPAC 7.0.23 As shown in Figure 1, the steric congestion
between the isopropenyl group and R-radical in 24A, generated
from 20a, makes it less favorable than the alternative 24B, which
gives rise to the desired compound 21 (Figure 1).
(23) Minimum energy structures were located by the global search
program GMMX (Version 1.0) (Serena software, Bloomington, IN). The
lowest energy structure 24C located in this fashion was then subjected to
molecular mechanics minimization using the MMX force field (Gajewski,
J. J.; Gilbert, K. E.; Mckelvey, J. In AdVances in Molecular Modeling; Liotta,
D., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2, pp 65-92) in the computer
program PCMODEL (Version 5.01) (Serena software, Bloomington, IN).
Finally, this molecular mechanics structure was reminimized by employing
the PM3 model in the program MOPAC (Version 7.0) (Serena software,
Bloomington, IN).
(24) For intramolecular Diels-Alder reactions of Br-containing trienes,
see: Roush, W. R.; Kageyama, M.; Rita, R.; Brown, B. B.; Warmus, J. S.;
Moriarty, K. J. J. Org. Chem. 1991, 56, 1192-1210 and references therein.
(25) Youn, I. K.; Yon, G. H.; Pak, C. S. Tetrahedron Lett. 1986, 27,
2409-2412.
(20) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. Tetra-
hedron Lett. 1986, 27, 4025-4028.
(21) (a) Barton, D. H. R.; Ferreira, J. A.; Jaszberenyi, J. C. In PreparatiVe
Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York,-
1997; pp 15-172. (b) Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem.
Soc. 1997, 119, 6949-6950.

4920 J. Am. Chem. Soc., Vol. 120, No. 20, 1998
Toyota et al.
Figure 1.
a deoxygenation reaction;21 Bu3SnH and catalytic amounts of
AIBN in toluene were added to 12 in toluene (0.01 M) over a
period of 3 h. Under these reaction conditions, the homoallyl
radical generated from 12 was smoothly rearranged, as expected,
via successive 3-exo-trig cyclization and 3-exo fragmentation,
to furnish 5c as the sole product in 68% overall yield in two
steps.31 The spectral properties (1H NMR and IR) of (()-5c
were identical in all respects to those of (-)-5c provided by
Coates.
Figure 2.
Conclusions
We have synthesized racemic methyl kaur-16-en-19-oate (6c),
methyl trachyloban-19-oate (4c), and methyl atis-16-en-19-oate
(5c) via a common intermediate 30. The key step in the
synthesis of 5c is a homoallyl-homoallyl radical rearrangement
that allowed, in a one-pot process, the construction of the
atisirene skeleton without isomerization of the exomethylene
moiety. Moreover, this successful approach opens a novel
pathway for the syntheses of other atisirene-type diterpenoids
and diterpene alkaloids such as atisine.
Total Synthesis of (()-Methyl Atis-16-en-19-oate (5c)
With the efficient synthesis of 29 realized, the stage was now
set for the completion of the synthesis. Ester 29 was converted
to 30 via stereoselective methylation (84%) and hydrolysis of
the ethylene acetal moiety (100%). To confirm the stereo-
chemistry of keto ester 30, it was subjected to Wolff-Kishner
reduction. Namely, treatment of 30 with excess NH2NH2‚H2O
and KOH in bis(ethylene glycol) at 200 °C furnished the desired
(()-methyl kaur-16-en-19-oate (6c)26 (51% in two steps) after
reesterification with CH2N2. It is surprising that (()-methyl
trachyloban-19-oate (4c)27,28 was also obtained in 11% overall
yield in two steps.29 It should be further noted that the present
approach employing the intramolecular Diels-Alder reaction
of the bromo diene 14 provides an efficient route for these
diterpenes.
Experimental Section32
General Method for the Preparation of Silyl Enol Ethers (16a-
c). To a stirred solution of LDA (1.2 mmol) in THF (2 mL) cooled to
-78 °C was added dropwise a solution of substrate 1717 (1.0 mmol) in
THF (1 mL). After 45 min, a solution of TBDMSCl (1.5 mmol) and
HMPA (1.2 mmol) in THF (1 mL) was added at the same temperature,
and the resulting mixture was allowed to warm to 0 °C. After removal
of the solvent, the residue was diluted with hexane, washed with H2O
and brine, and dried over K2CO3. Removal of the solvent and
chromatography of the crude product on silica gel with hexanes-EtOAc
(20:1 v/v) afforded the TBDMS enol ether as a colorless oil (yields of
95-100%). TMS/TES enol ethers were prepared in the same manner
as the corresponding TBDMS enol ethers, by quenching the lithium
enolates with chlorotrimethylsilane (1.5 equiv)/chlorotriethylsilane (1.5
equiv). TMS enol ether was purified by bulb-to-bulb distillation.
Finally, 30 was transformed into (()-5c as shown in Scheme
7. Reduction of 30 with NaBH4 produced 31 in 93% yield as
a 1:3.6 mixture in which the â-oriented hydroxyl group was
predominant.30 Hydroxyesters 31 were then acylated with 1,1′-
thiocarbonyldiimidazole to afford 12, which was submitted to
(26) Mori, K.; Matsui, M. Tetrahedron Lett. 1966, 175-180; Tetrahedron
1968, 24, 3095-3111.
(27) Pyrek, J. S. Tetrahedron 1970, 26, 5029-5032.
(28) (a) Cory, R. M.; Naguib, Y. M. A.; Rasmussen, M. H. J. Chem.
Soc., Chem. Commun. 1979, 504-506. (b) Cory, R. M.; Chan, D. M. T.;
Naguib, Y. M. A.; Rastall, M. H.; Renneboog, R. M. J. Org. Chem. 1980,
45, 1852-1863 and references therein.
(29) For a possible mechanism, we propose a sigmatropic elimination
of N2 from a â-oriented diazene intermediate (CH-NdNH).
(30) Lewis, N. J.; MacMillan, J. J. Chem. Soc., Perkin Trans. 1 1980,
1270-1278.
(31) Although deoxygenation of the corresponding thiobenzoate, prepared
from naturally occurring 12R-acetoxykaur-16-en-19-oic acid, was performed
for degradation purposes, the reported product was (-)-kaurenoic acid (mass
spectral analysis), see: Beale, M. H.; Bearder, J. R.; MacMillan, J.; Matsuo,
A.; Phinney, B. O. Phytochemistry 1983, 22, 875-881.
(32) See the Experimental Section of ref 17b.

Total Synthesis of (()-Methyl Atis-16-en-19-oate
J. Am. Chem. Soc., Vol. 120, No. 20, 1998 4921
4.0 and 2.0), 5.05-5.18 (2H, m), 5.55 (1H, d, J ) 10.0), 5.85 (1H,
Scheme 6
ddt, J ) 17.5, 10.0, and 7.5), and 5.91 (1H, dd, J ) 10.0 and 2.0). 13
C
NMR (75 MHz, C6D6): δ 5.43, 7.00, 32.92, 36.64, 38.29, 43.64, 54.90,
64.72, 96.59, 100.56, 117.51, 125.80, 135.22, 136.76, and 147.91. Anal.
Calcd for C19H34O3Si: C, 67.41; H, 10.12. Found: C, 67.32; H, 10.42.
Palladium-Catalyzed Cycloalkenylation Reaction. (()-5-(2-
(Methoxymethoxy)ethyl)-7-methylidene-cis-bicyclo[3.2.1]oct-3-en-
2-one (15)17b (as a Typical Procedure; Run 4). To a stirred solution
of TBDMS enol ether 16c (78.7 mg, 0.233 mmol) in DMSO (4.6 mL)
was added Pd(OAc)2 (2.60 mg, 11.6 µmol) at room temperature, and
the resulting solution was again stirred under O2 (1 atm) for 4 h. The
reaction mixture was diluted with Et2O and filtered through Celite to
remove Pd black. H2O (50 mL) was added to the filtrate, and the layers
were separated. The aqueous layer was further extracted with Et2O,
and the combined organic layers were washed with ice-cold 10% HCl,
saturated NaHCO3 and brine and dried. After removal of the solvent,
the residue was chromatographed. Elution with a 2:1 mixture of
hexane-EtOAc furnished 1517b (42.4 mg, 82%), 18 (1.7 mg, 3%), and
19 (1.6 mg, 3%), each as a colorless oil.
(()-5-(2-(Methoxymethoxy)ethyl)-7-methyl-cis-bicyclo[3.2.1]octa-
3,6-dien-2-one (18). IR: 1675 cm-1 1H NMR (300 MHz, C6D6): δ
.
1.78 (3H, d, J ) 1.8), 1.96 (1H, dt, J ) 14.0 and 6.5), 2.10 (1H, dt, J
) 14.0 and 6.5), 2.46 (1H, ddd, J ) 9.5, 4.5, and 1.8), 2.56 (1H, d, J
) 9.5), 3.15 (1H, br d, J ) 4.5), 3.36 (3H, s), 3.66 (2H, t, J ) 6.6),
4.62 (2H, s), 5.35 (1H, dd, J ) 10.0 and 1.8), 6.01 (1H, br s), and 7.25
(1H, dd, J ) 10.0 and 1.8). 13C NMR (75.3 MHz, CDCl3): δ 15.67,
35.38, 51.08, 55.47, 55.67, 62.18, 64.74, 96.60, 121.71, 139.19, 142.85,
160.01, and 199.99. Anal. Calcd for C13H18O3: C, 70.24; H, 8.16.
Found: C, 70.20; H, 8.10.
(()-4-(2-(Methoxymethoxy)ethyl)-4-(2-propenyl)-cyclohexa-2,5-
.
dien-1-one (19). IR: 1665 and 1625 cm-1 1H NMR (300 MHz,
CDCl3) δ 2.00 (2H, br t, J ) 7.0), 2.38 (2H, d, J ) 7.3), 3.29 (3H, s),
3.37 (2H, br t, J ) 7.0), 4.50 (2H, s), 5.00-5.12 (2H, m), 5.50-5.67
(1H, m), and 6.32 (2H, dt, J ) 10.5 and 2.3). 13C NMR (75 MHz,
CDCl3): δ 38.67, 44.21, 44.50, 55.38, 64.12, 96.55, 119.20, 129.88,
131.80, 153.75, and 186.20. Anal. Calcd for C13H18O3: C, 70.24; H,
8.16. Found: C, 70.00; H, 8.44.
(1R*,2R*,4S*,5S*)-5-((Methoxymethoxy)ethyl)-4-(methylethenyl)-
7-methylidenebicyclo[3.2.1]octan-2-ol (20a) and (1R*,2S*,4S*,5S*)-
5-((Methoxymethoxy)ethyl)-4-(methylethenyl)-7-methylidenebicyclo-
[3.2.1]octan-2-ol (20b). To a stirred solution of ketone 1517b (134 mg,
0.508 mmol) in 2-propanol (5 mL) was added NaBH4 (193 mg, 5.09
mmol) at room temperature, and then the mixture was stirred at room
temperature for 12 h. After removal of the solvent, saturated brine (7
mL) was added. The resulting mixture was extracted with CHCl3, and
then the organic layer was dried and evaporated to leave an oil, which
was chromatographed. Elution with a 5:1 mixture of hexane-EtOAc
afforded R-alcohol 20a (52.9 mg, 39%) followed by â-alcohol 20b
(()-2-(tert-Butyldimethylsiloxy)-5-(2-(methoxymethoxy)ethyl)-5-
(2-propenyl)cyclohexa-1,3-diene (16c). IR: 1670 and 1040 cm-1. 1H
NMR (300 MHz, C6D6): δ 0.22 (6H, s), 1.07 (9H, s), 1.75 (1H, dt, J
) 13.5 and 7.0), 1.86 (1H, dt, J ) 13.5 and 7.0), 2.11-2.30 (4H, m),
3.27 (3H, s), 3.65 (2H, t, J ) 7.0), 4.56 (2H, s), 4.85-4.93 (1H, m),
5.04-5.16 (2H, m), 5.55 (1H, d, J ) 10.0), and 5.77-5.93 (2H, m).
13C NMR (75 MHz, C6D6): δ -4.24, 18.30, 25.96, 32.87, 36.63, 38.27,
43.61, 54.89, 64.69, 96.56, 101.27, 117.51, 125.77, 135.17, 136.73,
and 147.86. Anal. Calcd for C19H34O3Si: C, 67.41; H, 10.12.
Found: C, 67.35; H, 10.04.
(62.4 mg, 46%), each as a colorless oil. 20a: IR: 3450 cm-1 1H
.
NMR (300 MHz, CDCl3): δ 1.23 (1H, br dd, J ) 11.5 and 5.0), 1.52
(1H, d, J ) 14.5), 1.56 (1H, ddd, J ) 14.0, 8.5, and 6.0), 1.77 (1H, br
s), 1.93 (3H, d, J ) 0.6), 2.03 (1H, ddd, J ) 14.0, 8.5, and 5.5), 2.08
(1H, ddd, J ) 14.0, 8.5, and 4.5), 2.22 (1H, d, J ) 8.5), 2.28-2.34
(2H, m), 2.44 (1H, dd, J ) 11.5 and 1.5), 2.71 (1H, dd, J ) 5.0 and
3.5), 3.35 (1H, br s), 4.82-4.91 (3H, m), and 5.04-5.07 (1H, m). 13
C
NMR (75.4 MHz, CDCl3): δ 23.71, 31.55, 32.94, 37.93, 43.85, 45.07,
48.85, 49.76, 55.15, 64.79, 72.24, 96.43, 105.67, 113.32, 149.37, and
152.40. Anal. Calcd for C16H26O3: C, 72.13; H, 9.84. Found: C,
.
72.17; H, 9.80. 20b: IR: 3450 cm-1 1H NMR (500 MHz, CDCl3):
(()-5-(2-(Methoxymethoxy)ethyl)-5-(2-propenyl)-2-(trimethylsi-
loxy)cyclohexa-1,3-diene (16a). IR: 1680, 1650, and 1020 cm-1. 1H
NMR (300 MHz, C6D6): δ 0.19 (9H, s), 1.60-1.80 (2H, m), 2.19 (2H,
d, J ) 5.5), 2.06-2.24 (2H, m), 3.35 (3H, s), 3.51-3.66 (2H, m), 4.59
(2H, s), 4.72-4.80 (1H, m), 4.96-5.09 (2H, s), 5.55 (1H, d, J ) 10.0),
5.65 (1H, dd, J ) 10.0 and 2.0), and 5.70-5.83 (1H, m). 13C NMR
(75 MHz, C6D6): δ 0.32, 32.86, 36.63, 38.36, 43.70, 54.90, 64.71,
96.56, 101.00, 117.47, 125.83, 135.19, 136.76, and 147.76. Anal. Calcd
for C16H28O3Si: C, 64.82; H, 9.52. Found: C, 64.53; H, 9.36.
(()-5-(2-(Methoxymethoxy)ethyl)-5-(2-propenyl)-2-(triethylsiloxy)-
δ 1.40 (1H, ddd, J ) 14.0, 11.5, and 8.0), 1.44 (1H, ddd, J ) 12.0,
8.0, and 5.5), 1.60 (1H, br s), 1.78 (1H, ddd, J ) 15.0, 9.0, and 5.5),
1.78-1.81 (3H, m), 1.84 (1H, ddd, J ) 15.0, 9.0, and 5.5), 1.89 (1H,
dd, J ) 12.0 and 1.5), 2.27 (1H, br d, J ) 8.0), 2.32 (1H, dt, J ) 12.0
and 2.5), 2.61 (1H, br dd, J ) 5.5 and 3.5), 3.35 (3H, s), 3.47 (1H,
ddd, J ) 13.5, 9.0, and 6.7), 3.58 (1H, ddd, J ) 13.5, 9.0, and 5.5),
3.88 (1H, ddd, J ) 11.5, 6.0, and 3.5), 4.60 (2H, s), 4.76 (1H, br s),
4.82 (1H, br s), 4.90 (1H, br s), and 4.91 (1H, br s). 13C NMR (125.65
MHz, CDCl3): δ 24.62, 35.09, 37.37, 38.31, 44.21, 44.74, 50.45, 50.67,
55.22, 64.89, 70.20, 96.45, 106.58, 114.24, 147.95, and 150.94. Anal.
Calcd for C16H26O3: C, 72.14; H, 9.84. Found: C, 71.94; H, 9.91.
cyclohexa-1,3-diene (16b). IR: 1655 and 1050 cm-1 1H NMR (300
.
MHz, C6D6): δ 0.76 (2H, q, J ) 7.7), 1.10 (3H, t, J ) 7.7), 1.76 (1H,
dt, J ) 13.5 and 7.3), 1.87 (1H, dt, J ) 13.5 and 7.3), 2.12-2.30 (4H,
m), 3.27 (3H, s), 3.66 (2H, t, J ) 7.3), 4.57 (2H, s), 4.90 (1H, dt, J )

4922 J. Am. Chem. Soc., Vol. 120, No. 20, 1998
Toyota et al.
Scheme 7
2-[(1S*,2S*,4S*)-1-(2-(Methoxymethoxy)ethyl)-5-methyl-
idenebicyclo[2.2.2]octan-2-yl]prop-1-ene (21). (A) From 20b: To a
stirred solution of 20b (40.3 mg, 0.151 mmol) in 1,2-dichloroethane
(1 mL) was added 1,1′-thiocarbonyldiimidazole (90.8 mg, 0.459 mmol)
at room temperature, and then the mixture was again stirred at room
temperature for 13 h. After removal of the solvent, the residue was
chromatographed. Elution with a 2:1 mixture of hexane-EtOAc gave
the thioimidazolide (46.8 mg, 82%) as a colorless oil. 1H NMR (300
MHz, CDCl3): δ 1.57 (1H, ddd, J ) 12.5, 6.0, and 2.0), 1.62 (1H,
ddd, J ) 14.0, 9.0, and 6.0), 1.85-2.11 (7H, m), 2.26 (1H, dd, J )
16.0 and 2.0), 2.40-2.51 (2H, m), 3.00 (1H, dd, J ) 6.0 and 3.0),
3.34 (2H, s), 3.48-3.70 (2H, m), 4.86-4.88 (1H, m), 4.92 (1H, t, J )
1.5), 4.96-5.03 (2H, m), 5.08 (1H, ddd, J ) 9.0, 6.0, and 3.0), 7.02
(1H, dd, J ) 1.1 and 1.5), 7.62 (1H, t, J ) 1.5), and 8.33 (1H, t, J )
1.1). 13C NMR (75.4 MHz, CDCl3): δ 24.37, 29.23, 37.70, 38.04,
44.28, 44.31, 46.57, 50.43, 55.27, 64.68, 83.26, 96.53, 108.30, 115.13,
118.02, 130.88, 136.89, 147.18, 149.58, and 183.48. HRMS calcd for
C20H28N2O3S (M+): 376.1819. Found: 376.1772.
and then the resulting yellowish mixture was again stirred at room
temperature for 20 h. After removal of the solvent, the residue was
chromatographed. Elution with a 3:1 mixture of hexane-EtOAc
furnished the thioimidazolide (36.8 mg, 91%) as a colorless oil. 1H
NMR (300 MHz, CDCl3): δ 1.14 (1H, dd, J ) 11.5 and 5.0), 1.64
(1H, ddd, J ) 12.5, 8.0, and 6.0), 1.89 (3H, d, J ) 0.6), 1.88-1.99
(1H, m), 2.15 (1H, ddd, J ) 12.5, 7.5, and 5.0), 2.26-2.44 (5H, m),
3.15 (1H, br dd, J ) 5.0 and 3.0), 3.36 (3H, s), 3.46-3.64 (2H, m),
4.60 (2H, s), 4.96 (1H, t, J ) 1.5), 4.99 (1H, br s), 5.02 (1H, br s),
5.09 (1H, br t, J ) 2.5), 5.51 (1H, br t, J ) 4.0), 7.03 (1H, dd, J ) 1.4
and 0.8), 7.65 (1H, t, J ) 1.4), and 8.34 (1H, br s). 13C NMR (75.4
MHz, CDCl3): δ 24.15, 27.99, 33.92, 37.54, 43.79, 45.22, 45.66, 47.59,
55.24, 64.58, 83.78, 96.49, 108.18, 113.14, 118.17, 130.89, 137.04,
147.01, 149.88, and 183.59. HRMS calcd for C20H28N2O3S: 376.1819.
Found: 376.1819.
To a stirred solution of the above thioimidazolide (31.7 mg, 84.2
µmol) in degassed toluene (4 mL) was slowly added a degassed toluene
solution (0.4 mL) of Bu3SnH (34 µL, 0.123 mmol) and AIBN (1 mg,
6 µmol) over a period of 2 h under reflux. After 1 h of refluxing, the
solvent was evaporated to give an oil, which was directly chromato-
graphed. Elution with a 30:1 mixture of hexane-EtOAc provided
21 (11.8 mg, 56%) and 22 (2.4 mg, 11%) as a colorless oil. 22: IR
To a stirred solution of the above thioimidazolide (24.4 mg, 64.8
µmol) in degassed toluene (3 mL) was slowly added a degassed toluene
solution (0.3 mL) of Bu3SnH (0.025 mL, 90.2 µmol) and AIBN (0.6
mg, 3.7 µmol) over a period of 2.5 h under reflux. After 1 h of
refluxing, Et2O (5 mL) was added, and the resulting mixture was
successively washed with 5% HCl (2 mL), saturated NaHCO3 and brine,
dried, and evaporated to yield an oil, which was chromatographed.
Elution with a 30:1 mixture of hexane-EtOAc afforded 21 (10.8 mg,
(CHCl3): 1645 and 1660 cm-1 1H NMR (300 MHz, CDCl3): δ 1.33
.
(1H, br ddd, J ) 10.5, 3.5, and 1.0), 1.77 (3H, dd, J ) 1.2 and 0.6),
1.61 (1H, ddd, J ) 13.0, 9.0, and 5.5), 1.81-1.92 (2H, m), 2.20 (1H,
br dq, J ) 16.0 and 2.0), 2.40 (dt, J ) 16.0 and 2.0), 2.72 (1H, dd, J
) 3.5 and 1.5), 2.91 (1H, dd, J ) 6.5 and 3.5), 3.58 (3H, s), 3.56 (1H,
dt, J ) 9.0 and 5.5), 3.72 (1H, dt, J ) 9.0 and 5.0), 4.55 (1H, br s),
4.61 (2H, s), 4.71-4.76 (1H, m), 4.81-4.84 (1H, m), 4.86-4.90 (1H,
m), 5.27 (1H, dd, J ) 9.0 and 3.5), and 5.98 (1H, dddd, J ) 9.0, 6.5,
1.5, and 1.0); 13C NMR (75.3 MHz, CDCl3): δ 22.26, 37.29, 38.41,
43.42, 44.35, 44.39, 55.27, 57.16, 64.68, 96.50, 101.37, 115.02, 127.96,
132.92, 146.33, and 157.11. HRMS calcd for C16H24O2 (M+):
248.1776. Found: 248.1782.
67%) as a colorless oil. IR (CHCl3): 1639 and 1650 cm-1 1H NMR
.
(500 MHz, CDCl3): δ 1.31 (1H, ddd, J ) 11.5, 4.5, and 2.0), 1.34
(1H, ddd, J ) 11.5, 5.0, and 2.0), 1.40-1.81 (9H, m), 2.05-2.13 (1H,
m), 2.17-2.24 (3H, m), 3.33 (3H, s), 3.53 (2H, dt, J ) 9.0 and 6.0),
4.57 (2H, s), 4.60 (1H, q, J ) 2.0), 4.73 (1H, q, J ) 2.0), 4.76-4.78
(1H, m), 4.79-4.81 (1H, m). 13C NMR (125.65 MHz, CDCl3): δ
21.76, 26.76, 26.82, 33.95, 35.30, 36.05, 37.62, 42.39, 48.91, 55.26,
64.40, 96.55, 105.33, 113.62, 147.74, and 151.94. HRMS calcd for
C16H26O2: 250.1931. Found: 250.1939.
3-[Spiro[(1R*,4S*,5S*)-4-(methylethenyl)-7-methylidenebicyclo-
[3.2.1]octan-2,2′-1′,3′-dioxolan]-5-yl]propanenitrile (26). To a solu-
tion of 2517b (1.70 g, 6.44 mmol) in pyridine (5 mL) was added
p-toluenesulfonyl chloride (1.16 g, 8.41 mmol) at 0 °C, and then the
(B) From 20a: To a stirred solution of 20a (28.8 mg, 0.108 mmol)
in CH2Cl2 (2 mL) were added 1,1′-thiocarbonyldiimidazole (58.4 mg,
0.328 mmol) and DMAP (41.9 mg, 0.235 mmol) at room temperature,

Total Synthesis of (()-Methyl Atis-16-en-19-oate
J. Am. Chem. Soc., Vol. 120, No. 20, 1998 4923
mixture was placed in a refrigerator for 14 h. After the addition of
H2O (20 mL), the resulting solution was extracted with Et2O. The
ethereal layer was washed in succession with 10% CuSO4 (10 mL ×
3), H2O (5 mL), and brine, dried, and evaporated to leave the tosylate
(2.75 g) as a white solid, which was used in the next step without
further purification.
°C. After 10 min of stirring at 0 °C, H2O (1 mL) was added at 0 °C.
The mixture was diluted with hexane (3 mL) and Et2O (3 mL), and
the resulting mixture was again stirred at room temperature until a heavy
white precipitate began to form. After addition of MgSO4 at 0 °C, the
mixture was filtered through Celite. The filtrate was concentrated to
produce an oil, which was chromatographed. Elution with a 5:4 mixture
of hexane-Et2O afforded the desired Z-isomer (129 mg, 74%) and then
the E-isomer (24.9 mg, 14%), each as a colorless oil. Z-isomer: IR:
To a stirred solution of the above tosylate (2.75 g) in DMSO (16
mL) was added powdered NaCN (442 mg, 8.57 mmol) at room
temperature, and then the resulting clear solution was again stirred at
room temperature for 24 h. After addition of H2O (30 mL), the mixture
was extracted with Et2O. The ethereal layer was washed with H2O
(16 mL) and brine, dried, and evaporated to give a white solid, which
was chromatographed. Elution with a 5:1 mixture of hexane-EtOAc
afforded 26 (1.71 g, 97% for 2 steps) as a white solid. An analytical
sample, obtained as colorless prisms by recrystallization of a small
amount of this material from Et2O-hexane, exhibited mp 89.0-90.5
3400 cm-1 1H NMR (300 MHz, CDCl3): δ 1.29 (1H, dt, J ) 12.5
.
and 5.0), 1.36 (1H, ddd, J ) 12.0, 5.0, and 1.5), 1.57 (1H, d, J )
15.0), 1.67 (1H, dt, J ) 12.5 and 5.0), 1.93 (3H, s), 2.10 (1H, dd, J )
15.0 and 9.5), 2.27-2.40 (6H, m), 2.44 (1H, d, J ) 9.5), 2.59 (1H, br
d, J ) 5.0), 3.86-4.04 (4H, m), 4.22 (2H, d, J ) 6.0), 4.74-4.82 (1H,
m), 4.92 (2H, br s), 4.99-5.07 (1H, m), and 5.95 (1H, t, J ) 7.0). 13
C
NMR (75.4 MHz, CDCl3): δ 22.60, 26.70, 34.86, 36.57, 39.77, 44.35,
44.44, 49.60, 51.03, 63.57, 64.42, 67.98, 107.85, 110.45, 114.08, 126.27,
129.93, 148.34, and 149.82. Anal. Calcd for C19H27BrO3: C, 59.53;
H, 7.10; Br, 20.85. Found: C, 59.40; H, 7.10; Br, 20.74. E-isomer:
°C. IR (CHCl3): 2260 cm-1 1H NMR (300 MHz, CDCl3): δ 1.37
.
(1H, ddd, J ) 12.0, 5.5, and 1.5), 1.57 (1H, dd, J ) 15.0 and 1.5),
1.65 (1H, ddd, J ) 13.5, 10.5, and 6.0), 1.94 (3H, s), 1.97 (1H, ddd,
J ) 13.5, 10.5, and 5.5), 2.10 (1H, dd, J ) 15.0 and 9.5), 2.19-2.46
(6H, m), 2.60 (1H, dd, J ) 5.5 and 1.5), 3.86-4.04 (4H, m), 4.80 (1H,
br s), 4.86 (1H, br s), 4.93 (1H, br s), and 5.05 (1H, br s). 13C NMR
(75.4 MHz, CDCl3): δ 13.5, 22.17, 34.14, 34.86, 36.69, 44.00, 44.32,
49.71, 50.87, 63.88, 64.70, 108.80, 110.24, 114.96, 120.40, 148.32,
and 148.99. Anal. Calcd for C17H23NO2: C, 74.69; H, 8.48; N, 5.12.
Found: C, 74.54; H, 8.44; N, 4.89.
IR: 3450 cm-1 1H NMR (300 MHz, CDCl3): δ 1.27 (1H, dt, J )
.
12.5 and 4.5), 1.34 (1H, ddd, J ) 11.5, 5.5, and 1.5), 1.56 (1H, dd, J
) 15.0 and 1.5), 1.65 (1H, dt, J ) 12.5 and 4.5), 1.85 (1H, br t, J )
6.0), 1.93-2.34 (6H, m), 2.42 (1H, br d, J ) 9.5), 2.58 (1H, br d, J )
5.5), 3.86-4.02 (4H, m), 4.28 (2H, d, J ) 6.0), 4.81 (1H, dd, J ) 1.5
and 0.5), 4.89 (1H, d, J ) 1.5), 4.91 (1H, s), 5.02-5.04 (1H, m), and
5.99 (1H, t, J ) 8.0). 13C NMR (75.4 MHz, CDCl3): δ 22.43, 25.62,
35.03, 37.09, 38.08, 44.41, 44.71, 49.81, 51.06, 62.55, 63.77, 64.58,
108.08, 110.42, 114.06, 124.19, 135.31, 148.95, and 149.71. HRMS
calcd for C19H27BrO3 (M+): 382.1143. Found: 382.1166.
Ethyl 2-Bromo-3-[spiro[(1R*,4S*,5S*)-4-(methylethenyl)-7-
methylidenebicyclo[3.2.1]octan-2,2′-1′,3′-dioxolan]-5-yl]pent-2-en-
1-oate (27). To a stirred solution of 26 (186 mg, 0.680 mmol) in
toluene (5 mL) was added dropwise DIBALH (0.85 mL, 0.95 M in
hexane, 0.808 mmol) at -78 °C. After 5 min, saturated NH4Cl (2
mL) was added at -78 °C, and then the mixture was allowed to warm
to room temperature over a period of 10 min. After addition of 10%
HCl (20 drops) at room temperature, the resulting mixture was extracted
with Et2O. The ethereal layer was washed with saturated NaHCO3
and brine, dried, and evaporated to provide an oil, which was
chromatographed. Elution with a 7:1 mixture of hexane-EtOAc
furnished the aldehyde (172 mg, 91%), as a colorless oil, which was
immediately used in the next reaction. IR (CHCl3): 1722 and 2730
A mixture of the above Z-isomer (33.6 mg, 87.7 µmol) and MnO2
(379 mg) in toluene (3 mL) was stirred at room temperature for 4 h.
After filtration through Celite, the filtrate was concentrated to afford
the aldehyde, which was immediately used without purification.
To a stirred ylide, prepared from methyltriphenylphophonium
bromide (63.9 mg, 0.179 mmol) and BuLi (80.0 µL, 10% in hexane,
0.125 mmol), in THF (1 mL) was added dropwise a THF solution (1.5
mL) of the above aldehyde at room temperature. After 15 min of
stirring at room temperature, saturated NH4Cl (2 mL) was added, and
the resulting mixture was extracted with Et2O. The ethereal layer was
washed with H2O (2 mL) and brine, dried, and evaporated to furnish
an oil, which was chromatographed. Elution with a 15:1 mixture of
hexane-EtOAc afforded 14 (27.7 mg, 83%) as a colorless oil. IR:
cm-1 1H NMR (300 MHz, CDCl3): δ 1.37 (1H, ddd, J ) 11.0, 5.0,
.
and 1.7), 1.50-1.64 (2H, m), 1.85 (1H, ddd, J ) 14.0, 8.0, and 5.0),
1.92 (3H, s), 2.09 (1H, dd, J ) 14.5 and 8.5), 2.20-2.43 (5H, m), 2.5
(1H, ddd, J ) 10.5, 5.0, and 1.6), 2.59 (1H, br d, J ) 5.0), 3.85-4.03
(4H, m), 4.74-4.78 (1H, m), 4.87 (1H, d, J ) 1.5), 4.91 (1H, br s),
5.01-5.05 (1H, m), 9.75 (1H, t, J ) 1.6). 13C NMR (75.4 MHz,
CDCl3): δ 22.40, 30.05, 35.02, 36.84, 40.04, 43.87, 44.64, 50.11, 51.20,
63.85, 64.67, 108.36, 114.51, 148.79, and 204.84. HRMS calcd for
C17H24O3 (M+): 276.1725. Found: 276.1724.
1600, 1630, and 1655 cm-1 1H NMR (300 MHz, CDCl3): δ 1.23-
.
1.42 (2H, m), 1.57 (1H, dd, J ) 15.0 and 1.5), 1.70 (1H, ddd, J )
13.5, 11.5 and 5.5), 1.93 (3H, s), 2.10 (1H, dd, J ) 15.0 and 9.5),
2.16-2.43 (5H, m), 2.45 (1H, dd, J ) 9.5 and 1.0), 2.59 (1H, br d, J
) 5.5), 3.85-4.05 (4H, m), 4.73-4.82 (1H, m), 4.86-4.96 (2H, m),
5.00-5.07 (1H, m), 5.15 (1H, d, J ) 10.3), 5.51 (1H, d, J ) 16.5),
5.93 (1H, t, J ) 7.0), and 6.28 (1H, dd, J ) 16.5 and 10.3). 13C NMR
(75.4 MHz, CDCl3): δ 22.67, 27.52, 34.96, 36.61, 36.82, 44.49, 44.53,
49.74, 51.20, 63.74, 64.56, 107.98, 114.27, 117.29, 125.34, 135.90,
138.84, and 150.26. Anal. Calcd for C20H27BrO2: C, 63.33; H, 7.17;
Br, 21.06. Found: C, 63.25; H, 7.13; Br, 20.95.
A mixture of the above aldehyde (143.5 mg, 0.519 mmol) and the
Wittig reagent33 (326 mg, 0.793 mmol) in toluene (2 mL) was heated
at 80 °C for 4 h. After further addition of the Wittig reagent (64.6
mg, 0.157 mmol), heating of the resulting mixture was continued at
80 °C for 1 h. The solvent was removed under reduced pressure, and
the residue was chromatographed. Elution with a 7:1 mixture of
hexane-EtOAc gave rise to 27 (204 mg, 92%) as a mixture of Z- and
E-isomers in the ratio 5:1. IR: 1630, 1660, 1718 (middle, CdO of
(()-19,20-Dinor-4-bromokaur-3,16-dien-12-one 12-Ethylene Ac-
etal (13). A toluene solution (16 mL) of 14 (155 mg, 0.409 mmol)
was heated at 200 °C in a sealed tube for 45 h. After removal of the
solvent, the residue was chromatographed. Elution with a 15:1 mixture
of hexane-Et2O afforded 114 mg (74%) of 13 + 28 (5.7:1 mixture by
1H NMR) as a solid. Recrystallization of the Diels-Alder adducts
(13 + 28) from Et2O-hexane provided an analytical sample of 13 as
colorless prisms, mp 136.0-137.5 °C. IR (CHCl3): 1638 and 1655
cm-1. 13: 1H NMR (300 MHz, CDCl3): δ 1.08 (3H, s), 1.23 (1H,
ddd, J ) 11.0, 5.0 and 1.5), 1.30 (1H, d, J ) 8.5), 1.34-1.85 (9H, m),
1.87 (1H, dd, J ) 14.0 and 8.5), 2.42 (1H, dd, J ) 12.0 and 1.5), 2.60
(1H, d, J ) 5.0), 3.80-4.05 (4H, m), 4.95-5.02 (1H, m), and 5.97-
6.05 (1H, m). 13C NMR (75.4 MHz, CDCl3): δ 12.34, 25.22, 25.28,
29.51, 34.92, 37.82, 39.18, 39.60, 42.93, 49.37, 51.76, 51.88, 52.88,
52.77, 63.69, 64.64, 107.55, 110.43, 128.30, 128.39, and 150.02. Anal.
Calcd for C20H27BrO2: C, 63.33; H, 7.17; Br, 21.06. Found: C, 63.33;
E-ester), and 1730 (strong, CdO of Z-ester) cm-1 1H NMR (300 MHz,
.
CDCl3): δ 1.32 (2.5H, t, J ) 7.2; 3H for Z-ester), 1.34 (0.5H, t, J )
7.2; 3H for E-ester), 1.28-1.42 (1H, m), 1.52-1.62 (1H, m), 1.65-
1.83 (1H, m), 1.92 (0.5H, s; 3H for E-ester), 1.93 (2.5H, s; 3H for
Z-ester), 2.04-2.16 (1H, m), 2.20-2.62 (8H, m), 3.87-4.02 (4H, m),
4.26 (2H, q, J ) 7.2), 4.75-4.82 (1H, m), 4.87-4.95 (2H, m), 5.00-
5.06 (1H, m), 6.60 (0.17H, t, J ) 8.4; 1H for E-ester), and 7.24 (0.83H,
t, J ) 8.4; 1H for Z-ester). HRMS calcd for C21H29BrO4 (M+):
424.1248. Found: 424.1246.
(1R*,4S*,5S*)-5-[(Z)-4-Bromohexa-3,5-dienyl]-4-(methylethenyl)-
7-methylidenebicyclo[3.2.1]octane-2-one 2-Ethylene Acetal (14). To
a stirred solution of 27 (195 mg, 0.458 mmol) in toluene (5 mL) was
added dropwise DIBALH (1.0 mL, 0.95 M hexane, 0.95 mmol) at 0
H, 7.17; Br, 21.16. 13 + 28 (5.7:1): IR (CHCl3): 1710 cm-1 1H
.
NMR (300 MHz, CDCl3): δ 0.85-1.10 (1H, m), 1.02 (2.6H, s), 1.17-
1.38 (2H, m), 1.25 (0.4H, s), 1.56-2.24 (12H, m), 2.35 (0.15H, d, J )
(33) Denny, D. B.; Ross, S. T. J. Org. Chem. 1961, 27, 998-1000.

4924 J. Am. Chem. Soc., Vol. 120, No. 20, 1998
Toyota et al.
12.0), 2.43 (0.85H, d, J ) 12.0), 2.60 (1H, br d, J ) 5.0), 3.70 (2.6 H,
s), 3.72 (0.4H, s), 3.86-4.03 (4H, m), 4.84 (0.15H, br s), 4.87 (0.85H,
br s), 4.95-5.01 (1H, m), 6.48-6.55 (0.85H, m), 6.67-6.72 (0.15H,
m). HRMS clacd for C22H30O4 (M+): 358.2142, found: 358.2144.
(()-Methyl 20-Nor-12-oxokaur-16-en-19-oate 12-Ethylene Acetal
(29). To a stirred solution of a 5.7:1 mixture of the Diels-Alder
adducts 13 and 28 (68.0 mg, 0.179 mmol) and 2,2′-dipyridyl (a crystal
as indicator) in THF (3 mL) was added dropwise tBuLi (0.22 mL, 1.64
M in hexane, 0.361 mmol) at -78 °C. The reaction mixture remained
a red color for 40 min. When methyl chloroformate (80.0 µL, 1.04
mmol) was added at -78 °C, the color dissipated. After 0.5 h of
stirring, saturated NH4Cl (2 mL) was added at -78 °C. The resulting
mixture was extracted with Et2O, and then the ethereal layer was washed
with brine, dried, and evaporated to provide an oil, which was
chromatographed. Elution with a 7:1 mixture of hexane-EtOAc gave
the R,â-unsaturated ester (44.6 mg, 70%) as a colorless oil.
1.01 (1H, dt, J ) 12.0 and 4.0), 1.17 (1H, dd, J ) 11.0 and 2.0), 1.19
(3H, s), 1.48-1.64 (4H, m), 1.68-1.96 (5H, m), 2.13-2.22 (1H, m),
2.22 (1H, d, J ) 16.0), 2.34-2.44 (3H, m), 2.55 (1H, dd, J ) 16.0
and 9.0), 3.22 (1H, d, J ) 4.5), 3.63 (3H, s), 4.87 (1H, br s), and 5.00
(1H, t, J ) 2.0). 13C NMR (75.4 MHz, CDCl3): δ 13.38, 18.66, 21.47,
28.61, 35.88, 37.78, 38.99, 39.48, 39.56, 39.78, 43.76, 44.05, 48.12,
51.25, 56.33, 56.73, 60.58, 107.89, 148.93, 177.77, and 211.60. Anal.
Calcd for C21H30O3: C, 76.33; H, 9.15. Found: C, 76.29; H, 9.11.
(()-Methyl Kaur-16-en-19-oate (6c) and (()-Methyl Trachylo-
ban-19-oate (4c). 30 (43.7 mg, 0.132 mmol) was dissolved in bis-
(ethylene glycol) (4 mL), and then NH2NH2‚H2O (1 mL, 20.62 mmol)
was added. The resulting mixture was refluxed at 135 °C for 2 h.
After cooling to room temperature, KOH (83.1 mg, 1.26 mmol, 85%)
was added at room temperature, and the mixture was allowed to warm
to 200 °C over a period of 2 h. After 6.5 h of heating, 5% HCl (4 mL)
was added at room temperature, and then the resulting mixture was
extracted with EtOAc. The organic layer was washed with H2O (2
mL) and brine, dried, and evaporated to leave a white solid (32.1 mg),
which was taken up into Et2O (2 mL). The resulting solution was
treated with an ethereal solution of diazomethane at room temperature.
After 1 h of stirring at room temperature, AcOH was added until the
evolution of nitrogen gas ceased. Saturated K2CO3 (1 mL) was added,
and the mixture was extracted with Et2O. The ethereal layer was
washed with brine, dried, and evaporated to afford a white solid.
Chromatography of the residue on a column of silica gel impregnated
with 30% silver nitrate with a 1:3 mixture of benzene-petroleum ether
as solvent furnished 4c (4.6 mg, 11%) and 6c (21.3 mg, 51%). 6c,
whose spectral data were consistent with those reported,34 exhibited
To a stirred solution of the above material (8.9 mg, 24.8 µmol) in
MeOH (1 mL) was added Mg (turnings) (68.0 mg, 2.63 mmol) at room
temperature. After the addition was completed, the mixture was
irradiated with ultrasound for 1 min until gas evolution was apparent;
the mixture was then stirred at room temperature for 7 h. After addition
of saturated NH4Cl (2 mL) and 10% HCl (5 drops), the resulting mixture
was extracted with Et2O. The ethereal layer was washed with brine,
dried, and evaporated to yield a solid, which was chromatographed.
Elution with a 10:1 mixture of hexane-EtOAc gave rise to the saturated
ester (8.4 mg, 94%). Recrystallization from Et2O-hexane gave 29,
1
mp 151.5-152.8 °C, as a single isomer. IR (Nujol): 1735 cm-1. H
NMR (300 MHz, CDCl3): δ 0.77 (1H, dt, J ) 13.7 and 4.0), 0.99
(3H, s), 1.16-2.00 (15H, m), 2.09-2.19 (3H, m), 2.28 (1H, d, J )
12.0), 2.45 (1H, br t, J ) 5.0), 2.57 (1H, br d, J ) 5.0), 3.65 (3H, s),
3.84-4.02 (4H, m), 4.85 (1H, br s), and 4.95-4.99 (1H, m). 13C NMR
(75.4 MHz, CDCl3): δ 13.18, 18.52, 26.93, 28.51, 29.34, 36.90, 38.60,
40.02, 40.28, 43.14, 49.12, 49.55, 51.11, 52.28, 55.58, 63.63, 64.53,
107.30, 110.54, 150.35, and 175.94. Anal. Calcd for C22H32O4: C,
73.30; H, 8.95. Found: C, 73.59; H, 8.94.
mp 89.5-90.0 °C (prisms). IR: 1650 and 1715 cm-1 1H NMR (300
.
MHz, CDCl3): δ 0.83 (3H, s), 1.17 (3H, s), 2.26-2.66 (1H, m), 4.73
(1H, br s), 4.77-4.81 (1H, m). 13C NMR (75.4 MHz, CDCl3): δ 15.55,
18.52, 19.29, 22.05, 28.88, 33.23, 38.23, 39.54, 39.79, 40.89, 41.40,
43.94, 44.33, 49.06, 51.21, 55.18, 57.16, 103.05, 155.97, and 178.16.
Anal. Calcd for C21H32O2: C, 79.70; H, 10.19. Found: C, 79.89; H,
10.17. 4c: IR (CHCl3): 1715 cm-1 1H NMR (300 MHz, CDCl3): δ
.
0.56-0.59 (2H, m), 0.76 (3H, s), 1.12 (3H, s), 1.14 (3H, s), and 3.63
(3H, s). 13C NMR (75.4 MHz, CDCl3): δ 12.45, 18.89, 19.82, 20.66,
21.94, 22.50, 24.35, 28.80, 33.20, 38.23, 38.75, 39.33, 39.57, 40.84,
43.85, 50.44, 51.21, 52.80, 57.07, and 178.09. Comparison of spectral
data recorded for synthetic 4c with those provided by Professor R. M.
Coates comfirmed that the total synthesis of 4c had indeed been
accomplished.
(()-Methyl 12-Oxokaur-16-en-19-oate (30). To a stirred solution
of diisopropylamine (0.240 mL, 1.71 mmol) in THF (1.5 mL) at 10 °C
was added dropwise BuLi (1.0 mL, 10 wt % in hexane, 1.56 mmol).
After the solution was stirred for 0.5 h at -10 °C, it was cooled to
-78 °C, and a THF solution (2 mL) of the above saturated ester (62.3
mg, 0.173 mmol) was slowly added over a period of 20 min. The
mixture was again stirred at -78 °C for 1 h; HMPA (0.03 mL, 0.172
mmol) was rapidly added. After 8 min of stirring, MeI (1 mL, 16
mmol) was quickly added at -78 °C, and the resulting mixture was
stirred at -78 °C for 10 min and at 0 °C for 2 h. After addition of
saturated NH4Cl (4 mL) and H2O (1 mL) at 0 °C, the mixture was
extracted with Et2O. The ethereal layer was washed with saturated
Na2S2O4 and H2O, dried, and evaporated to afford a solid, which was
chromatographed. Elution with a 10:1 mixture of hexane-EtOAc
provided the ester (54.6 mg, 84%) as a white solid. Subjection of this
material to recrystallization from Et2O-hexane gave needles, mp
(()-Methyl 12-Hydroxykaur-16-en-19-oate (31). To a stirred
solution of 30 (16.6 mg, 50.2 µmol) in MeOH (2 mL) was added NaBH4
(16.1 mg, 0.462 mmol) at room temperature, and then the mixture was
again stirred at room temperature for 20 min. After removal of the
solvent, CHCl3 (5 mL), saturated brine (2 mL) and 10% HCl (5 drops)
were added. After separation, the aqueous layer was extracted with
CHCl3. The combined organic layers were washed with saturated
NaHCO3 and brine, dried, and evaporated to provide an oil, which was
chromatographed. Elution with a 4:1 mixture of hexane-EtOAc gave
rise to 31 (15.6 mg, 93%) as a colorless oil. IR (CHCl3): 1720 and
.
165.0-165.5 °C. IR (CHCl3): 1715 cm-1 1H NMR (300 MHz,
3450 cm-1 1H NMR (300 MHz, CDCl3): δ 0.80 (0.65H, s; 3H for
.
CDCl3): δ 0.72-0.86 (1H, m), 0.96 (3H, s), 1.17 (3H, s), 0.92-1.86
(15H, m), 2.12-2.22 (3H, m), 2.29 (1H, d, J ) 12.0), 2.57 (1H, br d,
J ) 5.5), 3.63 (3H, s), 3.84-4.02 (4H, m), 4.85 (1H, br s), and 4.95-
5.00 (1H, m). 13C NMR (75.4 MHz, CDCl3): δ 13.49, 19.03, 21.88,
28.85, 29.58, 36.90, 38.09, 38.95, 40.46, 40.61, 42.98, 43.88, 49.05,
51.21, 52.24, 55.99, 56.92, 63.63, 64.53, 107.27, 110.58, 150.40, and
178.03. Anal. Calcd for C23H34O4: C, 73.76; H, 9.15. Found: C,
73.74; H, 9.07.
â-OH), 1.00 (2.35H, s; 3H for R-OH), 1.17 (3H, s), 2.27 (1H, d, J )
12.0), 2.61 (0.22H, br d, J ) 5.0; 1H for â-OH), 2.64 (0.78H, br d, J
)5.0; 1H for R-OH), 3.64 (3H, s), 3.78 (1H, t, J ) 5.0), 4.75-4.79
(0.78H, m), 4.83-4.86 (0.78H, m), and 4.87-4.92 (0.44H, m). HRMS
calcd for C21H32O3 (M+): 332.235. Found: 332.2347.
(()-Methyl Atis-16-en-19-oate (5c). To a stirred solution of 31
(15.0 mg, 45.1 µmol) in CH2Cl2 (1 mL) were added 1,1′-thiocarbon-
yldiimidazole (21.6 mg, 90%, 0.109 mmol) and DMAP (14.0 mg, 0.115
mmol), and the resulting yellowish solution was stirred at room
temperature for 12 h. After removal of the solvent, the residue was
chromatographed. Elution with a 4:1 mixture of hexanes-EtOAc
afforded the thioimidazolide (16 mg) a colorless oil, which was pure
enough for the subsequent step.
To a stirred solution of the above ester (54.6 mg, 0.146 mmol) in
THF (3 mL) was added 15% HClO4 (1.5 mL) at room temperature,
and then the mixture was stirred at room temperature for 1 h. After
addition of saturated NaHCO3 at room temperature, the resulting
mixture was extracted with EtOAc. The organic layer was washed
with brine, dried, and evaporated to leave a solid, which was
chromatographed. Elution with a 6:1 mixture of hexane-EtOAc
furnished 30 (48.1 mg, 100%) as a white solid. Recrystallization of a
small amount of this material from Et2O-hexane yielded 30, mp
To a stirred solution of the previous thioimidazolide (16 mg) in
degassed toluene (4 mL) was slowly added a degassed toluene solution
116.0-117.0 °C (prisms). IR (CHCl3): 1705 and 1718 cm-1
.
1H NMR
(34) Mitscher, L. A.; Rao, G. S. R.; Veysoglu, T.; Drake, S.; Haas, T. J.
Nat. Prod. 1983, 46, 745-746.
(300 MHz, CDCl3): δ 0.69 (3H, s), 0.80 (1H, dt, J ) 12.0 and 5.0),

Total Synthesis of (()-Methyl Atis-16-en-19-oate
J. Am. Chem. Soc., Vol. 120, No. 20, 1998 4925
(0.4 mL) of Bu3SnH (0.02 mL, 72.1 µmol) and AIBN (1.3 mg, 7.9
µmol) over a period of 3 h under reflux. After 11.5 h of refluxing, the
solvent was removed, and then the residue was chromatographed.
Elution with a 30:1 mixture of hexane-EtOAc provided 5c (9.7 mg,
68% for two steps) as colorless prisms, mp 102.5-105.0 °C. IR
Synthetic (()-5c was in all respects (1H NMR, 13C NMR, and IR)
indistinguishable from an authentic sample of (-)-5c provided by
Professor T. Kato.
(CHCl3): 1718 cm-1 1H NMR (300 MHz, CDCl3): δ 0.79 (3H, s),
.
Acknowledgment. The authors are greatly indebted to
Professor R. M. Coates, Professor M. Yoshikawa, and Professor
T. Kato for generously providing samples and spectra of natural
5c, 6b, and 4c, respectively.
1.18 (3H, s), 3.65 (3H, s), 4.57 (1H, q, J ) 2.0), and 4.73 (1H, q, J )
2.0). 13C NMR (75.3 MHz, CDCl3): δ 11.99, 18.90, 20.40, 27.32,
28.36, 28.76, 28.85, 33.58, 36.66, 38.25, 38.31, 39.71, 39.80, 43.92,
48.24, 51.23, 52.17, 57.22, 104.56, 152.87, and 178.04. Anal. Calcd
for C21H32O2: C, 79.70; H, 10.19. Found: C, 79.90; H, 10.14.
JA9739042