10948 J. Am. Chem. Soc.

1994,116, 10948-10954

Asymmetric Tandem Claisen-Ene Strategy for Convergent

Synthesis of (+)-9(l l)-Dehydroestrone Methyl Ether:
Stereochemical Studies on the Ene Cyclization and Cyclic Enol
Ether Claisen Rearrangement for Steroid Total Synthesis
Koichi Mikami,* Kazuhiko Takahashi, Takeshi Nakai, and Tadafumi Uchimaru+
Contribution from the Department of Chemical Technology, Tokyo Institute of Technology,
Meguro-ku, Tokyo 152, Japan, and National Institute of Materials and Chemical Research, AIST,
MITI, Tsukuba, Science City 305, Japan
Received April 18, 1994®

Abstract: An asymmetric synthesis of (+)-9(ll)-dehydroestrone methyl ether (1), a key intermediate for estrogen
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analogs, is described using a new strategy of consecutive carbocyclizations for the D and C rings of the steroid
skeleton based on an asymmetric tandem Claisen—ene sequence. Studies of the stereochemical features of the cyclic
enol ether Claisen rearrangement and intramolecular ene reaction are also reported. In the model study of the ene
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cyclizations, high trans diastereofacial selectivity is found for the -alkylcrotyl and the .,/3-dialkylcrotyl ether systems
with a methoxycarbonyl group at the acetylenic terminus, which remarkably facilitates the ene cyclization. The
Claisen rearrangements of the enol ethers of cyclic ketones were found to exhibit a high level of either anti or syn
diastereoselectivity along with high E olefinic stereoselectivity by making judicious use of either 2,6-dimethylphenol
or PdCl2<RCN)2 as the catalyst.

Steroids have played vital roles as target molecules in the is theorized to proceed with high stereochemical control
development of new synthetic strategies, because of their well- (Scheme 1). Thus, this tandem strategy investigates two
defined structures which provide an opportunity to test new stereochemical questions: (1) diastereoselectivity induced on
methodologies and explore their stereochemistry.1,2 The concept C-8 and C-14 (steroid numbering) of II in the Claisen
of “tandem reaction sequence”* 45has been used for shortening rearrangements with the cyclic enol ether of steroid A,B-ring
123

of the synthetic sequence and for relaying of stereochemical component 4, which should proceed with a high level of 1,3-
control in a multistep synthesis of complex natural products. chirality transfer from C-12 to C-14 in compound I,6 (2)
Herein we report the asymmetric tandem Claisen rearrangement diastereofacial selectivity of the quaternary carbon C-13 (III)
and ene reaction sequence as an efficient strategy for the in the intramolecular ene reaction7 of substrate II having the
asymmetric synthesis of (+)-9(ll)-dehydroestrone methyl ether chiral center C-14 on the ene component rather than the
(1), a key intermediate for estrogens.4,5 The key transformation enophile.
is the convergent combination of the A,B and C,D ring synthons
Results and Discussion
by the asymmetric Claisen—ene sequence (I
—
III), which
—

Diastereofacial Selectivity in Intramolecular Ene Reac-

*
Address correspondence to this author at Tokyo Institute of Technology.
f National Institute of Materials and Chemical Research.
tions. Our total synthesis was preceded by the investigation
® Abstract
published in Advance ACS Abstracts, November 1, 1994. of the diastereofacial selectivity of the intramolecular ene
(1) Reviews: (a) Groen, . B.; Zeelen, F. J. Reel. Trav. Chim. Pays- reaction of type 5-(3,4)8 to construct the steroid D ring. The
Bas 1986,105, 465. (b) Taub, D. In The Total Synthesis of Natural Products; main point of interest was the stereocontrol over the newly
ApSimon, J., Ed.; John Wiley: New York, 1984; Vol. 6. (c) Blickenstaff,
R. T.; Ghosh, A. C.; Wolf, G. C. Total Synthesis of Steroids; Academic created quaternary carbons, which had not been previously
Press: New York, 1974. (d) Fieser, L. F.; Fieser, M. Steroids; Reinhold: explored.7,8 Furthermore, asymmetric ene cyclizations, hitherto-
New York, 1959.
reported, have used chiral enophiles9 rather than chiral ene
(2) Recent examples: (a) Horiguchi, Y.; Nakamura, E.; Kuwajima, I. J.
Am. Chem. Soc. 1989, 111, 6257. (b) Takahashi, T.; Shimizu, K.; Doi, T.; components to induce diastereofacial selectivity.
Tsuji, J. J. Am. Chem. Soc. 1988,110, 2674. (c) Stork, G.; Saccomano, N. Allylic propargyl ethers 7 with a variety of substituents were
A. Tetrahedron Lett. 1987, 28, 2087. (d) Johnson, W. S.; Lindell, S. D.; prepared as model ene systems [X = O]10a by standard methods
Steele, J. J. Am. Chem. Soc. 1987, 109, 5852. (e) Ziegler, F. E.; Wang, T.
F. J. Am. Chem. Soc. 1984, 106, 718. using phase transfer techniques.11 Methoxycarbonylation (zi-
(3) Reviews: (a) Ziegler, F. E. In Comprehensive Organic Synthesis; (6) Excellent review on the chirality transfer via sigmatropic re-
Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 6, p arrangements: Hill, R. K. In Asymmetric Synthesis; Morrison, J. D, Ed.;
875. (b) Mikami, K.; Nakai, T. Synthesis 1991, 594. Nakai, T.; Mikami, K. Academic Press: New York, 1984; Vol. 3.
Kagaku no Ryoiki 1982, 36, 661; Chem. Abstr. 1982, 96, 16001. For a (7) Reviews on intramolecular ene reactions: (a) Snider, B. B. In
recent example of the tandem Claisen—ene reaction, see: Mandar, T.; Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Perga-
Matsumoto, S.; Kohama, M.; Kawada, M.; Tsuji, J. J. Org. Chem. 1990, mon: London, 1991; Vols. 2 and 5. (b) Taber, D. F. Intramolecular Diels-
55, 5671. Alder and Alder Ene Reactions; Springer-Verlag: Berlin, 1984. (c) Oppolzer,
(4) (a) Posner, G. H.; Switzer, C. J. Am. Chem. Soc. 1986, 108, 1239. W.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 1978, 17, 476.
(b) Ziegler, F. E.; Lim, H. J. Org. Chem. 1982, 47, 5230. (c) Posner, G. (8) In an intramolecular ene reaction, the carbon numbers, where the
H.; Mallamo, J. P.; Black, A. Y. Tetrahedron 1981, 37, 3921. (d) Quinckert, tether connects the ene and enophile components constituting the [1,51-
G. ; Weber, W. D.; Schwartz, U.; Duemer, G. Angew. Chem., Int. Ed. Engl. hydrogen shift system, are exemplified in (m,n) fashion. The numerical
1980, 19, 1027; Quinckert, G.; Schwartz, U.; Stark, H.; Weber, W. D.; prefix l stands for the forming ring size. Thus, the present mode of five-
Baier, H.; Adam, F.; Duemer, G. Angew. Chem., Int. Ed. Engl. 1980, 19, membered ring cyclization can be referred to as 5-(3,4), which corresponds
1029. to the five-membered ring cyclization via Oppolzer’s type I ene reaction.
(5) A preliminary report of this work: Mikami, K.; Takahashi, K.; Nakai, For the notation of l-(m,n), see a comprehensive review on ene reactions:
T. J. Am. Chem. Soc. 1990, 112, 4035. Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021.

0002-7863/94/1516-10948$04.50/0 &copy; 1994 American Chemical Society

Synthesis of (+)-9( 11 )-Dehydroestrone Methyl Ether J. Am. Chem. Soc., Vol. 116, No. 24, 1994 10949

Scheme 1

OMe

(S)-(Z) 8fl syn

-

((*>-(£)) (8S anti)

-

B11LÍ/CICO2CH3, THF, —78 °C)12 of the propargyl ethers 7 gave Table 1. Thermal Ene Cyclization
the ester derivatives 7'. The ene cyclizations of the propargyl temp (°C)/ % trans:
ethers 7 and 7' were run on heating in sealed tubes. The trans entry ether R1 R2 R3 time (h) product yield" cid’
configuration of the major diastereomer was assigned through 1 7a H H H 250/6 8a 95
comparison of its 13C NMR spectrum with that of the minor 2 7'b H H C02Me 200/1 8b 98
diastereomer; the configuration of the isomer in which C-a 3 7'c Me H C02Me 130/24 8c 90 86:14
resonates at a lower field was assigned as trans.13 Table 1 4 7'd i-Pr H C02Me 130/24 8d 90 > 95: <5
5 7'e Ph H C02Me 130/24 8e 97 93:7
summarizes the products 8 and their relative stereochemistry, 7'f i-Pr Me 8f
6 C02Me 130/24 93 90:10
which reveals the following significant features of those ene 7 7'g Ph Me C02Me 130/24 8g 88 92:8
cyclizations. “
Isolated yield after column chromatography.b Determined by HPLC
A3 (Zorbax SIL, hexane/ethyl acetate) and/or *H NMR.

R=l introduction of an electron-withdrawing ester group at the

acetylenic terminus (e.g., entry 1 vs 2).10d
A’^X^ (2) Relatively high levels of 1,2-asymmetric induction, i.e.,
7 trans diastereofacial selection, were observed (entries 3—7).
Particularly noteworthy is that the remarkably high selectivity
(1) The ene cyclization is markedly enhanced by the is obtained with the substrates bearing the bulky a-substituents
(9) (a) Townsend, C. A.; Scholl, T.; Arigoni, D. J. Chem. Soc., Chem. (entries 4—7).
Commun. 1975,921. (b) Nakatani, Y.; Kawashima, K. Synthesis 1978,147. (3) It should be noted here that quaternary carbons can be
(c) Oppolzer, W.; Robbiani, C.; Battig, K. Helv. Chim. Acta 1980,63, 2015;
Tetrahedron 1984, 40, 1391. (d) Tietze, L.-F.; Kiedrowski, G. V. Tetra- generated with high levels of trans diastereofacial selectivity
hedron Lett. 1982, 22, 219. (e) Oppolzer, W.; Thirring, K. J. Am. Chem. as observed with the /3-methylcrotyl ether systems (entries 6
Soc. 1982, 104, 4978. (f) Smith, A. B. ; Fukui, M. J. Am. Chem. Soc. and 7).
1987, 109, 1269. (g) Funakoshi, K.; Sakai, K.; Mata, T.; Tamura, C. The high trans diastereofacial selectivity is desired in the
Tetrahedron Lett. 1989, 30, 4849 and references cited therein.
(10) (a) Mikami, K.; Takahashi, K.; Nakai, T. Chem. Lett. 1987, 2347.
stereoselective construction of the steroid D ring and hence is
A few reports have appeared on similar 5-(3,4) ene cyclizations of related of mechanistic importance. The trans diastereofacial selectivity
substrates: (b) [X = NR] Oppolzer, W.; Pfenninger, E.; Keller, K. Helv.
Chim. Acta 1973, 56, 1807. (c) [X = CH2] Reference 9a. (d) Snider, B. B.;
may be reasonably explained in terms of ab initio MM2
transition state models A and B.14 Of the two transition states
Killinger, T. A. J. Org. Chem. 1978, 43, 2161. (e) [X = C(CN)OSiR3)]
Stork, G.; Kraus, G. J. Am. Chem. Soc. 1976, 98, 6747. A and B, transition state A leading to the trans configuration is
(11) Mikami, K.; Azuma, K.; Nakai, T. Tetrahedron 1984, 46, 2303. sterically less congested than transition state B leading to the
(12) Taschener, M. J.; Rosen, T.; Heathcock, C. H. Org. Synth. 1985,
64, 108. (14) Houk, K. N.; Paddon-Row, . N.; Rondan, N. G.; Wu, Y. D.;
(13) Eliel, E. L.; Rao, V. S.; Dietrusiewicz, K. M. Org. Magn. Reson. Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, R. Science
1979, 12, 461. 1986, 231, 1108.
10950 J. Am. Chem. Soc., Vol. 116, No. 24, 1994 Mikami et al.

Table 2. Cyclic Enol Ether Claisen Rearrangements

temp
entry alcohol enol ether catalyst (°C)/time (h) product % yield" anti/synb
1 (£)-9a(R =
H)r 4 Hg(OAc)2 140/10 11a 95 61:39
2 100/17 91 77:23
3 DMP 100/17 94 94:6
4 PdCl2(PhCN)2 rt/3 95 13:87
5 (Z)-9a (R =
H)d DMP 100/17 95 15:85
6 PdCl2(PhCN)2 rt/24 406 21:79
7 (£)-9b (R =
¡-Bu/ DMP 100/10 lib* 95 >95:<5
8 PdCl2(PhCN)2 rt/1 95 <5:>95
9 (£)-9a (R =
H)c 10 DMP 120/14 12a 95 88:12
10* PdCl2(MeCN)2 rt/10 78 12:88
11 (Z)-9a (R = H/ DMP 120/14 95 25:75
12 (£)-9c (R = Me)' DMP 120/14 12c* 95 81:19
13 (Z)-9c (R = Mey DMP 120/14 95 11:89
"
Isolated yield after column chromatography. 6 The stereoisomeric ratio was determined by HPLC (Zorbax SIL, hexane/ethyl acetate) and/or
NMR. c
94% E. d 93% Z. ‘ The reaction was quite sluggish because of the Z £ isomerization. f 100% E. * The (£)-olefin was formed exclusively.
—

h
The substrate used is 1 -(crotyloxy)-1 -cyclopentene which was prepared by a literature procedure: Takai, K.; Mori, I; Oshima, K.; Nozaki, H.
Bull. Chem. Soc. Jpn. 1984, 57, 446. ' 94% E. ¡ 98% Z.

cis configuration, as shown by the calculated steric energies of allylic alcohols 9a—c with the two types of cyclic enol ethers
(X = O or X = CH2 (A' vs B')). 418 and 10.19 All the Claisen rearrangements were carried out
in toluene solutions of the allylic alcohols and cyclic enol ethers
(0.2 M each) in the presence of the catalyst (10 mol %)
[Hg(OAc)2, DMP, or PdCl2L2 (L = PhCN or MeCN)]. Table
2 reveals several significant features of these cyclic enol ether
Claisen variants.

OMe

Final Energy (kcal/mol)

9 10
159.80(0.00) 160.91 (1.11)

(1) The conventional Claisen procedure using the catalyst

157.76 (0.00) 158.79(1.03)
Hg(OAc)2 shows only a moderate syn/anti selectivity (entries
1 and 2), presumably because the acetic acid once formed causes

Diastereoselectivity in Cyclic Enol Ether Claisen Rear- epimerization.20

rangements. Our strategy for steroid synthesis employs a cyclic (2) The rearrangement catalyzed by DMP exhibits a remark-
enol ether which triggers the tandem Claisen—ene sequence
ably enhanced anti selectivity when employing the E allylic
(Scheme 1). The Claisen rearrangement is an important alcohol (entries 3, 7, 9, and 12) and hence syn selectivity when
synthetic tool for acyclic stereocontrol, wherein the olefinic employing the Z counterpart (entries 5,11, and 13). Apparently,
stereocontrol of the enol ether part is the key to diastereocontrol the lower acidity of DMP is responsible for the enhanced
over the newly created chiral centers of the product.15 Previous
stereoselectivity.
work has shown that the acyclic enol ether Claisen variants show (3) Surprisingly enough, the Pd(H)-catalyzed rearrangement
only low diastereoselectivity because of the lack of olefinic not only proceeds smoothly even at room temperature but also
stereoselectivity in the allylic enol ether formation. By contrast, exhibits the opposite stereoselectivity, i.e., the E allylic alcohol
the cyclic (stereodefined) enol ether Claisen variant would induces syn selectivity (entries 4, 8, and 10). Unfortunately,
provide a high level of diastereoselectivity.16 Furthermore, we no rearrangement occurred with /3-substituted allylic alcohols
have found that the judicious choice of the catalyst employed, such as the chiral allylic alcohol 3. This failure parallels the
2,6-dimethylphenol (DMP) or PdCl2(RCN)2, permits the highly significant limitation reported for the Pd(II)-catalyzed Cope
stereoselective formation of either the syn or anti product.173
rearrangement of 2,5-disubstituted 1,5-dienes.21
Table 2 summarizes the results of the Claisen rearrangements
(18) The enol ether 4 was prepared in 86% isolated yield by applying a
(15) Comprehensive review on the Claisen rearrangements: Ziegler, F. literature procedure: Miller, R. B.; Gutierres, C. G. J. Org. Chem. 1978,
E. Chem. Rev. 1988, 88, 1423. 43, 1569.
(16) The Claisen variant with cyclic orthoesters has been reported. (19) Prepared in 84% isolated yield following a literature procedure:
Review: Lythgoe, B. Chem. Soc. Rev. 1981, 10, 449. Wohl, R. A. Synthesis 1974, 38.
(17) (a) Mikami, K.; Takahashi, K.; Nakai, T. Tetrahedron Lett. 1987, (20) After completion of this work, the syn/anti selectivity of the cyclic
28,5879. After completion of this work, two reports dealing with the Claisen ketal Claisen rearrangement was reported to be attenuated by propionic
variant with ketals of cyclic ketones appeared: (b) Baan, J. L.; Bickelhaupt, acid via epimerization of the product (ref 17c).
F. Tetrahedron Lett: 1986, 27, 6267. (c) Daub, G. W.; Griffith, D. A. (21) Reviews on catalysis of the Cope and Claisen rearrangement:
Tetrahedron Lett. 1986, 27, 6311. Also see: Ziegler, F. E.; Klein, S. I.; Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579. (b) Lutz, R.
Pati, U. K.; Wang, T.-F. J. Am. Chem. Soc. 1985, 107, 2730. P. Chem. Rev. 1984, 84. 205.
Synthesis of (+)-9(ll)-Dehydroestrone Methyl Ether J. Am. Chem. Soc., Vol. 116, No. 24, 1994 10951

(4) In all cases where an internal olefin is formed, an Z selective Still—Wittig olefination.24 More importantly, Ziegler
extremely high E selectivity is observed for both the DMP- and has already reported that the syn diastereomer can be stereo-
Pd(II)-catalyzed rearrangements (entries 7, 8, and 12). Thus, selectively transformed via the epimerization at C-8 to the
the extremely high level of 1,3-chirality transfer would be desired anti diastereomer.46
expected6 in the cyclic enol ether Claisen rearrangements. The Still—Wittig olefination of methyl ketone 1425 was
The stereochemical assignment of the diastereomeric Claisen carried out in THF without the use of HMPA as a cosolvent24
at —78 °C using [5-(trimethylsilyl)-4-pentynyl]phosphonium salt
products deserves special comment. The product stereochem-
and n-BuLi to afford, after desilylation (n-BuaNF), (Z)-enyne
istry in the conventional Hg(II)- and acid-catalyzed Claisen
anti configuration 15b (R = H) exclusively. When the reaction was done at —30
processes is readily assignable to the E
—1-

based on the well-established chairlike transition states.6,15 The °C, ca. 5% of the E isomer was formed (ó3.Me 1.73 ppm for
stereochemistry of 12c was further confirmed through its (Z)-15b and 1.63 ppm for (£)-15b). Methoxycarbonylation (n-
conversion to the known pentanolide diastereomer 13c22 via BuLi/ClC02CH3, THF, -78 °C)12 of 15b followed by depro-
tection of the acetonide (p-TsOH, MeOH) and selective
Baeyer—Villiger oxidation with peracetic acid. The comparison
showed that synAlc, where the 1'-methyl NMR signal appeared protection of the primary hydroxyl group with dimethylthexyl-
at a lower field than that of anti- 12c, was correlated to syn- silyl chloride (DMF, imidazole, -40 °C) gave stereochemically
13c, where the oxymethine NMR signal appeared at a higher pure (5,Z)-3b in 86% overall yield from 5.
field as compared to that of anti- 13c. The stereochemistry of
12a was also confirmed through its similar conversion to the
pentanolide 13a which exhibited a similar trend in the NMR to
that of 13c. The stereochemical assignments of 11a and lib
were made on the basis of similar NMR trends to those observed
for 12a and 12c. Furthermore, it should be noted that the syn/
anti pairs of all the products 11 and 12 showed similar
differences in their HPLC retention times; syn diastereomers ·: R =
SiMe3
had longer retention times than anti diastereomers. b:R = H
c: R =
COjMe

Now, the stage was set for the one-pot Claisen—ene sequence.
A toluene solution of 3b (the C,D-ring component) and the
cyclic enol ether 4 (the , -ring component) in the presence
of DMP (10 mol %) was heated in a sealed tube at 180 °C for
60 h. The tandem Claisen—ene product 2 was isolated in 76%
yield after hydrolysis (1 N HC1, THF). A careful NMR analysis
(500 MHz) of 2 showed that the 13,14-configuration was
predominantly trans and the 8,14-configuration was 90% syn.26
Particularly noteworthy is the dramatic switch in diastereo- The transformation of the tandem product to the estrogen
selectivity observed by changing the catalyst from DMP to skeleton was accomplished following Ziegler’s procedure.46
PdCl2(RCN)2. The E
—1-
anti selectivity of the DMP-catalyzed Ozonolysis (O3, MeOH, —35 °C, Me2S) of 2 afforded Ziegler’s
rearrangement is easily visualized by the well-established diketoaldehyde 16 (syn:anti = 9:1) in 67% yield. The use of
chairlike transition state C, whereas the E syn selectivity of CH2CI2 or CH2Cl2/MeOH as the solvent was found to afford a
—

the Pd(H)-catalyzed rearrangement can be explained by the complex mixture. The isomeric mixture was subjected to
boatlike transition state D where the diene moiety may act as a epimerization at C-8 (NaOMe/MeOH, 25 °C)46 to give an anti-
bidentate ligand. Previously, a similar boatlike transition state rich mixture {syn:anti = 1:4). The desired 8H,3 isomer anti-16
was proposed for the PdCl2(PhCN)2-catalyzed Cope rearrange- was isolated in 69% yield. Application of the modified
ment of cis-1,2-divinylcyclobutane 23 Thus, the DMP- and McMurry coupling reaction (TiCb/ZnfAg), DME)27 to anti-16
Pd(II)-catalyzed cyclic enol ether Claisen rearrangements for the C-ring construction furnished the desired compound 1
constitute stereocomplementary processes for the addition of in 56% isolated yield. Its physical and spectral data were in
acyclic side chains onto the -position of cyclic ketones. accord with the literature values: [cl]21d +258° (c 0.70, CHCI3),
mp 144-145 °C (EtOAc/EtOH) [lit.4a [a]25D +247.2° (>97.3%
ee) (c 0.50, CHCI3), mp 144—145 °C]. The optical purity of 1
was 100% ee as judged from the reported [ ] value. The
overall yield of 1 was 17% in 5 steps from 6-methoxy-l-
tetralone (6) and in 11 steps from (R)-glyceraldehyde 5.

Conclusions
In summary, the key feature of the present strategy is the
Asymmetric Tandem Claisen—Ene Reaction. We studied successful combination of the asymmetric Claisen rearrangement
the preparation of the starting chiral allylic alcohol for the
(24) Streekumar, C.; Durst, K. P.; Still, W. C. J. Org. Chem. 1980, 45,
asymmetric tandem Claisen—ene reaction. To introduce the 145 4260.
chirality into the Claisen product II, either (R,E)-3 or (5,Z)-3, (25) The ketone 14 was prepared from 5 via the standard method
which respectively leads to 8S-anti or 8R-syn diastereomers, is [MeMgl, DMSO, (COCl)2, Et3N]; [a]“D +74.1° [lit. [a]20D +53.3°]:
Dumont, R. Helv. Chim. Acta 1983, 66, 814.
required (Scheme 1). We decided on (5,Z)-3 because it is (26) The aldehyde protons of 8Ha-2 and 8H,-¡-2 were observed at 9.70
readily available from (R)-glyceraldehyde 5 by using the highly and 9.45 ppm, respectively. The trans,syn configuration of 2 thus deduced
was confirmed after transformation to the known rrani.ryn-diketoaldehyde
(22) For the *H NMR data of the pentanolide diastereomers 13c, see: 16 (ref 4b).
S.-Rouvier, C. Tetrahedron Lett. 1984, 25, 4371. (27) (a) McMurry, J. E. Chem. Rev. 1989, 89, 1513. (b) Lenoir, D.
(23) Heimbach, P.; Molin, M. J. Organomet. Chem. 1973, 49, 477. Synthesis 1989, 883.
10952 J. Am. Chem. Soc., Vol. 116, No. 24, 1994 Mikami et al.

aqueous NH4CI was added, and the mixture was extracted with ether,
washed with brine, and dried over magnesium sulfate. Removal of
the solvent followed by column chromatography on silica gel gave
carbomethoxy ethers T.
Methyl 4-(2(£)-Buten-l-yloxy)-2-butynoate (7'b): *H NMR (90
anti-16
MHz) 1.71 (d, 3H, J = 5.1 Hz), 3.72 (s, 3H), 3.94 (d, 2H, J = 5.7
syn-16
Hz), 4.70 (s, 2H), 5.3—5.9 (m, 2H); IR 2950, 2210, 1710, 1430, 1350,
1250, 1100, 1050, 970, 935, and 890 cm"* 1.
and ene reaction in tandem for the carbocyclization of the D Methyl 4-(3(E)-Penten-2-yloxy)-2-butynoate (7'c): NMR (90
ring that allows for a relatively quick construction of the estrogen MHz) 1.27 (d, 3H, J = 6.9 Hz), 1.74 (dd, 3H, J = 6.3, 1.0 Hz), 3.81
framework in a highly stereocontrolled fashion.28 Particularly (s, 3H), 4.00 (dq, 1H, J = 6.9, 6.9 Hz), 4.24 (s, 2H), 5.30 (ddq, 1H, J
noteworthy are the stereochemical outcomes of the asymmetric
=
15.0, 8.7, 1.0 Hz), 5.74 (dd, 1H, J = 15.0, 6.3 Hz); IR 2960, 2880,
tandem sequence: (1) high levels of chirality transfer and 2250, 1720, 1440, 1260, 1100, 970, and 940 cm-1.

diastereoselectivity in the cyclic enol ether Claisen rearrange-

Methyl 4-(2-Methyl-4(E)-hexen-2-yloxy)-2-butynoate (7'd):
NMR (90 MHz) d 0.85 and 0.93 (2d, 6H, J = 6.8 Hz), 1.75 (dd, 3H,
ment which serves as an efficient process for asymmetric
J = 6.3, 1.3 Hz), 1.6—2.0 (m, 1H), 3.48 (dd, 1H, J = 8.3, 6.6 Hz),
addition of acyclic side chains onto the -position of cyclic 3.83 (s, 3H), 4.0—4.4 (m, 2H), 5.0-6.0 (m, 2H); IR 2960, 2240, 1720,
ketones, (2) high trans diastereofacial selectivity even for the 1435, 1260, 1090, 1055, 975, and 750 cm"1; HRMS m/z caled for
construction of the quaternary centers in the 5-(3,4) ene Ci2Hi803 210.1256, found 210.1292.
carbocyclization. Finally, the present approach to the 9(11)- Methyl 4-(l-Phenyl-2(E)-buten-l-yloxy)-2-butynoate (7'e):
steroidal skeleton permits easy access to 11-oxygenated estro- NMR (90 MHz) ó 1.74 (d, 3H, J 5.7 Hz), 3.80 (s, 3H), 4.24 (s, 2H),
=

gens having pronounced biological activities29 as well as 19- 4.94 (d, 1H, J 6.3 Hz), 5.4-6.0 (m, 2H), 7.2-7.6 (m, 5H); IR 2950,
=

norcorticoids through the utilization of the 17-side chain of 2.30 2240, 1720, 1600, 1495, 1435, 1260, 1050, 970, 750, and 700 cm"1;
HRMS m/z caled for Ci5Hi603 246.1100, found 244.1122.
Experimental Section Methyl 4-(2,4-Dimethyl-4(£)-hexen-3-yloxy)-2-butynoate (7'f):
NMR (90 MHz) 0.75 and 1.02 (2d, 6H, J = 8.0 Hz), 1.51 (br s, 3H),
General Procedures. IR spectra were recorded on a JASCO A-102 1.64 (d, 3H, J = 8.4 Hz), 1.4-2.0 (m, 1H), 3.22 (d, 1H, J = 6.6 Hz),
spectrophotometer. Polarimetric analyses were run on a JASCO DIP- 3.80 (s, 3H), 3.9—4.3 (m, 2H), 5.2—5.6 (m, 1H); IR 2970, 2240, 1750,
140 polarimeter. NMR spectra were taken on Varían EM-390, JEOL
1720, 1440, 1260, 1090, 1060, 950, 820, and 750 cm"1.
FX-90Q, JEOL GX-270, Varían Gemini 200, and JEOL GX-500
Methyl 4-(2-Methyl-l-phenyl-2(E)-buten-l-yloxy)-2-butynoate
spectrometers and reported in parts per million downfield from internal (7'g): NMR (90 MHz) 1.43 (br s, 3H), 1.67 (d, 3H, J = 6.9 Hz),
TMS in CDClj. GLC analyses were run on a Shimadzu GC-3BT 3.80 (s, 3H), 4.27 (s, 2H), 4.91 (s, 1H), 5.6-5.9 (m, 1H), 7.2-7.5 (m,
chromatograph by using helium as the carrier gas and a 3 mm x 3 m 5H); IR2970, 2240, 1720, 1600, 1500, 1440, 1380, 1260, 1050, 940,
stainless steel column packed with PEG-20M and SE-30 and a
820, and 750 cm-1.
Shimadzu GC-8A chromatograph by using nitrogen as the carrier gas
General Procedure for the Ene Cyclization of Ether 7'. An argon-
and a 0.24 mm x 50 m glass capillary column packed with ULBON
purged NMR tube or Pyrex glass tube was charged with 0.3 or 3 mL
HR-20 at the indicated temperature. HPLC analyses were run on a
of benzene-t/6 or toluene containing 0.25 or 2 mmol of ene substrate
JASCO TRIROTAR SR-1 pump, equipped with a 4.6 mm x 250 mm
7', respectively. The tube was then flushed with argon and sealed.
Finepak SIL-5 column using Shimadzu RID-6A as a refractive index The sealed tube was immersed to 2/3 of its length and heated in an oil
detector and on a Shimadzu LC-6A pump equipped with a 4.6 mm x
bath at the desired temperature (as monitored by NMR, TLC, and/or
250 mm Zorbax SIL column and Shimadzu RID-6A as a refractive
GLC analyses). The tube was opened, and the ene products 8 were
index detector. Analytical TLC was performed by using Merck
isolated by column chromatography on silica gel.
precoated TLC plates and 60F-254 silica gel with indicator. Column NMR (90 MHz)
3-Ethenyl-4-methylenetetrahydrofuran (8a):
chromatography was performed by using Wakogel C-200 (Wako) and <53.0—3.4 (m, 1H), 3.33 (dd, 1H, J = 8.0, 8.0 Hz), 3.85 (dd, 1H, J =
Kiesegel 60 (Merck). Elemental analyses were performed by 8.0, 8.0 Hz), 4.10 (t, 2H, J = 1.6 Hz), 4.5-5.S (m, 5H).
YAN ACO CHN CORDER MT-3. Mass spectra were obtained on a
JEOL JMS-300. 3-Ethenyl-4(Z)-(carbomethoxyinethylene)tetrahydrofuran (8b):
NMR (90 MHz) 3.74 (s, 3H), 3.4-4.9 (m, 5H), 5.0-5.6 (m, 4H);
Materials. Tetrahydrofuran (THF), diethyl ether, and 1,2-dimethoxy-
IR (neat) 2960, 1720, 1670, 1435, 1355, 1210, 1110, 1080, and 935
ethane (DME) were predried with LiAULt and distilled over benzophe-
cm-1.
none ketyl under a nitrogen atmosphere prior to use. Toluene and
methanol were purified from sodium under a nitrogen atmosphere. 3-Ethenyl-4(Z)-(carbomethoxymethylene)-2-methyltetrahydro-
furan (8c): IR (neat) 2960, 1720, 1435, 1355, 1210, 1090, 1000, and
Dichloromethane, dimethyl sulfoxide (DMSO), dimethylformamide
930 cm'1; NMR (90 MHz) (trans-8c) 1.34 (d, 3H, J = 6.3 Hz),
(DMF), and triethylamine (TEA) were dried from CaHa under a nitrogen
2.7—3.0 (m, 1H), 3.74 (s, 3H), 3.4-3.S (m, 1H), 4.S-4.9 (m, 6H),
atmosphere.
(cis-8c) 1.13 (d, 3H, J = 6.3 Hz), 3.2-3.45 (m, 1H).
Synthesis of Carbomethoxy Ethers 7'.12 To a solution of allyl
3-Ethenyl-4(Z)-(carbomethoxymethylene)-2-isopropyltetrahydro-
propargyl ether 711 in THF was added dropwise a hexane solution of
n-BuLi (1.05 molar ratio) at —78 °C under argon atmosphere, and the furan (8d): IR (neat) 2930, 1710, 1430, 1350, 1215, 1010, 920, and
mixture was stirred at that temperature for 1 h. Methyl chloroformate 700 cm"1; NMR (90 MHz) (trans-8d) 1.00 (d, 6H, J = 6.8 Hz),
1.6—2.0 (m, 1H), 3.0-3.3 (m, 1H), 3.3-3.6 (m, 1H), 3.70 (s, 3H),
(1.5 molar ratio) was added to the mixture, and the resulting mixture
was warmed to room temperature and stirred for 2 h. To this mixture
43-5.9 (m, 6H), (cis-8d) <5 0.79 and 0.95 (2d, 6H, J = 6.8 Hz), 1.5-
2.0 (m, 1H), 3.2—3.5 (m, 2H), 3.70 (s, 3H), 4.3-6.0 (m, 6H); 13C NMR
(28) Posner has also reported the efficient asymmetric synthesis of 1, (trans-Sd) 166.6, 136.0, 128.1, 118.9, 112.0, 87.7, 71.2, 53.7, 51.2,
which is transformed (EtsSiH/CFsCC^H) to estrone methyl ether in 90% 30.9, 19.3, and 17.8, (cis-Sd) <5 166.3, 134.4, 128.1, 117.0, 112.4, 87.4,
yield (ref 4c), via eight steps in 7.0% overall yield from 6-methoxy-l- 71.1, 53.5, 51.1, 28.8, 19.9, and 18.5.
tetralone (6) through the Michael addition reaction to the enantiopure
cyclopentenone sulfoxide (ref 4a). 3-Ethenyl-4(Z)-(carbomethoxymethylene)-2-phenyltetrahydro-
(29) (a) Gabbard, R. B.; Harmer, L. F.; Segaloff, A. Steroids 1981, 37, furan (8e): IR (neat) 2960, 1715, 1665, 1435, 1355, 1260, 1220, 1030,
243. (b) Schoenamon, K.; Van Vielt, N.; Zeelen, F. J. Eur. J. Med. Chem. 755, and 700 cm-1; HRMS m/z caled for C15H16O3 246.1100, found
1980, 15, 333. 244.1133; NMR (90 MHz) (trans-Se) 3.0-3.3 (m, 1H), 3.76 (s,
(30) Review: Livingston, D. A. In Advances in Medicinal Chemistry·, 3H), 4.2—4.6 (m, 7H), 6.9-1 A (m, 5H), (m-8e) b 3.4-3.S (m, 1H),
Maryanoff, B. E., Maryanoff, C. A., Eds.; JAI Press: London; 1992; Vol. 3.70 (s, 3H), 4.2—4.6 (m, 7H), 6.9-1.6 (m, 5H); 13C NMR (trans-8e)
1. Hogg, J. A.; Beal, P. F.; Nathan, A. H.; Lincoln, F. H.; Schneider, W.
P.; Magerlein, B. J.; Hanze, A. R.; Jackson, R. W. J. Am. Chem. Soc. 1955, 166.3, 165.2, 139.1, 133.6, 128.2, 127.9, 126.2, 120.3, 112.0, 84.6,
77, 4436. Also see: Johnson, W. S.; Eschener, S.; Metcalf, B. W. J. Am. 71.7, 58.7, and 51.1, (cis-8e) 166.3, 165.2, 139.1, 134.3, 129.5, 128.0,
Chem. Soc. 1976, 98, 1039. 126.4, 121.9, 114.9, 82.7, 71.3, 55.4, and 52.6.
Synthesis of (+)-9( 11 )-Dehydroestrone Methyl Ether J. Am. Chem. Soc., Vol. 116, No. 24, 1994 10953

3-Ethenyl-4(Z)-(carbomethoxymethylene)-2-isopropyl-3-meth- mmol) in toluene (2 mL) at room temperature under an argon

yltetrahydrofuran (8f): IR (neat) 2950, 1720, 1660, 1430, 1350,1220, atmosphere. After stirring at that temperature for 20 h, the resulting
1165, 1060, 1010, and 680 cnT1; NMR (500 MHz) (trans-St) mixture was filtered through Florisil. Removal of the solvent followed
0.82 and 1.05 (2d, 6H, J = 6.8 Hz), 1.17 (s, 3H), 1.7—1.9 (m, 1H), by column chromatography on silica gel gave 12a (55 mg, 78%).
3.19 (d, 1H, J = 9.4 Hz), 3.69 (s, 3H), 4.62 (dd, 1H, J = 18.0, 2.6 Synthesis of 6-Methyl-5-octa-7-enolide 13a. To a mixture of 12a
Hz), 5.00 (dd, 1H, J = 18.0, 2.6 Hz), 5.22 (d, 1H, J = 16.7 Hz), 5.23 (276 mg, 2 mmol) and sodium acetate (1.4 g, 17 mmol) in dichlo-
(d, 1H, J = 11.5 Hz), 5.57 (t, 1H, J = 2.6 Hz), 5.75 (dd, 1 ,/ = 16.7, romethane was added 40% peracetic acid (4.5 mL, 4.5 mmol) at —78
11.5 Hz), (cis-St) 0.90 and 1.03 (2d, 6H, J = 6.8 Hz), 1.32 (s, 3H), °C. The mixture was warmed to room temperature over 36 h
1.7—1.9 (m, 1H), 3.13 (d, 1H, J = 8.6 Hz), 3.70 (s, 3H), 4.6-4.7 (m, (monitored by TLC) and then poured into saturated sodium bicarbonate
2H), 5.0-5.1 (m, 1H), 5.2—5.3 (m, 1H), 5.61 (t, 1H, J = 2.6 Hz), solution. The layers were separated, and the aqueous layer was
5.90 (dd, 1H, J = 17.5, 10.7 Hz); 13C NMR (trans-St) 172.1, 166.8, extracted with dichloromethane. The combined organic layers were
142.0, 114.6, 111.0, 91.6, 70.6, 52.8, 51.1, 29.6, 21.1, 19.1, and 17.9, washed with water and dried over magesium sulfate. Removal of the
(ds-8f) <5 171.4, 166.8, 138.8, 113.6, 111.6, 93.0,70.6, 54.3, 52.6, 29.5, solvent followed by column chromatography afforded the lactone 13a
21.9, 18.9, and 13.0. (203 mg, 66%): IR (neat) 2990, 1715, 1380, 1240, 1175, 1055, 915,
3-Ethenyl-4(Z)-(carbomethoxymethylene)-3-methyl-2-phenyltet- and 735 cm"1; NMR (90 MHz) (iwri-13a) 1.11 (d, 3H, J = 8.4
rahydrofuran (8g): IR (neat) 2950, 1720, 1430, 1370, 1240, 1190, Hz), 1.3-2.7 (m, 7H), 4.24 (m, 1H), 4.9-S.2 (m, 2H), 5.83 (ddd, 1H,
1100, 1040, 940, 720, and 700 cm"1; HRMS m/z caled for C16Hi803 J = 18.0, 9.7, 7.5 Hz), (syn-13a) <5 1.13 (d, 3H, J = 8.1 Hz), 1.2-2.6
258.1256, found 258.1261; NMR (trans-8g) 0.83 (s, 3H), 3.75 (m, 7H), 4.14 (m, 1H), 5.0-5.3 (m, 2H), 5.70 (ddd, 1H, J = 18.0,
(s, 3H), 4.71 (s, 1H), 4.9-6.1 (m, 6H), 7.2-7.4 (m, 5H), (cis-Sg) 10.5, 7.8 Hz); 13C NMR (anf/-13a) 171.6, 138.5, 116.2, 83.4, 42.3,
1.30 (s, 3H), 3.75 (s, 3H), 4.72 (s, 1H), 4.9—6.1 (m, 6H), 7.2-7.4 (m, 29.6, 24.8, 18.5, and 15.5, (syn-13a) ó 171.5, 139.0, 116.0, 83.5, 42.9,
5H). 29.7, 25.4, 18.6, and 15.5; HPLC (Zorbax SIL, hexane:ethyl acetate =
General Procedure for the Claisen Rearrangement. A solution 60:1, flow rate 1.0 mL/min) (anti- 13a) ír = 17.7 min, (sy«-13a) ír =
of a catalyst (0.1 mmol) in toluene (1 mL) was stirred for 15 min at 18.1 min.
room temperature under a nitrogen atmosphere. To this solution was Synthesis of 6-Methyl-5-octa-7-enolide 13b. The titled compound
added a solution of ally lie alcohol (1 mmol) and enol ether (1.2 mmol) was synthesized by the above procedure: IR (neat) 2950, 1715, 1450,
in toluene (3 mL), and the resulting mixture was stirred at the described 1390, 1240, 1170, 1045, and 915 cm"1; NMR (500 MHz) (anti-
temperature. After the reaction completed, the reaction mixture was lib) 1.08 (d, 3H, J = 7.0 Hz), 1.68 (dd, 3H, J = 6.4, 1.5 Hz), 1.4—
filtered through Florisil. Removal of the solvent followed by silica 2.0 (m, 4H), 2.4—2.7 (m, 3H), 4.19 (ddd, 1H, J = 11.6, 4.0, 3.0 Hz),
gel column chromatography afforded the rearranged product. 5.35-5.42 (m, 1H), 5.45-5.6 (m, 1H), (syrc-13b) 1.09 (d, 3H, J =
2-(3-Buten-2-yl)-6-methoxy-l,2,3,4-tetrahydronaphthalen-l- 6.7 Hz), 1.67 (dd, 3H, J = 6.4, 1.5 Hz), 1.4-2.0 (m, 4H), 2.3-2.7 (m,
one (11a): IR (neat) 2950, 1670, 1600, 1500, 1450, 1340, 1250, 1160, 3H), 4.07 (ddd, 1H, J = 11.1, 6.7, 2.9 Hz), 5.34 (ddq, 1H, J = 15.3,
1120, 1030, 1000, 915, 880, 850, 830, and 760 cnT1; >H NMR (90 7.9, 1.5 Hz), 5.53 (dqd, 1H, J = 15.3, 6.4, 0.6 Hz); 13C NMR (anti-
MHz) (anti- 11a) 0.99 (d, 3H, J = 7.2 Hz), 1.6-2.6 (m, 4H), 2.9- lib) 171.5, 131.4, 126.9, 83.8,41.5, 29.7, 25.0, 18.8, 17.8, and 16.1,
3.3 (m, 2H), 3.83 (s, 3H), 4.9-5.3 (m, 2H), 5.91 (ddd, 1H, J = 18.0, 13C NMR (syn-13b) d 171.4, 131.9, 126.7, 84.0, 42.0, 29.6, 25.5, 18.6,

10.2, 6.6 Hz), 6.69 (d, 1H, J = 2.4 Hz), 6.80 (dd, 1H, J = 8.7, 2.4 17.8, and 16.1; HPLC (Zorbax SIL, hexane.ethyl acetate = 60:1, flow
Hz), 8.01 (d, 1H, J = 8.7 Hz), (syn-lla) 1.10 (d, 3H, J = 7.2 Hz), rate 1.0 mL/min) (anti-lib) ír = 15 9 min, (syn-13b) ír = 16.7 min.
1.5—2.3 (m, 4H), 2.8-3.1 (m, 2H), 3.83 (s, 3H), 4.8-5.1 (m, 2H), Preparation of the Methyl Ketone 14 from (R)-Glyceraldehyde
5.72 (ddd, 1H, J = 17.7, 10.4, 7.4 Hz), 6.64 (d, 1H, J = 2.4 Hz), 6.78 Acetonide 5. To a stirred solution of methylmagnesium iodide (100
(dd, 1H, J = 8.7, 2.4 Hz), 8.00 (d, 1H, J = 8.7 Hz); 13C NMR (anti- mmol) in ether (70 mL) was slowly added a solution of glyceraldehyde
11a) 197.4, 163.4, 146.4, 142.6, 129.9, 126.8, 114.4, 113.8, 112.4, 5 (11.7 g, 70 mmol) in ether (30 mL) at 0 °C under argon atmosphere,
55.4, 52.1, 35.7, 29.5, 23.8, and 14.5, (syn-lla) 197.8, 163.4, 146.2, and the resulting mixture was stirred for 3 h at that temperature. The
141.1, 129.9, 126.6, 114.4, 113.1, 112.4, 55.3, 52.4, 36.0, 28.5, 24.6, reaction mixture was poured into ice—water and neutralized with 1 N
and 17.6; HPLC (Zorbax SIL, hexane:ethyl acetate = 15:1, flow rate HC1. The layers were separated, and the aqueous layer was extracted
1.0 mL/min) (anti-lla) ír = 11.1 min, (syn-lla) ír = 12.1 min. with ether. The combined extracts were washed with brine and dried
2-(6-Methyl-3(£)-hepten-2-yl)-6-methoxy-l,2,3,4-tetrahydronaph- over magnesium sulfate. Removal of the solvent afforded crude
thalen-l-one (lib): IR (neat) 2900, 1660, 1595, 1440, 1325, 1240, alcohol, which was used for the next oxidation step without purification.
1020, and 960 cm*1; NMR (90 MHz) (anti-lib) 0.84 (d, 6H, J To a solution of oxalyl chloride (7.3 mL, 83 mmol) in dichloro-
=
6.6 Hz), 0.95 (d, 3H, J = 7.2 Hz), 1.3-2.2 (m, 5H), 2.4-3.4 (m, methane (120 mL) was slowly added a solution of dimethyl sulfoxide
4H), 3.83 (s, 3H), 5.2-S.6 (m, 2H), 6.6-6.S (m, 2H), 8.00 (d, 1H, J (11.7 mL, 165 mmol) in dichloromethane (15 mL) at —60 °C under an
= 8.7 Hz), (syn-llb) 0.80 (d, 3H, J = 6.6 Hz), 1.04 (d, 3H, J = 7.2 argon atmosphere (exothermic gas evolution). After stirring for 20
Hz), 1.2—2.2 (m, 5H), 2.4-3.0 (m, 4H), 3.83 (s, 3H), 5.1—5.5 (m, min at that temperature, a solution of the alcohol (4.4 g, 30 mmol) in
2H), 6.6—6.8 (m, 2H), 8.00 (d, 1H, J = 8.7 Hz); HPLC (Zorbax SIL, dichloromethane (15 mL) was added. Stirring was continued for 20
hexane:ethyl acetate = 19:1, flow rate 1.2 mL/min) (anti-lib) fR = min before triethylamine (52 mL, 375 mmol) was added, keeping the
11.6 min, (syn-llb) ír = 12.9 min. temperature below —40 °C. After 10 min the reaction mixture was
2-(3-Buten-2-yl)cyclopentanone (12a): IR (neat) 2900, 1710, 1400, warmed to room temperature and 30 min later poured into water. The
1150, and 910 cm"1; NMR (90 MHz) (anti-lla) 0.99 (d, 3H, J layers were separated, and the aqueous layer was extracted with
=
6.9 Hz), 1.3-2.1 (m, 8H), 4.9-5.1 (m, 2H), 5.82 (ddd, 1H, J = dichloromethane. The combined extracts were washed with 1.5 N HC1
18.9, 9.6, 6.6 Hz), (syn-12a) <5 1.10 (d, 3H, J = 6.6 Hz), 1.2-2.3 (m, and saturated sodium bicarbonate solution and dried over magnesium
8H), 4.9—5.2 (m, 2H), 5.66 (ddd, 1H, J = 17.4, 10.4, 7.5 Hz); HPLC sulfate. Removal of the solvent afforded crude methyl ketone 14, which
(Zorbax SIL, hexane:ethyl acetate = 60:1, flow rate 1.0 mL/min) (anti- was used for the next reaction without further purification. Analytically
lla) ír = 17.7 min, (syn-12a) ír = 18.1 min. pure product was purified by fractional distillation to give the titled
2-(3(E)-Penten-2-yI)cyclopentanone (12c): IR (neat) 2900, 1700, compound: bp 55—56 °C (12 rnmHg); [cx]26d +74.1° (c 1.60, CHC13)
1460, 1190, 960, and 855 cm"1; NMR (90 MHz) (anti-lie) 0.93 [lit.25 [a]20D +53.3°]; NMR ó 1.40 and 1.50 (2s, 6H), 2.26 (s, 3H),
(d, 3H, J = 6.9 Hz), 1.5—2.8 (m, 11H), S.2-5.6 (m, 2H), (syn-12c) 4.00 (dd, 1H, J = 6.0, 8.4 Hz), 4.25 (dd, 1H, J = 8.4, 7.2 Hz), 4.47
1.07 (d, 3H, J = 7.2 Hz), 1.63 (d, 3H, J = 5.4 Hz) 1.3- 2.7 (m, 8H), (dd, 1H, J = 7.2, 6.0 Hz); IR (neat) 3000, 1710, 1380, 1220, 1070,
5.2—5.7 (m, 2H); HPLC (Zorbax SIL, hexane:ethyl acetate = 60:1, and 850 cm-1.
flow rate 1.0 mL/min) (anf/-12c) fR = 15.9 min, (syn-llc) fR = 16.7 Preparation of 2,2-Dimethyl-4(S)-(hepta-6-yn-2(Z)-en-2-yl)-l,3-
min. dioxolane (15b). To a suspension of [5-(trimethylsilyl)-4-pentynyl]-
Palladium-Catalyzed Claisen Rearrangement of l-(Crotyloxy)- phosphonium bromide (19.2 g, 40 mmol) in THF (100 mL) was added
1-cyclopentene: Synthesis of 2-(3-Buten-2-yl)cyclopentanone (12a). a 1.6 N hexane solution of n-BuLi (25 mL, 40 mmol) at 0 °C under
To a solution of PdCl2(MeCN)2 (13 mg, 0.05 mmol) in toluene (1 mL) argon atmosphere. After stirring for 30 min at that temperature, a
was added a solution of 1 -(crotyloxy)-1 -cyclopentanone (70 mg, 0.5 solution of the methyl ketone 14 (30 mmol) in THF (20 mL) was slowly
10954 J. Am. Chem. Soc., Vol. 116, No. 24, 1994 Mikami et al.

added dropwise at —78 °C. After stirring for 3 h at that temperature, mixture was neutralized with saturated sodium bicarbonate solution,
the mixture was slowly warmed to room temperature. To the mixture washed with brine, and dried over magnesium sulfate. Removal of
was added hexane (200 mL), and the precipitate was removed by the solvent followed by column chromatography on silica gel afforded
filtration on Celite. Removal of the solvent yielded the crude Wittig a diastereomeric mixture of the ketoaldehyde 2. Data for 8,14-syn-
product 15a (R = SiMe3), which was used for the next deprotection 13,14-irans-2: [a]19D +77.1° (c 2.31, CHC13); mp 129 °C; ‘H NMR
step directly. (500 MHz) 1.16 (s, 3H), 1.6—1.8 (m, 2H), 2.0-2.4 (m, 3H), 2.5-
To a solution of the Wittig product in THF (30 mL) was added a 1 3.0 (m, 6H) 3.2—3.3 (m, 1H), 3.69 (s, 3H), 3.85 (s, 3H), 5.73 (t, 1H,
N THF solution of ÍI-BUN4F (30 mL, 30 mmol) at room temperature. J = 2.5 Hz), 6.67 (d, 1H, J = 2.2 Hz), 6.82 (dd, 1H, J = 8.9, 2.4 Hz),
After the reaction completed, the reaction mixture was poured into 7.95 (d, 1H, J = 8.9 Hz), 9.70 (t, 1H, /= 1.2 Hz); 13C NMR 201.4,
water. The mixture was extracted with ethyl acetate, washed with brine, 197.8, 174.1, 167.0, 163.6, 145.6, 130.0, 126.2, 113.5, 112.4, 111.3,
and dried over magnesium sulfate. Removal of the solvent gave 55.4, 53.3, 51.0, 48.8, 47.7, 44.3, 31.6, 27.9, 27.4, 26.8, and 23.4; IR
desilylated product 15b (R = H). Analytically pure sample was purified (CHCI3) 2900,1700,1660,1590,1490,1450,1430,1350,1300-1160,
by fractional distillation (65-67 °C (2 mmHg)) to afford the titled 1020, and 970 cm"1. Anal. Caled for C22H26O5: C, 71.33; , 7.07.
compound 15b: [a]28D +0.16° (c 1.68, CHC13); NMR (200 MHz) Found: C, 71.03; , 7.14. Data for 8,14-anii-13,14-frans-2: NMR
1.37 and 1.45 (2s, 6H), 1.74 (br s, 3H), 1.96 (t, 1H, / = 1.5 Hz), (90 MHz) 1.16 (s, 3H), 1.6-3.3 (m, 12H), 3.69 (s, 3H), 3.85 (s,
2.0—2.4 (m, 4H), 3.61 (t, 1H, J = 8.1 Hz), 4.02 (dd, 1H, J = 8.1, 7.5 3H), 5.65 (m, 1H), 6.67 (d, 1H, J = 2.5 Hz), 6.82 (dd, 1H, J = 8.8,
Hz), 4.97 (dd, 1H, J = 8.1, 7.5 Hz), 5.3—5.6 (m, 1H); 13C NMR 2.5 Hz), 7.95 (d, 1H, J = 8.8 Hz), 9.45 (m, 1H)
133.8, 127.5, 109.2, 83.8, 73.8, 68.8, 67.7, 26.6, 26.4, 25.6, 19.1, and Ozonolysis of the Claisen-Ene Product 2; 2-(FormylmethyI)-
17.9; IR (neat) 3300, 2950, 2100,1450, 1380,1245,1210,1160,1060, 3-(6-methoxy-l-oxo-l,2,3,4-tetrahydronaphthalen-2-yl)-2-methylcy-
860, and 650 cnT1; MS mle 179 (M+ 15(CH3)), 136 (M+ 58(CH3- clopentanone (16, Ziegler’s Diketoaldehyde). A stream of ozone was
- -

COCH3)). bubbled into a suspension of the mixture of 2 (276 mg, 0.74 mmol) in
Preparation of Methyl 8(5)-Hydroxy-7-methyl-9-[(thexyldi- methanol (15 mL) at —35 °C for 10 min till the suspension turned to
methylsilyl)oxy]nona-2-yn-6(Z)-enoate ((S,Z)-3). To a solution of a clear solution. To this solution was added dimethyl sulfide (0.5 mL)
15b (4.47 g, 23 mmol) in THF (50 mL) was added a 1.6 N hexane at that temperature, and the resultant mixture was warmed to room
solution of n-BuLi at —78 °C under an argon atmosphere. After stirring temperature. After stirring for 3 h, solvent was removed, which
for 30 min at that temperature, methyl chloroformate (3.1 mL, 40 mmol) followed by column chromatography on silica gel yielded the diaster-
was added all at once. After the mixture was slowly warmed to room eomeric mixture of 16 (157 mg, 67%). Data for 8,14-syn-16: NMR
temperature, it was poured into water. The resultant mixture was (90 MHz) 1.06 (s, 3H), 1.2-3.0 (m, 12H), 3.90 (s, 3H), 6.6-6.9 (m,
extracted with ethyl acetate, washed with saturated ammonium chloride 2H), 8.00 (d, 1H, J = 8.9 Hz), 9.76 (br s, 1H). Data for 8,14-anri-16:
solution and brine, and dried over magnesium sulfate. Removal of [a]23D -0.48° (c 0.91, CHCI3); NMR (500 MHz) 1.06 (s, 3H),
the solvent gave the methoxycarbonyl compound 15c (R = C02Me), 1.5-1.7 (m, 2H), 2.0-3.2 (m, 8H), 2.77 (d, 2H, J = 14.1 Hz), 3.84 (s,
which was used for the next reaction without purification. 3H), 6.66 (d, 1H, 7 = 2.1 Hz), 6.81 (dd, 1H, J = 8.5, 2.1 Hz), 7.92 (d,
A solution of 15c (30 mL, crude) and a catalytic amount of 1H, / = 8.5 Hz), 9.35 (s, 1H); IR (CHCI3) 2900, 1725, 1710, 1660,
p-toluenesulfonic acid in methanol (50 mL) were stirred for 2 days at 1590, 1260, and 730 CnT1.
room temperature. Two-thirds of the solvent was removed and diluted Isomerization of the Diketoaldehyde 8,14-syn-16 to 8,14-anri-16.
with ether. The solution was neutralized with saturated sodium To a solution of the diastereomeric mixture 16 was added a catalytic
bicarbonate solution, washed with brine, and dried over magnesium amount of sodium methoxide. The mixture was stirred for 4 h at room
sulfate. Removal of the solvent afforded the diol 3a, which was used temperature. Two-thirds of the solvent was removed under reduced
for the next silylation step. pressure, and the residue was diluted with ethyl acetate. The mixture
To a solution of imidazole (0.68 g, 10 mmol) in DMF (5 mL) was was washed with saturated ammonium chloride solution and brine and
added a solution of thexyldimethylsilyl chloride (1.97 g, 11 mmol) in dried over magnesium sulfate. Removal of the solvent followed by
DMF (5 mL) at 0 °C under a nitrogen atmosphere. After stirring for short path column chromatography gave the diketoaldehyde anti-16
30 min, the reaction vessel was cooled to -40 °C. To this mixture (69%).
was added a solution of the diol (2.12 g, 10 mmol) in DMF (10 mL). Synthesis of 9( 1 l)-Dehydroestrone Methyl Ether (1). A suspen-
After stirring for 4 h at that temperature, the reaction mixture was sion of TiCl3 (230 mg, 1.5 mmol) and zinc-silver couple (193 mg, 3
poured into water. The mixture was extracted with ethyl acetate three mmol based on silver) in DME was refluxed for 2 h under an argon
times, and the combined extracts were washed with water four times. atmosphere (color of the suspension turned to green). To this reaction
Then the extract was washed with brine and dried over magnesium mixture was added a solution of the diketoaldehyde anti-16 (93 mg,
sulfate. Removal of the solvent followed by column chromatography 0.3 mmol) in DME (5 mL). The reaction mixture was refluxed for 2
on silica gel gave the titled allyl alcohol 3b (3.16 g, 86% from 5): h. Upon cooling to room temperature, the reaction mixture was passed
[a]MD +23.9° (c 2.01, CHC13); NMR (90 MHz) <5 0.10 (s, 6H), through Florisil, and the Florisil was washed with ethyl acetate.
0.80 (s, 6H), 0.88 (s, 6H), 1.5-1.8 (m, 1H), 1.70 (br s, 3H), 2.0-2.4 Removal of the solvent followed by column chromatography on silica
(m, 4H), 3.49 (d, 2H, J = 8.1 Hz), 3.80 (s, 3H), 4.52 (t, 1H, J = 8.1 gel yielded the titled compound 1 (31 mg, 56%): [a]21t> +258° (c 0.70,
Hz), 5.2—5.4 (m, 1H); 13C NMR 154.0, 136.5, 125.5, 89.0, 73.1, CHCI3) [lit.43 [a]25D +247.2° (>97.3% ee) (c 0.50, CHC13)]; NMR
70.4, 65.2, 52.4, 34.2, 25.6, 25.2, 20.3, 19.8, 18.5, and 3.5; IR (neat) (500 MHz) 0.94 (s, 3H), 1.4—1.8 (m, 4H), 2.2-3.0 (m, 8H), 3.79 (s,
3400, 2950, 2220, 1700, 1460, 1430, 1260, 1100, 1060, 840, and 770 3H), 6.13 (t, 1H, J = 2.8 Hz), 6.61 (d, 1H, J = 2.8 Hz), 6.73 (dd, 1H,
cm"1; MS m/e 337 (M+ -

17(OH)), 293 (M+ -

61(C02CH3)). J = 8.6, 2.8 Hz), 7.53 (d, 1H, J = 8.6 Hz); IR (CHC13) 2900, 1725,
Tandem Claisen—Ene Reaction of 3 and 4: Synthesis of !-((£)- 1600, 1490, 1210, and 720 cm-1; HRMS m/z caled for CigH2202
Carbomethoxymethylene)-2-(formylmethyl)-3-(6-methoxy-l-oxo- 282.1621, found 282.1648.
l,2,3,4-tetrahydronaphthalen-2-yl)-2-methylcyclopentane (2). A
solution of 3b (177 mg, 0.5 mmol), the enol ether 4, and DMP (6.1 Acknowledgment. We thank Professor F. E. Ziegler for
mg, 0.05 mmol) in toluene was heated at 180 °C for 60 h in a sealed sending authentic spectra of 1, syn-16, and anti-16. This work
tube under a nitrogen atmosphere. After the reaction mixture was was supported in part by the “Hattori-Hokokai” foundation and
concentrated under reduced pressure, THF (30 mL) and 3 N HC1 (5 the Grant-in-Aid for Encouragement of Young Scientist from
mL) were added. The mixture was stirred for 10 h at 30 °C. The the Ministry of Education, Science and Culture (Japan).