Stereoselective synthesis of decarestrictine D from a previously inaccessible (2Z,4E)-alkadienyl alcohol precursor

Article abstract of DOI:10.1021/ol050148t

(Chemical Equation Presented) The core structure of decarestrictine D was constructed by stereoselective oxygenation of (2Z,4E)-alkadienyl alcohol, which could be synthesized by a nickel-catalyzed coupling reaction between the corresponding cis bromide an

Full text of DOI:10.1021/ol050148t

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1533-1536
Stereoselective Synthesis of
Decarestrictine D from a Previously
Inaccessible (2Z,4E)-Alkadienyl Alcohol
Precursor
Yuichi Kobayashi,* Moriteru Asano, Shinya Yoshida, and Akira Takeuchi
Department of Biomolecular Engineering, Tokyo Institute of Technology, Box B-52,
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Received January 22, 2005
ABSTRACT
The core structure of decarestrictine D was constructed by stereoselective oxygenation of (2Z,4E)-alkadienyl alcohol, which could be synthesized
by a nickel-catalyzed coupling reaction between the corresponding cis bromide and trans borate. Efficiency in macrocyclization of the seco
acid with Yamaguchi reagent was found to be protective-group-dependent, and the best yield of 40% was obtained with the seco acid with
tri-MOM protective groups.
Decarestrictine D (1), isolated from Penicillium corylophilum
and Polyporus tuberaster,1 shows inhibitory activity against
cholesterol biosynthesis at 10-7 M,1a and the structural
difference of 1 from that of other well-known inhibitors such
as mevinolin and compactin implies another mode of action
to be operative with 1. In addition, 1 exhibits no other effects
such as antibacterial or antifungal activities. Taking together
its strong and selective biological profile, 1 is an attractive
compound for developing a new cholesterol-lowering drug.
So far, the synthesis of 1 and the seco acid has been reported
by three groups.2-4 However, the syntheses suffer from the
low 1,3-chiral induction at C(7) by the C(9) alkoxyl group
in the construction of the central core structure by Andrus2
and Chapleur4 and excess use of the toxic Cr reagent twice
in Pilli’s synthesis.3 In addition, the macrolactonization and
macrocyclization at C(7)-C(8) have been accomplished with
rather low yields of <33%.
Previously, we have reported a nickel-catalyzed coupling
reaction between alkenyl borates and highly congested (Z)-
3-alkoxy-1-alkenyl halides to furnish hitherto hardly acces-
sible (2Z,4E)-alkadienyl alcohol derivatives,5 and later, the
reaction has been applied to the synthesis of korormicin6 and
(1) (a) Grabley, S.; Granzer, E.; Hu¨tter, K.; Ludwig, D.; Mayer, M.;
Thiericke, R.; Till, G.; Wink, J.; Philipps, S.; Zeeck, A. J. Antibiot. 1992,
45, 56-65. (b) Go¨hrt, A.; Zeeck, A.; Hu¨tter, K.; Kirsch, R.; Kluge, H.;
Thiericke, R. J. Antibiot. 1992, 45, 66-73. (c) Ayer, A. W.; Sun, M.;
Browne, L. M.; Brinen, L. S.; Clardy, J. J. Nat. Prod. 1992, 55, 649-653.
(2) Andrus, M. B.; Shih, T.-L. J. Org. Chem. 1996, 61, 8780-8785.
(3) (a) Pilli, R. A.; Victor, M. M. Tetrahedron Lett. 1998, 39, 4421-
4424. (b) Pilli, R. A.; Victor, M. M. J. Braz. Chem. Soc. 2001, 12, 373-
385.
(5) Kobayashi, Y.; Nakayama, Y.; Mizojiri, R. Tetrahedron 1996, 54,
1053-1062.
(4) Colle, S.; Taillefumier, C.; Chapleur, Y.; Liebl, R.; Schmidt, A.
Bioorg. Med. Chem. 1999, 7, 1049-1057.
(6) Kobayashi, Y.; Yoshida, S.; Nakayama, Y. Eur. J. Org. Chem. 2001,
1873-1881.
10.1021/ol050148t CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/15/2005

dihydro-leukotriene B4,7 both of which molecules possess
this structural unit. These simple but successful applications
of this coupling reaction prompted another, higher use of
the dienyl alcohols coupled with an oxygenation reaction in
construction of highly oxygenated compounds. This con-
ceptual idea inspired a practical transformation as delineated
in Scheme 1 of dienyl alcohol 2 into diol-acetate 4 through
Scheme 3. Preparation of the C(6)-C(10) Intermediate 6
Scheme 1. Key Transformation to Decarestrictine D (1)
(PMB ) p-MeOC6H4CH2-) under the literature conditions
(NaH and NaI in THF)10 resulted in concomitant removal
of the TMS group, though incompletely, to afford a mixture
of 11 and the PMB ether of 10 in a 1:2 ratio. Without
separation, the mixture was treated with K2CO3 in MeOH
to produce 11 in 81% from 10. The reverse sequence, i.e.,
removal of the TMS group from 10 followed by PMB
protection was less productive since most of the volatile
alcohol produced in the first step was lost during isolation.
Finally, acetylene 11 was converted into the boronate ester
6 in 57% yield by hydroboration with (Ipc)2BH, ligand
exchange with MeCHO,11 and transesterification of the
resulting diethyl boronate 12 with diol 13.
the hydroxyl-group-directed epoxidation and a palladium-
catalyzed reaction of the resulting epoxide 3 with AcOH.
Product 4 possesses the full functionality and correct chirality
found in decarestrictine D (1), and we thought the transfor-
mation meets the criterion of chirality economy. Herein, we
report results along this line, and lactonization of seco acid
5, for which the protective groups of the hydroxyl groups at
C(3) and C(4) play a crucial role for success.
Synthesis of the other key intermediate 8 (Scheme 4) was
commenced with addition of the lithium anion derived from
Scheme 2 shows the coupling reaction of the boronate ester
6 and cis alkenyl bromide 8 to produce the key dienyl alcohol
Scheme 4. Preparation of the C(1)-C(5) Fragment 8
Scheme 2. Preparation of Dienyl Alcohol 2
2, and the synthesis of each coupling partner is delineated
in Schemes 3 and 4, respectively. The first step in the
synthesis of 6 was a BF3‚OEt2-assisted reaction8 of epichlo-
rohydrin 9 of 98.9% ee with the lithium anion derived from
TMS acetylene, and the resulting chloro alcohol was reduced
to 109 in 82% yield from 9. Protection of 10 with PMBCl
15 and n-BuLi to aldehyde 14. Racemic alcohol rac-16
produced in 91% yield was then subjected to the kinetic
(7) Nakayama, Y.; Kumar, G. B.; Kobayashi, Y. J. Org. Chem. 2000,
65, 707-715.
(8) (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391-394.
(b) Subburaj, K.; Okamoto, S.; Sato, F. J. Org. Chem. 2002, 67, 1024-
1026.
(9) White, D. J.; Somers, T. C.; Reddy, G. N. J. Org. Chem. 1992, 57,
4991-4998.
1534
Org. Lett., Vol. 7, No. 8, 2005

resolution12 by using Sharpless asymmetric epoxidation13 to
furnish a mixture of epoxy alcohol 17 and the remaining
allylic alcohol (S)-16. The ee of (S)-16, obtained in 43%
yield based on rac-16 after chromatography, was >99% by
1H NMR spectroscopy of the derived MTPA ester. Bromi-
nation of (S)-16 with Br2 at -78 °C took place without
injuring the TBDPS group, and subsequent treatment of the
bromine adduct with Bu4NF at -78 °C afforded cis bromide
Scheme 5. Synthesis of Known Intermediate 19
1
8 with complete stereoselection as judged by H NMR and
13C NMR spectroscopy.
Nickel-catalyzed coupling of 6 and 8 (Scheme 2) was
executed by addition of MeLi (1.1 equiv) to a mixture of
boronate ester 6 (1 equiv) and NiCl2(dppf) (0.067 equiv) in
THF followed by reaction with cis bromide 8 (0.67 equiv)
at room temperature for 14 h to furnish dienyl alcohol 2 in
76% yield based on 8. Noteworthy here is that the hydroxyl
group present in 8 did not quench the anionic borate 7, and
thus the molar ratio of the boronate ester 6 could be reduced
to less than 2 equiv of the bromide 8.
Epoxidation of dienyl alcohol 2, the first step of the key
transformation (Scheme 1), proceeded with m-CPBA (1.3
equiv) in a completely stereoselective manner, and subse-
quent palladium-catalyzed reaction of epoxide 3 with AcOH
(2 equiv) furnished 4 in 68% yield from 2. Neither the
regioisomer nor the C(7) diastereomer (structure not shown)
was detected by NMR spectroscopy and TLC analysis. The
two chiral centers, thus created, should have the configura-
tions depicted in 4 on the basis of the literature precedents
for the respective steps.14,15 This speculation was later
confirmed to be correct by transformation to the known
compounds (see the next paragraph).
In the previous synthesis,2 macrolactonization of seco acid
5a was achieved by using the Corey-Nicolaou reagent
((2-PyS)2, PPh3, AgClO4) to produce lactone 20 in 33% yield,
whereas the Keck reagent (DCC, DMAP, H+) and the
Yamaguchi reagent (Cl3C6H2COCl, DMAP) did not afford
the lactone (Scheme 6). To improve the yield, lactonization
Scheme 6. Macrolactonization of Acetonide Seco Acid 5a
The remaining tasks toward completion of the synthesis
were functional group manipulation and macrolactonization.
First, 4 was converted into the Andrus acetonide 192 by a
sequence of reactions depicted in Scheme 5 in good overall
1
yield. The H NMR and 13C NMR spectra of synthetic 19
were all consistent with the data reported.2 A formal synthesis
of decarestrictine D (1) was thus achieved. In addition, the
chiral centers at C(4) and C(7) of 4 constructed by the key
transformation were thus established.
of the same seco acid 5a, derived from the above aldehyde
19 by the literature procedure (NaClO2 then DDQ), was
studied with the Yamaguchi reagent,16 since we were familiar
with this reagent through the syntheses of other macrolides.17
Under slightly modified conditions, the cyclization was
accomplished but furnished 20 only in 17% yield. One reason
we speculated for the failure reported by Andrus (0%) and
the low yield described above (17%) is that the two reac-
tion sites (CO2H and OH) are projected into opposite direc-
tions of the acetonide plane, thus rendering the unfavorable
10-membered lactonization18 even more difficult.
(10) Paquette, L. A.; Barriault, L.; Pissarnitski, D.; Johnston, J. N. J.
Am. Chem. Soc. 2000, 122, 619-631.
(11) Kamabuchi, A.; Moriya, T.; Miyaura, N.; Suzuki, A. Synth.
Commun. 1993, 23, 2851-2859.
(12) Kinetic resolution of γ-silylallylic alcohols: Kitano, Y.; Matsumoto,
T.; Sato, F. Tetrahedron 1988, 44, 4073-4086.
(13) (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B.J. Am. Chem. Soc. 1981, 103, 6237-6240. (b) Gao,
Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless,
K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(14) Epoxidation of cis allylic alcohols: (a) Rossiter, B. E.; Verhoeven,
T. R.; Sharpless, K. B. Tetrahedron Lett. 1979, 4733-4736. (b) Narula, A.
S. Tetrahedron Lett. 1981, 22, 2017-2020. (c) Tomioka, H.; Suzuki, T.;
Oshima, K.; Nozaki, H. Tetrahedron Lett. 1982, 23, 3387-3390. (d) Adam,
W.; Kumar, R.; Reddy, T. I.; Renz, M. Angew. Chem., Int. Ed. Engl. 1996,
35, 880-882.
(15) (a) Trost, B. M.; Molander, G. A. J. Am. Chem. Soc. 1981, 103,
5969-5972. (b) Tsuji, J.; Kataoka, H.; Kobayashi, Y. Tetrahedron Lett.
1981, 22, 2575-2578. (c) Deardorff, D. R.; Myles, D. C.; MacFerrin, K.
D. Tetrahedron Lett. 1985, 26, 5615-5618. (d) Deardorff, D. R.; Sham-
bayati, S.; Linde II, R. G.; Dunn, M. M. J. Org. Chem. 1988, 53, 189-
191. (e) Echavarren, A. M.; Tueting, D. R.; Stille, J. K. J. Am. Chem. Soc.
1988, 110, 4039-4041. (f) White, J. D.; Jensen, M. S. J. Am. Chem. Soc.
1995, 117, 6224-6233.
(16) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
(17) (a) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J. Org.
Chem. 1998, 63, 7505-7515. (b) Kobayashi, Y.; Okui, H. J. Org. Chem.
2000, 65, 612-615. (c) Kobayashi, Y.; Matsuumi, M. J. Org. Chem. 2000,
65, 7221-7224. (d) Kobayashi, Y.; Kumar, G. B.; Kurachi, T.; Acharya,
H. P.; Yamazaki, T.; Kitazume, T. J. Org. Chem. 2001, 66, 2011-2018.
(e) Kobayashi, Y.; Wang, Y.-G. Tetrahedron Lett. 2002, 43, 4381-4384.
Org. Lett., Vol. 7, No. 8, 2005
1535

The above hypothesis led us to examine another seco acid
5b, in which such a negative bias against lactonization is
eliminated (Scheme 7). The acetyl group of 4 was first
Deprotection of the MOM group of 25, the last step, was
attempted under the conditions using CF3CO2H/CH2Cl2,
Dowex-50/MeOH, BF3‚OEt2, and (CH2SH)2/CH2Cl2 to pro-
vide a mixture of products, whereas PPTS in refluxing
n-BuOH was found to produce decarestrictine D (1) cleanly
1
in 81% yield. The H and 13C NMR spectra of 1 measured
Scheme 7. Synthesis of Decarestrictine D (1) through a New
seco Acid 5b
in CDCl3 and in CD3OD were identical with those
reported.1c,2,3 In addition, the specific rotation ([R]24 -68
D
(c 0.066, MeOH)) and mp (121-123 °C, recrystallized from
CH2Cl2/hexane) were also in good agreement with the
reported data: [R]20D -62 (c 1.0);1a 118-120 °C (synthetic);2
116 °C (natural).1b
In summary, synthesis of decarestrictine D (1) was
accomplished through dienyl alcohol 2, which was prepared
by the nickel-catalyzed coupling reaction. The key transfor-
mation of 2 to 4 proceeded efficiently with creation of the
C(4) and C(7) chiral centers. Moreover, lactonization was
achieved in higher yield with a new seco acid 5b than the
previous seco acid 5a.
Acknowledgment. Epichlorohydrin 9 was kindly gifted
by Takasago International Corporation. This work was
supported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, Sports, and Culture,
Japan.
Supporting Information Available: Experimental pro-
cedures and copies of the 1H amd 13C NMR spectra of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
removed by using MeLi, and the resulting triol was converted
to MOM ether 21. After removal of the TBDPS protection,
the resulting alcohol 22 was converted to ester 23 in 75%
yield. The PMB group was then removed with DDQ, and
the ester group was hydrolyzed to afford seco acid 5b, which
upon Yamaguchi lactonization furnished lactone 25 in 40%
OL050148T
(19) Perhaps, lactonization of 5b with (2-PyS)2, PPh3, and AgClO4 may
furnish a better yield of 25 by extrapolation of the results summarized in
Scheme 6. However, this possibility was not studied partly because of the
explosive nature of AgClO4: (a) Brinkley, S. R., Jr. J. Am. Chem. Soc.
1940, 62, 3524. (b) Hein, F. Chem. Tech. (Berlin) 1957, 9, 97; Chem. Abstr.
1957, 51, 54429.
1
yield.19 The H NMR and 13C NMR spectra of lactone 25
indicated the existence of a single conformational isomer.20
(20) On the other hand, lactone 20 derived from 5a (Scheme 6) exists
as a mixture of the three conformational isomers on the basis of the 1H
NMR spectrum, according to Andrus (ref 2).
(18) Difficulty in formation of medium ring lactones: Rousseau, G.
Tetrahedron 1995, 51, 2777-2849.
1536
Org. Lett., Vol. 7, No. 8, 2005