Construction of eight-membered ether rings by olefin geometry-dependent internal alkylation: First asymmetric total syntheses of (+)-3-(E)- and (+)-3-(Z)-pinnatifidenyne

Article abstract of DOI:10.1021/ja035538u

The first and highly stereoselective asymmetric total syntheses of eight-membered ring ether marine natural products (+)-3-(E)-pinnatifidenyne and (+)-3-(Z)-pinnatifidenyne have been accomplished. Notable features of our syntheses include a novel and effi

Full text of DOI:10.1021/ja035538u

Published on Web 07/17/2003
Construction of Eight-Membered Ether Rings by Olefin
Geometry-Dependent Internal Alkylation: First Asymmetric
Total Syntheses of (+)-3-(E)- and (+)-3-(Z)-Pinnatifidenyne
Hyoungsu Kim,† Won Jun Choi,† Jaeyoon Jung,† Sanghee Kim,‡ and
Deukjoon Kim*,†
Contribution from the Research Institute of Pharmaceutical Sciences, College of Pharmacy,
Seoul National UniVersity, San 56-1, Shinrim-Dong, Kwanak-Ku, Seoul 151-742, Korea, and
Natural Products Research Institute, College of Pharmacy, Seoul National UniVersity,
28 Yungun-Dong, Jongro-Ku, Seoul 110-460, Korea
Received April 9, 2003; E-mail: deukjoon@plaza.snu.ac.kr
Abstract: The first and highly stereoselective asymmetric total syntheses of eight-membered ring ether
marine natural products (+)-3-(E)-pinnatifidenyne and (+)-3-(Z)-pinnatifidenyne have been accomplished.
Notable features of our syntheses include a novel and efficient construction of oxocene 5 by a highly stereo-
and regioselective internal alkylation and direct ketone synthesis of ketone 16 from the R-alkyloxy amide
moiety in oxocene 5.
Scheme 1. Olefin Geometry-Dependent Internal Alkylation
Introduction
Medium-ring ethers constitute important structural features
present in a number of biologically active marine natural
products.1 Because of the well-known difficulty of their
construction by standard cyclization methods due to unfavorable
entropic and enthalpic factors,2 the development of efficient
approaches to these medium-sized rings,3a-c particularly eight-
membered ones,3d-f has been an important challenge to synthetic
organic chemists. Although many unique and interesting
methods have been designed for this purpose, there still remains
a need for efficient and general approaches to the construction
of medium-ring ethers.
During our studies directed toward the total syntheses of
natural products based upon intramolecular SN2′ alkylations,4
we accidentally discovered “olefin geometry-dependent” internal
alkylation (vide infra), which led us to develop an efficient and
unprecedented method for eight-membered ring formation as
shown in Scheme 1.
°C, as anticipated, provided exclusively trans-disubstituted SN2′
product 2 in 82% yield. On the other hand, the treatment of the
corresponding cis-allylic chloride 1b5 with KHMDS in THF at
50 °C afforded a 6:1 mixture of eight-membered ring ether 3
and tetrahydropyran 2 in quantitative yield. Although more
studies are needed to explain a striking difference in regio-
chemical behavior (SN2 vs SN2′) observed during the above
“olefin geometry-dependent” intramolecular alkylations, it is
probable that the geometrically restricted cis configuration of
the olefin might decrease the entropic and enthalpic barriers
associated with formation of the eight-membered ring.
Thus, intramolecular amide enolate alkylation of a readily
available trans-allylic chloride 1a5 with KHMDS in THF at 80
† College of Pharmacy, Seoul National University.
‡ Natural Products Research Institute, College of Pharmacy, Seoul
National University.
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-48. (b) Faulkner, D. J.
Nat. Prod. Rep. 2001, 18, 1-49. (c) Faulkner, D. J. Nat. Prod. Rep. 2000,
17, 1-6 and earlier reviews in the same series.
(2) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95-102. (b) Kreiter,
C. G.; Lehr, K.; Leyendecker, M.; Sheldrik, W. S.; Exner, R. Chem. Ber.
1991, 124, 3-12.
Results and Discussion
(3) For recent reviews, see: (a) Mehta, G.; Singh, V. Chem. ReV. 1999, 99,
881-930. (b) Yet, L. Chem. ReV. 2000, 100, 2963-3007. (c) Petasis, N.
A.; Patane, M. A. Tetrahedron 1992, 48, 5757-5821. For a recent example
of the total synthesis of natural products with eight-membered ether rings,
see: (d) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473-
5476 and references therein. (e) Boeckman, R. K., Jr.; Jhang, J.; Reeder,
M. R. Org. Lett. 2002, 4, 3891-3894. (f) Saitoh, T.; Suzuki, T.; Sugimoto,
M.; Hagiwara, H.; Hoshi, T. Tetrahedron Lett. 2003, 44, 3175-3178.
(4) Choi, W. J. M.S. Thesis, Seoul National University, 1995.
To illustrate the potential of the present methodology, we
set out to synthesize (+)-3-(E)-pinnatifidenyne (4a) and (+)-
3-(Z)-pinnatifidenyne (4b),6 which were isolated from the red
(5) Prepared in three steps from the known cis- and trans-6-(tetrahydropyran-
2-yloxy)hex-4-en-1-ol as follows: (1) 2-bromo-N,N-dimethylacetamide,
NaH, THF; (2) PTSA, EtOH; (3) CCl4, Ph3P.
9
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J. AM. CHEM. SOC. 2003, 125, 10238-10240
10.1021/ja035538u CCC: $25.00 © 2003 American Chemical Society

Syntheses of (+)-3-(E)- and (+)-3-(Z)-Pinnatifidenyne
A R T I C L E S
Scheme 2. Retrosynthetic Analysis of Pinnatifidenynes
selective removal of the DMB protecting group of 14 with
DDQ11b,c and subsequent treatment of the resulting alcohol with
CCl4 and trioctylphosphine in the presence of pyridine (74%).
Thus obtained chloride 15 was converted to the internal
alkylation substrate 6 by removal of the THP protecting group
under acidic conditions followed by bromination of the resulting
allylic alcohol with CBr4 and PPh3 in 88% overall yield for the
two steps.
With the requisite cyclization substrate 6 in hand, we then
addressed the key intramolecular amide enolate alkylation to
construct the oxocene skeleton. To our satisfaction, bromoamide
6 underwent a smooth cyclization to furnish the desired oxocene
5 in 86% yield without a detectable amount of the corresponding
SN2′ product upon treatment with 1.1 equiv of LiHMDS in THF
at room temperature. The relative stereochemistry of the newly
generated C(12) stereocenter of the oxocene 5 was assigned as
cis to C(6) by NOESY studies. This stereochemical outcome
can be rationalized by invoking a transition state geometry as
shown in A.
seaweed Laurencia pinnatifida in 1982. The structures of these
eight-membered ring ether marine natural products were as-
signed on the basis of spectral, chemical, and X-ray diffraction
analyses. In our retrosynthetic analysis for 3-(E)- and 3-(Z)-
pinnatifidenyne, as summarized in Scheme 2, we envisioned
that key oxocene 5 could be stereoselectively synthesized from
cyclization substrate 6 by our intramolecular amide enolate
alkylation strategy. Further analysis indicated known (2R,3S)-
1,2-epoxy-4-penten-3-ol 77a should be an ideal synthetic precur-
sor for asymmetric synthesis of acyclic substrate 6.
For reasons of brevity and efficiency, direct conversion13 of
the R-alkyloxy amide moiety in oxocene 5 to the ketone group
of 16 would be more desirable than the more cumbersome
conventional sequence involving nonstereoselective addition14
of EtMgBr to the corresponding aldehyde and reoxidation. To
our delight, this direct ketone synthesis could be cleanly
performed by treatment of R-alkyloxy amide 5 with EtMgBr in
THF at 0 °C for 1 h to furnish ketone 16 in 92% yield. Ketone
16 was reduced diastereoselectively with L-Selectride in a
Felkin-Ahn sense14 to provide exclusively alcohol 17 in
quantitative yield. Mitsunobu inversion of the secondary alcohol
17 with p-nitrobenzoic acid in the presence of DIAD/PPh3,
followed by reductive removal of the p-nitrobenzoate group with
LAH, afforded epimeric alcohol 18 in 79% overall yield.
Introduction of the bromine functionality at C(13) with inversion
of configuration was carried out by a slight modification of the
conventional method (CBr4, Oct3P, 1-methylcyclohexene)15 to
provide the desired bromide 19 (83%) along with its ∆13,14
elimination product (∼3%).16
Our total syntheses of the pinnatifidenynes are depicted in
Scheme 3. Protection of the secondary hydroxy group of epoxy
alcohol 77b (>98% ee)8 as a 2-(trimethylsilyl)ethoxymethyl
(SEM)9a ether 8, followed by regioselective opening with
propargyl tetrahydropyranyl ether under Yamaguchi condi-
tions,10 afforded homopropargylic alcohol 9 in 81% overall
yield. After protection of the hydroxy group of alcohol 9 with
3,4-dimethoxybenzyl bromide (DMB-Br), the resulting acety-
lene 10 was semihydrogenated using Lindlar catalyst to produce
cis-olefin 11 in 92% yield from alcohol 9. Regioselective
hydroboration of the terminal olefin moiety of bis-alkene 11
with 9-BBN (83%) and subsequent PMB protection11a of the
resulting primary alcohol 12 afforded suitably protected ether
13 in 94% yield. Removal of the SEM protecting group of 13
with TBAF,9b followed by O-alkylation with 2-bromo-N,N-
dimethylacetamide of the resulting alcohol, led to amide 14 in
75% overall yield.
After completion of the C(12) side chain, we turned our
attention to assembly of the unsaturated C(6) appendage.
Removal of the PMB group of bromide 19 with DDQ afforded
alcohol 20 in 97% yield. Dess-Martin periodinane oxidation17
Crucial chlorination12 of the C(7) hydroxy group with
inversion of configuration was successfully accomplished by
(6) (a) Gonzalez, A. G.; Martin, J. D.; Martin, V. S.; Norte, M.; Perez, R.;
Ruano, J. Z. Tetrahedron 1982, 38, 1009-1014. (b) Reassignment of
absolute configuration: Norte, M.; Gonzalez, A. G.; Cataldo, F.; Rodriguez,
M. L.; Brito, I. Tetrahedron 1991, 47, 9411-9418.
(13) (a) Suzuki, K.; Katayama, E.; Matsumoto, T.; Tsuchihashi, G. Tetrahedron
Lett. 1984, 25, 3715-3718. (b) Suzuki, K.; Ohkuma, T.; Tsuchihashi, G.
Tetrahedron Lett. 1985, 26, 861-864. (c) Suzuki, K.; Tomooka, K.;
Katayama, E.; Matsumoto, T.; Tsuchihashi, G. J. Am. Chem. Soc. 1986,
108, 5221-5229. (d) Larcheveˆque, M.; Petit, Y. Synthesis 1986, 60-64.
(e) Fujita, M.; Hiyama, T. J. Org. Chem. 1988, 53, 5405-5415. (f)
Shimano, M.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 7727-7730. (g)
Carreira, E. M.; Bois, J. D. J. Am. Chem. Soc. 1994, 116, 10825-10826.
(h) Carreira, E. M.; Bois, J. D. J. Am. Chem. Soc. 1995, 117, 8106-8125.
(i) Shinohara, T.; Suzuki, K. Tetrahedron Lett. 2002, 43, 6937-6940.
(14) A nucleophilic addition to a similar system is nonstereoselective, see:
Burton, J. W.; Clark, J. S.; Derrer, S.; Stock, T. C.; Bendall, J. G.; Holmes,
A. B. J. Am. Chem. Soc. 1997, 119, 7483-7498 and ref 3d.
(7) (a) Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987,
109, 1525-1529. (b) Prepared from commercially available divinyl carbinol
via modified Sharpless asymmetric epoxidation using cumene hydroper-
oxide instead of tert-butylhydroperoxide, see: Romero, A.; Wong, C. H.
J. Org. Chem. 2000, 65, 8264-8268.
(8) The ee value was determined as >98% by 19F and 1H NMR of the
corresponding Mosher esters.
(9) (a) Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343-3346.
(b) Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1989, 30, 7149-7152.
(10) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391-394.
(11) (a) Ruder, S. M.; Ronald, R. C. Tetrahedron Lett. 1987, 28, 135-138. (b)
Oikawa, Y.; Yochika, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885-
888. (c) Horita, K.; Yochika, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021-3028.
(12) (a) Hooz, J.; Gilani, S. S. H. Can. J. Chem. 1968, 46, 86-87. (b) Suzuki,
T.; Matsumura, R.; Oku, K.; Taguchi, K.; Hagiwara, H.; Hoshi, T.; Ando,
M. Tetrahedron Lett. 2001, 42, 65-67. Chlorination under comparable
conditions after construction of the oxocene skeleton 5 was problematic.
Even the improved chlorination conditions reported by Boeckman in their
synthesis of (+)-laurenyne3e which appeared after completion of our work
produced an eliminated compound as the major product. See the Supporting
Information.
(15) (a) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345-4348. (b)
Matsumura, R.; Suzuki, T.; Hagiwara, H.; Hoshi, T.; Ando, M. Tetrahedron
Lett. 2001, 42, 1543-1546.
(16) Alcohol 18 was stereoselectively transformed in a sequence identical to
that of 3-(E)-13-epipinnatifidenyne16a and 3-(Z)-13-epipinnatifidenyne,16b
recently isolated marine natural products. However, the spectral data of
our synthetic material are distinctively different from those of the natural
products. Professsor V. Roussis (University of Athens, Greece) is currently
reinvestigating their structural assignment. See the Supporting Information.
(a) Iliopoulou, D.; Vagias, C.; Harvala, C.; Roussis, V. Phytochemistry
2002, 59, 111-116. (b) San-Martin, A.; Darias, J.; Soto, H.; Contreras, J.
S.; Rovirosa, J. Nat. Prod. Lett. 1997, 10, 303-311.
(17) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
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A R T I C L E S
Kim et al.
Scheme 3. Total Syntheses of Pinnatifidenynesa
a Reagents and conditions: (a) SEMCl, NaH, THF, 0 °C to room temperature, 3 h, 90%; (b) HCCCH2OTHP, n-BuLi, BF3‚Et2O, THF, -78 °C, 1 h, 90%;
(c) DMBBr, NaH, THF/DMF, 0 °C to room temperature, 2 h, 92%; (d) H2, Lindlar cat., pyridine, EtOAc, room temperature, 3 h, 100%; (e) 9-BBN, THF,
0 °C to room temperature, 3 h, then NaOH, H2O2, -20 °C to room temperature, 10 h, 83%; (f) PMBBr, NaH, THF/DMF, 0 °C to room temperature, 13 h,
94%; (g) TBAF, DMPU, 4 Å MS, 80 °C, 5 h, 76%; (h) 2-bromo-N,N-dimethylacetamide, NaH, THF, room temperature, 8 h, 99%; (i) DDQ, CH2Cl2, pH
7.4 buffer, 0 °C, 1 h, 85%; (j) CCl4, Oct3P, pyridine, 80 °C, 4 h, 87%; (k) PTSA, EtOH, room temperature, 1 h, 99%; (l) CBr4, Ph3P, pyridine, CH2Cl2, -20
°C, 30 min, 89%; (m) LiHMDS, THF, room temperature, 40 min, 86%; (n) EtMgBr, THF, 0 °C, 1 h, 92%; (o) L-Selectride, THF, -78 °C, 1 h, 100%; (p)
DIAD, Ph3P, p-NO2PhCO2H, THF, 0 °C, 3 h, 82%; (q) LiAlH4, THF, 0 °C, 1 h, 96%; (r) CBr4, Oct3P, 1-methylcyclohexene, toluene, room temperature to
80 °C, 4 h, 86%; (s) DDQ, CH2Cl2, pH 7.4 buffer, 0 °C to room temperature, 1 h, 97%; (t) Dess-Martin periodinane, CH2Cl2, room temperature, 1 h; (u)
CHI3, CrCl2, THF, 0 °C to room temperature, 4 h, 68% (for two steps); (v) TMS-acetylene, (Ph3P)4Pd, CuI, Et2NH, room temperature, 1 h, >73%; (w)
TBAF, THF, 0 °C, 1 h, 97%; (x) [Ph3P+CHI]I-, KHMDS, THF, -30 to -78 °C, 1 h, 92% (for two steps); (y) TMS-acetylene, (Ph3P)4Pd, CuI, Et2NH,
room temperature, 4 h, 73%; (z) TBAF, THF, 0 °C, 1 h, 96%.
of the primary alcohol 20 and subsequent Takai olefination18
Conclusion
of the resulting unstable aldehyde 21 with CHI3/CrCl2 produced
(E)-vinyl iodide 22a as the major isomer (E:Z ) 8:1) in 68%
We have accomplished the first total syntheses of the eight-
membered ring ether marine natural products (+)-3-(E)- and
total yield for the two steps. On the other hand, isomeric (Z)-
(+)-3-(Z)-pinnatifidenyne utilizing a novel and efficient “olefin
vinyl iodide 22b was selectively synthesized from the same
geometry-dependent” internal alkylation with excellent stereo-
aldehyde 21 using Stork’s iodophosphorane ([Ph3PCH2I]+I-,
selectivity. The scope of the present methodology and its
KHMDS)19 as a single stereoisomer in 92% yield from alcohol
application to the synthesis of other natural products are under
investigation in our laboratories.
20.
Sonogashira20 coupling reaction of each (E)- and (Z)-vinyl
iodide (22a and 22b) with (trimethylsilyl)acetylene in the
presence of (PPh3)4Pd/CuI provided (E)-enyne 23a (73%) and
(Z)-enyne 23b (73%), respectively. Finally, simple removal of
the trimethylsilyl protecting groups of (E)-enyne 23a and (Z)-
Acknowledgment. This research was supported by the
Ministry of Health and Welfare (01-PJ2-PG6-01NA01-0002),
and 2002 BK21 Project for Medicine, Dentistry, and Pharmacy.
enyne 23b with TBAF afforded (+)-4a and (+)-4b in 97% and
96% yield, respectively, whose 1H and 13C NMR spectral data
were in good agreement with those reported for the natural
products.21
Supporting Information Available: General experimental
procedures including spectroscopic and analytical data for all
1
new compounds along with copies of the H and 13C NMR
spectra for 4a, 4b, 5, 6, 8-20, and 22a-23b (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408-
7410.
(19) (a) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174. (b) Williams,
G. M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B. J. Am. Chem. Soc.
1999, 121, 4900-4901.
(20) Sonogashira, R. K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 12,
4467-4470.
JA035538U
(21) For copies of 1H and 13C NMR spectra, see the Supporting Information.
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