Enantioselective synthesis of the cyclopentyl core of the axinellamines [9]

Full text of DOI:10.1021/ja0019575

J. Am. Chem. Soc. 2000, 122, 8793-8794
8793
Chart 1
Enantioselective Synthesis of the Cyclopentyl Core of
the Axinellamines
Jeremy T. Starr, Guido Koch, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie
Eidgeno¨ssische Technische Hochschule
UniVersita¨tstrasse 16, CH-8092, Zu¨rich, Switzerland
Arnold and Mabel Beckman Laboratory for
Chemical Synthesis, California Institute of Technology
Pasadena, California 91125
Scheme 1a
ReceiVed June 5, 2000
Axinellamines A-D (1-4) are novel bis-guanidine alkaloids
isolated from the marine sponge Axinella sp. of which Axinel-
lamines B-D (2-4) have been shown to possess bactericidal
activity against Helicobacter pylori, a bacterium implicated in
pepticular and gastric cancer.1 These natural products are note-
worthy for the structural complexity of the polycyclic framework
incorporating fused and spirocyclic ring systems. Moreover,
embedded within these structures is a stereochemically complex
and densely functionalized cyclopentyl core that presents a
daunting synthetic challenge. A similarly substituted cyclopentane
core can be found in palau’amine 5 which critically differs from
that of 1-4 in the relative stereochemical relationships of the
pendant functionality.2 Palau’amine 5 has attracted considerable
attention due to its potent antibiotic, immunosuppressive, and
cytotoxic properties (Chart 1).
a
a) tBuMe2SiCl, imidazole, DMF, 100%; b) CH2Cl2 then crystallize
from c-C6H12; c) ClPh ∆; d) crystallize from c-C6H12; 74% (b + 3 cycles
of c and d).
Scheme 2a
Progress toward the synthesis of the palau’amine core has been
reported in an elegant model study by Overman;3 however, a fully
functionalized cyclopentane intermediate en route to either 5 or
axinellamines A-D (1-4) has not been published. We herein
report an enantioselectiVe synthesis of the fully functionalized
cyclopentyl core 25 of axinellamines A-D (1-4) from racemic
spiro[2.4]hepta-4,6-diene-1-methanol 6.4
The synthesis commenced with silylation of inexpensive and
easily prepared racemic spiro[2.4]hepta-4,6-diene-1-methanol 6
with tert-butyldimethylsilyl chloride (100%). The highly exo-
thermic Diels-Alder reaction of 7 with N-phenylmaleimide in
CH2Cl2 at 0 °C then gave a 1:1 mixture of the two endo adducts
8 and 9. Diastereomer 85 preferentially crystallized from cyclo-
hexane, and the balance of material was recovered following
filtration and evaporation of the mother liquor. When a solution
of the recovered diastereomer 9 in chlorobenzene (ClPh) was
subsequently heated to reflux, 9 underwent retro-cycloaddition
and Diels-Alder cycloaddition to regenerate the 1:1 mixture of
endo isomers 8 and 9 from which 8 could be crystallized as before.
Three such cycles furnished 8 as a single diastereomer from a
200-g scale reaction in 74% yield (Scheme 1).
a
a) HF-CH3CN/THF (4:1), 99%; b) I2, PPh3, imidazole, CH2Cl2,
t
93%; c) Bu3SnH, air, PhH, 86%; d) Me2 BuSiCl, Et3N, DMF, 92%; e) 1
N LiOH, THF; f) MePh, 95% (2 steps); g) quinine (1.1 equiv), MeOH
(3 equiv), CCl4, MePh (93% ee), 100%; h) LDA (5 equiv), Et2O, 0 °C
then 1 N NaHSO4, 73% (2 steps); i) LiAlH4, Et2O, 81%; j) phthalimide,
DEAD, PPh3, THF, 88%; k) OsO4 (0.05 equiv), (DHQD)2Pyr (0.05 equiv),
NMO (3 equiv), tBuOH, 98%; l) NaIO4, K2CO3 (3 equiv), THF/H2O (1:
1), 92%; m) NaClO2, DMSO, BuOH/H2O (4:1), pH ) 4; n) (COCl)2,
CH2Cl2; o) NaN3, DMSO; p) PhH ∆, 67% (4 steps).
t
Desilylation of 8 (99%) and conversion of the resulting alcohol
10 to the iodide 11 (93%) was followed by radical-induced
cyclopropane-ring fragmentation using a modification of Naka-
mura’s conditions for dehalogenative hydroxylation (Scheme 2).6
Iodide 11 was dissolved in benzene and vigorously aerated at 23
°C while Bu3SnH was added over 2 h. After another 15 h, the
addition of hexanes led to precipitation of 12 in 72% yield as a
white solid that was free of organotin contamination. An additional
14% of 12 could be obtained by purification of the filtrate. After
protection of 12 (tBuMe2SiCl, 92%), imide 13 was converted to
anhydride 14 in 95% yield (two steps) by a sequence involving
imide hydrolysis (1M LiOH, THF) to an acid-anilide, followed
by dissolution of this unpurified product in toluene at 23 °C to
allow spontaneous cyclization with expulsion of aniline. Following
acidic workup, the isolated anhydride 14 was spectroscopically
(1) (a) Urban, S.; Leone, P. D.; Carroll, A. R.; Fechner, G. A.; Smith, J.;
Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 1999, 64, 731.
(2) (a) Kinnel, R. B.; Gehrken, H. P.; Swali, R.; Skoropowski, G.; Scheuer,
P. J. J. Org. Chem. 1998, 63, 3281. (b) Kinnel, R. B.; Gehrken, H. P.; Scheuer,
P. J. J. Am. Chem. Soc. 1993, 115, 3376.
(3) Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Am.
Chem. Soc. 1997, 119, 7159.
1
pure by H NMR.7
(6) (a) Sawamura, M.; Kawaguchi, Y.; Nakamura, E. Synlett 1997, 801.
(b) Sawamura, M.; Kawaguchi, Y.; Sato, K.; Nakamura, E. Chem. Lett. 1997,
705. (c) Nakamura, E.; Sato, K.; Imanishi, Y. Synlett 1995, 525. (d) Nakamura,
E.; Inubushi, T.; Aoki, S.; Machii, D. J. Am. Chem. Soc. 1991, 113, 8980.
(7) Analytically pure samples could be readily obtained by crystallization
from cyclohexane.
(4) (a) Starr, J. T.; Baudat, A.; Carreira, E. M. Tetrahedron Lett. 1998, 39,
5675. (b) Ledford, B. E., Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 11811.
(c) Corey, E. J.; Shiner, C. S.; Volante, R. P.; Cyr, C. R. Tetrahedron Lett.
1975, 1161.
1
(5) Determined by nOe difference H NMR analysis.
10.1021/ja0019575 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/26/2000

8794 J. Am. Chem. Soc., Vol. 122, No. 36, 2000
Communications to the Editor
Scheme 3
The remaining task in completing the axinellamine cyclopentyl
core was the stereoselective installation of the chlorine. We
envisioned accomplishing this goal via decarboxylation of a
Barton ester in the presence of a suitable chlorine donor.14
Selective protection of the aldehyde syn to the carbamate could
be effected by acetalization of 22 with 1,3-propane diol in Et2O
to afford 23 in 59% yield.15 Aldehyde 23 was then cleanly
converted in quantitative yield to carboxylic acid 24 using
Masamune’s oxidation conditions (KMnO4, tBuOH/water,
pH ) 7).16
a) BnOH (1.2 equiv), BuLi (1.2 equiv), THF, 0 °C, 76%; b) O3/O2,
CH2Cl2, -78 °C then PPh3 (1 equiv); c) PPh3 (0.2 equiv, 16 h) or K2CO3
(3 equiv, 0.5h), 86%; d) 1,3-propanediol, Et2O, PPTS (3 equiv), 59%; e)
t
Installation of the hindered chlorine was then achieved by
treating 24 with EDC (2 equiv), DMAP (0.3 equiv), and
2-thiopyridine-N-oxide (1.3 equiv) in rigorously deoxygenated
CCl4 to form the corresponding Barton ester, followed by stirring
the solution for 12 h to allow spontaneous homolytic cleavage of
the ester, decarboxylation, and then abstraction of chlorine from
solvent.
The resulting product 25 was isolated in 76% yield from 23 in
>10:1 dr.17 That the chlorine was installed with the desired
stereochemistry in the major isomer was determined by nOe
experiments showing reciprocal enhancements between the chlo-
romethine C-H and carbamate N-H confirming the fully
functionalized cyclopentyl core 25 of axinellamines A-D 1-4
had been synthesized.
We have described the first route to the fully functionalized
cyclopentyl core found in the axinellamines A-D 1-4. The route
commences with the racemic starting material, spiro[2.4]hepta-
4,6-diene-1-methanol 6, and proceeds through racemic (6-11)
then meso (12-14) intermediates to an optically active final
product 25. This strategy takes maximal advantage of an
inexpensive, readily available racemic starting material by
converting it to a meso intermediate and then employing a
desymmetrization reaction at an advanced stage. Studies are
currently underway to convert 25 to the axinellamines and will
be reported in due course.
KMnO4 (1.5 equiv), pH ) 7, BuOH/H2O (2:1), 100%.
Up to this point in the route, the synthesis had been conducted
with intermediates that were initially racemic (6-11) and
subsequently meso (12-14). To access the targeted axinellamine
core in optically active form, a desymmetrization reaction was
required. Thus, utilizing methodology recently reported by Bolm,8
treatment of 14 with methanol (5 equiv) and quinine (1 equiv) in
CCl4/toluene gave, after workup, methyl ester-acid 15 in 93%
ee.9 Selective CR-epimerization of the methyl ester (LDA, 5 equiv,
Et2O, 0 °C) gave trans acid-ester 16 in 73% yield from 14.10
Reduction of 16 with LiAlH4 gave a diol which was converted
to bis(phthalimide) 17 in 71% yield (two steps). Chemoselective
cleavage of the monosubstituted olefin in 17 was achieved by
treatment of 17 with OsO4 (0.05 equiv), (DHQD)2Pyr (0.05 equiv),
and NMO (3 equiv) in THF/H2O to give diastereomeric diols
which following treatment with NaIO4 afforded aldehyde 18
(90%).11,12 This aldehyde underwent oxidation and conversion to
the corresponding acyl azide which, without purification, par-
ticipated in Curtius rearrangement to afford isocyanate 19.
Treatment of 19 with 1.2 equiv of BnOLi in THF at 0 °C then
afforded the desired Cbz-protected amine 20 in 76% yield
(Scheme 3).
The nearly fully functionalized cyclopentyl core was then
revealed by exposure of 20 to ozone, followed by reductive
workup (1.2 equiv PPh3), to give the unexpected trans-dial 22.
Acknowledgment. We thank Professor Volker Gramlich of the
ETH-Z Laboratory of Crystallography for X-ray crystallographic analyses
on compound 16. We thank the National Science Foundation for a pre-
doctoral fellowship for J.T.S. This research has been supported by an
award from the Packard Foundation, Swiss National Science Foundation,
as well as generous support from Merck, Astra-Zeneca, and Hoffman
LaRoche.
1
Careful monitoring of the workup by H NMR spectroscopy
revealed that epimerization was observed only in the presence of
excess PPh3, and by strictly limiting the stoichiometry to 1.0 equiv,
cis-dial 21 could be observed in solution. However, in contrast
to trans-dialdehyde 22, which was well-behaved on silica and in
subsequent handling, attempts to purify 21 were not successful.
Therefore, we chose to proceed with the trans-dial 22; optimiza-
tion of the workup conditions (K2CO3, 3 equiv)13 to promote clean
conversion to the trans-dial gave 22 in 86% yield.
Supporting Information Available: Experimental details and char-
acterization for key intermediates (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(8) Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999, 195.
JA0019575
(9) The enantiomeric excess was determined by preparation of the amide
derived from (R)-(+)-R-phenethylamine and integration of the methyl doublets
(14) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985,
41, 3901.
1
in the H NMR spectrum.
(10) The structure of 16 was determined by X-ray diffraction analysis,
confirming the stereochemical outcome of cyclopropyl carbinyl radical
fragmentation (11 f 12), methanolysis (14 f 15), and CR-epimerization (15
f 16).
(11) Although the use of (DHQD)2Pyr as a ligand for osmium imparted
minimal diastereoselectivity, its use was necessary for achieving the desired
chemoselectivity in the dihydroxylation step.
(12) Schroder, M. Chem. ReV. 1980, 80, 187 and references therein.
(13) (a) AM1 minimization of simplified models of 21 and 22 on PC-
Spartan Pro indicated a 3.1 kcal/mol preference for the trans-dialdehyde. (b)
For use of K2CO3 in a similar epimerization see: Hibbs, D. E.; Hursthouse,
M. B.; Jones, I. G.; Jones, W.; Malik, K. M. A.; North, M. J. Org. Chem.
1999, 64, 5413.
(15) The selectivity for 23 in the acetal-forming reaction was established
by reciprocal NOE enhancements between the acetal methine proton and the
carbamate N-H proton as well as the aldehyde R-proton and the carbamate
N-H in the mono aldehyde 23. AM1 calculations indicate that there is only
a minor energy difference (0.3 kcal/mol) between the heats of formation of
the two possible acetals. We speculate that the reaction is under kinetic control
by factors that are unclear presently. Studies are underway to provide insight
into the observed group selectivity.
(16) Abiko, A.; Roberts, J. C.; Takewasa, T.; Masamune, S. Tetrahedron
Lett. 1986, 27, 4537.
(17) AM1 minimization of simplified models of 25 and its diastereomer
on PC-Spartan Pro indicated a 1.3 kcal/mol preference for the desired chlorine
1
stereochemistry. Diastereomer ratio was determined by H NMR.