Synthesis of the ring system of phomactin D using a Suzuki macrocyclization.

Article abstract of DOI:10.1021/ol0062345

[reaction: see text]The ring system of phomactin D was synthesized in racemic form in an efficient manner from 2,3-dimethylcyclohexanone. Notable transformations include (1) an alkylation of the enolate of a vinylogous thiolester to install a quaternary s

Full text of DOI:10.1021/ol0062345

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2687-2690
Synthesis of the Ring System of
Phomactin D Using a Suzuki
Macrocyclization
Nicholas C. Kallan and Randall L. Halcomb*
Department of Chemistry and Biochemistry, UniVersity of Colorado,
Boulder, Colorado 80309-0215
halcomb@colorado.edu
Received June 20, 2000
ABSTRACT
The ring system of phomactin D was synthesized in racemic form in an efficient manner from 2,3-dimethylcyclohexanone. Notable transformations
include (1) an alkylation of the enolate of a vinylogous thiolester to install a quaternary stereocenter, (2) a conjugate addition of cyanide to
an r,â-unsaturated aldehyde, (3) the formation of a Weinreb amide directly from a cyanohydrin, and (4) an intramolecular Pd-mediated Suzuki
coupling of a B-alkyl-9-BBN derivative and a vinyl iodide to form the macrocyclic ring.
Platelet activating factor (PAF) is an ether-phospholipid that
is responsible for several cellular functions, including media-
tion of anaphylaxis and platelet aggregation.1 In recent years,
the search for new molecules that inhibit the effects of PAF
has resulted in the discovery of a family of naturally
occurring diterpenes from the marine fungus Phoma sp. that
have been given the nom de guerre phomactins (Figure 1).2
phomactin D (1) was found to be the most biologically active.
Because of their biochemical activity and unique molecular
structures, the phomactins are worthy targets for the develop-
ment of synthesis methods and strategies that may be broadly
applicable.3,4
The general synthesis plan is illustrated in Scheme 1. A
fundamental premise from the outset was that the epoxide
moiety could be introduced in a stereoselective manner late
in the synthesis.3 Therefore, a logical intermediate would
be compound 7. Compound 7 would be synthesized as
shown, using the cyclohexanone derivative 2 as a point of
(1) (a) Braquet, P.; Touqui, L.; Shen, T. Y.; Vargaftig, B. B. Pharm.
ReV. 1987, 39, 97-145. (b) Cooper, K.; Parry, M. J. Ann. Rep. Med. Chem.
1989, 24, 81-90.
(2) (a) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano,
H.; Hata, T.; Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463-5464. (b)
Sugano, M.; Sato, A.; Iijima, Y.; Furuya, K.; Haruyama, H.; Yoda, K.;
Hata, T. J. Org. Chem. 1994, 59, 564-569. (c) Sugano, M.; Sato, A.; Iijima,
Y.; Furuya, K.; Kuwano, H.; Hata, T. J. Antibiot. 1995, 48, 1188-1190.
(d) Sugano, M.; Sato, A.; Saito, K.; Takaishi, S.; Matsushita, Y.; Iijima, Y.
J. Med. Chem. 1996, 39, 5281-5284.
Figure 1. Structures of representative phomactins.
(3) Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Tetrahedron Lett. 1996,
37, 7107-7110.
(4) (a) Foote, K. M.; Hayes, C. J.; Pattenden, G. Tetrahedron Lett. 1996,
37, 275-278. (b) Chen, D. Q.; Wang, J. Q.; Totah, N. I. J. Org. Chem.
1999, 64, 1776-1777. (c) Seth, P. P.; Totah, N. I. J. Org. Chem. 1999, 64,
8750-8753.
These compounds are structurally quite complex, and they
all possess an unusual bicyclo[9.3.1]pentadecane ring system
within their molecular framework. Of these compounds,
10.1021/ol0062345 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/18/2000

Scheme 1
departure. It was anticipated that compound 2 could be
allyl bromide provided compound 9 with 15:1 diastereo-
selectivity at the newly formed quaternary carbon.7 Reduction
of the ketone of 9 with NaBH4 and subsequent treatment
with mercuric chloride provided the enal 10.6 In preparation
for subsequent transformations, the aldehyde was reduced
and protected as the tert-butyldiphenylsilyl ether 11 using
the sequence shown. Extension of the allyl side chain was
then carried out in order to both install the necessary carbons
and to introduce a functional group to allow for the
macrocyclization. This was accomplished first by hydro-
boration of the monosubstituted olefin of 11 followed by an
oxidation of the resulting alcohol to give aldehyde 12. A
Corey-Fuchs procedure was then employed to introduce the
alkyne moiety and produce compound 13.8 Interestingly, the
silyl protecting group of 13 was found to be unstable to some
of the subsequent transformations; therefore it was removed
at this stage by treatment with fluoride. A methylzirconation
reaction, combined with a quench with iodine, proceeded
converted to the R,â-unsaturated carbonyl-containing com-
pound 3 in a straightforward manner. A conjugate addition
of a formyl anion equivalent, in actuality cyanide as described
below, could potentially provide compound 4. Although an
axial addition of cyanide was in fact observed, it is reasonable
to expect that the corresponding aldehyde could be epimer-
ized to the equatorial position at a later point. Addition of a
vinyl nucleophile such as 5 to the carbonyl of 4 would give
6, which, after a macrocyclization reaction, would lead to
the key intermediate 7. This overall strategy has in fact been
demonstrated to be feasible, as described in this Letter. The
implementation of this general synthesis design concept, as
well as the development of some novel synthesis transforma-
tions to facilitate this effort, are presented.
As shown in Scheme 2, the sequence began with (()-2,3-
dimethylcyclohexanone 2.5 Conversion to the vinylogous
thiolester 8 proceeded uneventfully.6 Alkylation of 8 with
Scheme 2a
a Reagents and conditions: (a) NaOMe, HCO2Et, benzene, 0 °C to rt (97%); (b) p-CH3C6H4SH, benzene, reflux (90%); (c) KHMDS,
toluene, -78 °C; allyl bromide (80%); (d) NaBH4, 10:1 MeOH:0.1 N NaOH, rt; HgCl2, acetone/H2O, rt (95%); (e) NaBH4, CeCl3‚7H2O,
EtOH, 0 °C; (f) TBDPSCl, imidazole, DMF, rt (91% for 2 steps); (g) 9-BBN, THF, 0 °C to rt; 1.0 M NaOH, H2O2, 0 °C; (h) oxalyl
chloride, DMSO, -78 °C; NEt3, -78 °C to rt (98% for 2 steps); (i) Zn, PPh3, CBr4, CH2Cl2, 0 °C to rt (76%); (j) n-BuLi (3 equiv), THF,
-78 °C to rt (92%); (k) Bu4NF, THF, rt; (l) AlMe3, Cp2ZrCl2 (cat.), CH2Cl2, 0 °C to rt; I2, THF, -45 to 0 °C (90% for 2 steps); (m) oxalyl
chloride, DMSO, -78 °C; NEt3, -78 °C to rt (96%).
2688
Org. Lett., Vol. 2, No. 17, 2000

Scheme 3a
a Reagents and conditions: (a) NaCN, NH4Cl, 8:1 CH3CN:H2O, reflux; (b) Dess-Martin periodinane, NaHCO3, CH2Cl2, rt;
CH3O(CH3)NH2Cl, 0 °C (60% from 15); (c) t-BuLi, ether, -78 °C; HOAc, THF -78 °C (55%); (d) DIBAL-H, toluene, -78 °C; (e)
TBSCl, imidazole, DMF, 45 °C (80% for 2 steps); (f) 9-BBN, toluene, 50 °C; Pd(dppf)Cl2, Cs2CO3, AsPh3, DMF/H2O, 50 °C (16%).
smoothly to afford vinyl iodide 14.9 Note that the olefin
geometry in 14 was produced with the desired E configu-
ration as expected. The presence of the vinyl iodide moiety
allowed for a later bond formation by means of a metal-
mediated coupling reaction to form the macrocycle, while
also being sufficiently inert to the intervening transforma-
tions. The aldehyde was then regenerated using a Swern
oxidation to provide 15.
NMR, but sufficient quantities of material to allow un-
ambiguous structural determination were not produced. One
rationalization, among several possible hypotheses, that can
be invoked to explain this observation assumes that the
aldehyde intermediate that is produced after the conjugate
addition is readily epimerized under the reaction conditions.
In turn, the equatorial aldehyde is the one that leads to the
product, because it is the predominant isomer at equilibrium
and/or reacts faster than the axial aldehyde. However, this
hypothesis can be neither confirmed nor disproved on the
basis of the current observations.
The cyanohydrin 16 was oxidized to the acyl cyanide 17
using Dess-Martin periodinane.11 The acyl cyanide was not
isolated, rather when the oxidation step was complete, N,O-
dimethylhydroxylamine hydrochloride was added directly to
the reaction mixture, and amide 18 was produced in 60%
overall yield from 15.12 Amides such as 18 are well-known
to react with organometallic nucleophiles to give ketones,13
and this property was utilized to advantage in this sequence.
Treatment of 18 with the dienyllithium reagent derived from
the reaction of iodide 1914 with tert-butyllithium produced
ketone 20, which possessed all of the carbons of phomactin
D. Protection of the ketone of 20 was then accomplished
first by reduction to the corresponding alcohol with DIBAL-H
After investigating several formyl anion equivalents as
appropriate nucleophiles for conjugate addition to 15, it was
found that cyanide met the necessary criteria for the route.
Treatment of 15 with sodium cyanide and ammonium
chloride in refluxing water/acetonitrile accomplished a
Nagata-type reaction10 and afforded the dicyano derivative
16 (Scheme 3). The nucleophilic addition to the â-carbon
occurred from an axial direction relative to the six-membered
ring, and a second equivalent of cyanide added to the
aldehyde to provide the cyanohydrin group. Furthermore, the
cyclohexane carbon of 16 that bears the cyanohydrin moiety
possessed predominantly the stereochemical configuration
shown, with the cyanohydrin occupying an equatorial posi-
tion (see below). Trace amounts of products that could
potentially be the epimers at the nitrile- and cyanohydrin-
1
bearing carbons of the cyclohexane were detected by H
(5) Duhamel, P.; Dujardin, G.; Hennequin, L.; Poirier, J.-M. J. Chem.
Soc., Perkin Trans. 1 1992, 3, 387-396.
(6) Ireland, R. E.; Marshall, J. A. J. Org. Chem. 1962, 27, 1620-1627.
(7) (a) Cuesta, X.; Gonza´lez, A.; Bonjoch, J. Tetrahedron: Asymmetry
1999, 10, 3365-3370. (b) Mori, K.; Tamura, H. Liebigs Ann. Chem. 1988,
97-105.
(8) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3772.
(9) Rand, C. L.; Horn, D. E. V.; Moore, M. W.; Negishi, E. J. Org.
Chem. 1981, 46, 4093-4096.
(10) (a) Nagata, W.; Yoshioka, M.; Hirai, S. J. Am. Chem. Soc. 1972,
94, 4635-4643. (b) Nagata, W.; Yoshioka, M.; Murakami, M. J. Am. Chem.
Soc. 1972, 94, 4644-4653. (c) Nagata, W.; Yoshioka, M.; Murakami, M.
J. Am. Chem. Soc. 1972, 94, 4654-4672.
(11) Dess, B. D.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
(12) The relative configuration of the stereocenters of 18 was determined
using NOE difference NMR experiments. An NOE was observed between
the protons of the methyls C-19 and C-20 and between the C-19 methyl
and H-15, indicating that both methyls and H-15 must be on the same face
of the cyclohexane. Also, H-15 had only small coupling constants and H-1
had one large coupling constant (to H-14ax) and two small ones, indicating
that H-1 must be axial and H-15 must be equatorial. See Supporting
Information for complete data.
(13) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(14) Prepared in a manner analogous to that of 1-iodo-2-methyl-(1Z,3)-
butadiene: Ma, S.; Negishi, E. J. Org. Chem. 1997, 62, 784-785.
Org. Lett., Vol. 2, No. 17, 2000
2689

and then silylation of the resulting hydroxyl group to provide
21. Reduction of 20 proceeded smoothly at -78 °C to give
a 4:1 mixture of alcohol diastereomers favoring the dia-
stereomer shown.15 Only the major product was carried
forward in the sequence.16
In summary, a synthesis of the phomactin D ring system
in racemic form was accomplished. A key reaction in the
synthesis was the conjugate addition of cyanide to an R,â-
unsaturated aldehyde with concomitant formation of a
cyanohydrin. A method was developed and implemented that
converted the cyanohydrin directly to a Weinreb amide in a
single synthesis operation, thus installing a functional group
that would allow for subsequent bond formations. Finally,
an unusual intramolecular variant of the Suzuki coupling was
used to effect the annulation of the macrocycle. The route
presented here establishes a firm foundation for further
pursuits toward a total synthesis of phomactin D. Adapting
the route for a nonracemic synthesis will also be reported in
due course.
At this point, the key macrocyclization reaction was
investigated. A Suzuki coupling protocol was chosen to effect
ring closure.17 Treatment of 21 with 9-BBN provided the
alkyl borane 22.18 This intermediate was not isolated but was
directly exposed to Pd, resulting in the formation of
macrocycle 23.19 Although the yield of the transformation
is somewhat low (16%), this nevertheless constitutes a proof-
of-principle. To the best of our knowledge, an example of
this particular variation of the Suzuki reaction, namely,
reaction of a B-alkyl-9-BBN derivative with a vinyl halide,
to accomplish ring closure of a macrocycle of this nature
has not previously been published.20-22 Furthermore, many
opportunities for optimization remain which have yet be
explored, and it is strongly anticipated that this yield can be
optimized to a synthetically useful level.
Acknowledgment. This research was supported by the
NIH (GM53496), Pfizer, and Novartis. R.L.H. also thanks
the National Science Foundation (Career Award) and the
Camille and Henry Dreyfus Foundation (Camille Dreyfus
Teacher-Scholar Award) for support. This work was greatly
facilitated by a 500 MHz NMR spectrometer that was
purchased partly with funds from an NSF Shared Instru-
mentation Grant (CHE-9523034). Bob Barkley (University
of Colorado) is thanked for obtaining mass spectra.
(15) The relative configuration of the carbon bearing the TBS ether in
the major diastereomer 21 was assigned on the basis of analogy to a
derivative with slightly different side chains on the cyclohexane ring whose
structure was unambiguously proven by X-ray crystallography. Also, the
NMR spectral characteristics (chemical shifts, splitting patterns, and coupling
constants) of the protons on the cyclohexane ring for each of the two
compounds were virtually identical.
(16) An alternative route to intermediates such as 21 would involve
regeneration of the aldehyde from the cyanohydrin group in 16 and
subsequent addition of the vinyllithium formed from iodide 19. In practice,
the approach in Scheme 3 was very efficient and produced favorable
diastereomeric ratios. Therefore, alternative routes were not investigated.
(17) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-321. (b) Miyaura, N.; Suzuki,
A. Chem. ReV. 1995, 95, 2457-2483. (c) For an example of an intermo-
lecular Suzuki coupling between a B-alkyl-9-BBN derivative and a vinyl
iodide, see: Harris, C. R.; Kuduk, S. D.; Balog, A.; Savin, K.; Glunz, P.
W.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 7050-7062.
(18) Hydroboration of a similarly substituted model diene with 9-BBN
in the presence of an equivalent molar amount of an appropriately substituted
vinyl iodide, followed by oxidation with basic peroxide, afforded the primary
alcohol almost exclusively. An analogous selective hydroboration of a
similarly substituted diene has been observed previously; see ref 17a.
(19) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014-
11015.
Supporting Information Available: Spectral data for
compounds 8-15, 18, 20, the alcohol precursor to 21, and
23. This information is available free of charge via the
Internet at http://pubs.acs.org.
OL0062345
(20) Miyaura, N.; Suginome, H.; Suzuki, A. Tetrahedron Lett. 1984, 25,
761-764.
(21) White, J. D.; Tiller, T.; Ohba, Y.; Porter, W. J.; Jackson, R. W.;
Wang, S.; Hanselmann, R. Chem. Commun. 1998, 1, 79-80.
(22) A simultaneous publication describing this transformation has come
to our attention: Chemler, S. R.; Danishefsky, S. J. Org. Lett. 2000, 2,
2695.
2690
Org. Lett., Vol. 2, No. 17, 2000