Total synthesis of (+)-phomactin A using a B-alkyl Suzuki macrocyclization

Article abstract of DOI:10.1021/ja0296531

A total synthesis of (+)-phomactin A is described using a B-alkyl Suzuki macrocyclization to incorporate the isolated trisubstituted olefin. This macrocyclization was accomplished with the sensitive hydrated furan ring in place. (R)-(+)-pulegone was used

Full text of DOI:10.1021/ja0296531

Published on Web 01/22/2003
Total Synthesis of (+)-Phomactin A Using a B-Alkyl Suzuki Macrocyclization
Peter J. Mohr and Randall L. Halcomb*
Department of Chemistry and Biochemistry, UniVersity of Colorado, Boulder, Colorado 80309-0215
Received December 9, 2002 ; E-mail: halcomb@colorado.edu
The phomactins, a class of diterpenes isolated by Sugano and
co-workers1 in the early 1990s, have drawn much attention from
the synthetic community over the past few years.2 In addition to
their biological activity as platelet activating factor (PAF) antago-
nists, the phomactins possess a structurally unique architecture,
which is marked by a highly substituted cyclohexane that is bridged
by a 12-membered macrocycle. Phomactin A (1, Scheme 1),
arguably the most structurally complex member of the phomactin
family, also contains a pyran ring and a sensitive2b,i hydrated furan
ring. This reduced furanochroman has been addressed by several
groups;2b,c,i however, only recently has phomactin A yielded to total
synthesis.3 This manuscript reports a nonracemic total synthesis of
phomactin A using a B-alkyl Suzuki reaction to install the
macrocycle.
hydroxymethyl group. Tin-lithium exchange of [(methoxymethoxy)-
methyl]tributylstannane7 and addition of the resulting anion to 4
gave a tertiary allylic alcohol, which oxidatively rearranged upon
treatment with PCC8 to give enone 5. The vinyl bromide was then
installed through an indirect sequence,9 using an epoxide as the
key intermediate. The ketone was first reduced under Luche
conditions to give exclusively the pseudoequatorial alcohol, fol-
lowed by directed epoxidation of the trisubstituted olefin to give
6. Oxidation of the alcohol with Dess-Martin periodinane and
regioselective epoxide opening with magnesium bromide then gave
bromohydrin 7. The tertiary alcohol was converted to the corre-
sponding trifluoroacetate, which rapidly eliminated under the basic
reaction conditions to install the vinyl bromide. The MOM-
protecting group was next removed and replaced with the more
labile DMB (3,4-dimethoxybenzyl) ether to give 8.10,11 The ketone
was then reduced to the pseudoequatorial alcohol,12 and subsequent
Mitsunobu inversion gave the desired pseudoaxial alcohol, which
was protected as a TBS ether to give 9.
Scheme 1. Synthesis Strategy for Phomactin A
Scheme 2. Synthesis of Vinyl Bromide 9a
Our synthesis strategy, shown in Scheme 1, centers on substituted
cyclohexene 2. This key intermediate would possess the entire
carbon framework and all relevant stereochemistry necessary to
complete the total synthesis. Three crucial ring closures would then
be carried out: an intramolecular epoxide opening to install the
pyran ring, a deprotection of the primary hydroxyl group to
spontaneously form the hydrated furan ring, and a B-alkyl Suzuki
coupling to install the 12-membered macrocycle. The macrocy-
clization would be carried out last, using the rigid structure of the
tricyclic core to potentially bias the system toward cyclization.
On the basis of this strategy, a convergent synthesis route to
intermediate 2 was designed from two commercially available and
inexpensive terpene starting materials, (R)-(+)-pulegone and ge-
raniol. These two compounds were used to synthesize vinyl bromide
9 and aldehyde 13, respectively, which were then coupled with a
nucleophilic addition reaction.
Methylation of (R)-(+)-pulegone and subsequent retro-aldol
reaction were carried out according to literature procedure4 to give
2,3-dimethylcyclohexanone, which was converted to the corre-
sponding enone 3 through a bromination/elimination sequence
(Scheme 2). The quaternary stereocenter was then installed using
an aldol reaction with phenylselenoacetaldehyde5 to give an
intermediate â-hydroxy ketone, which was cleanly converted to the
vinyl-substituted enone 4 upon treatment with methanesulfonyl
chloride and triethylamine.6 This two-step sequence proceeded with
complete diastereoselectivity and efficiently installed the vinyl group
necessary for the pivotal B-alkyl Suzuki coupling. A 1,3-enone
transposition was then carried out on 4 to install the MOM-protected
a Reagents and conditions: a) LDA, LiCl, MeI (70%); b) KOH, reflux
(75%); c) LDA, TMS-Cl, Br2 (90%); d) Li2CO3, LiBr, DMF (81%); e)
LDA, phenylselenoacetaldehyde (73%); f) MsCl, Et3N (86%); g) n-BuLi,
Bu3SnCH2OMOM, LiCl (70%); h) PCC (91%); i) NaBH4, CeCl3; j) mCPBA
(81% for two steps); k) Dess-Martin periodinane (86%); l) MgBr2‚Et2O
(83%); m) TFAA, Pyr. (95%); n) MgBr2‚Et2O, BuSH (91%); o) CSA, DMB-
ONPy (85%); p) NaBH4, CeCl3 (94%); q) PPh3, DEAD, p-nitrobenzoic
acid; then NaOCH3 (86%); r) TBS-Cl (92%).
The synthesis of aldehyde 13 began from geraniol (Scheme 3).
Geraniol was converted to known aldehyde 10 using Mori’s three-
step procedure.13 Aldehyde 10 was subjected to Corey-Fuchs14
conditions to give the corresponding terminal alkyne, which was
methylated to give 11.15 This intermediate was then converted to
the corresponding TBS-protected alcohol,16 which was transformed
to vinyl iodide 12 through a hydrozirconation/iodination sequence.17
This reaction proceeded with excellent regioselectivity, favoring
the desired vinyl iodide (12:1 mixture). The TBS group was then
removed with fluoride, and the resulting allylic alcohol was
9
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C O M M U N I C A T I O N S
converted to aldehyde 13 by Sharpless asymmetric epoxidation,18
followed by oxidation under Parikh-Doering19 conditions.
Acknowledgment. This research was supported by the NIH
(GM53496), Pfizer, and Novartis. R.L.H. thanks the NSF (Career
Award) and the Dreyfus Foundation (Camille Dreyfus Teacher-
Scholar Award) for support. P.J.M. thanks Pharmacia for a graduate
fellowship. This work was facilitated by a 400 MHz NMR
spectrometer that was purchased partly with funds from an NSF
Shared Instrumentation Grant (CHE-0131003).
Scheme 3. Synthesis of Aldehyde 13a
Supporting Information Available: Full experimental detail for
1
all new compounds, and H NMR spectra of synthetic 1, 4, 13-16,
and other key unnumbered intermediates (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano,
H.; Hata, T.; Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463. (b) Sugano,
M.; Sato, A.; Iijima, Y.; Furuya, K.; Haruyama, H.; Yoda, K.; Hata, T. J.
Org. Chem. 1994, 59, 564. (c) Sugano, M.; Sato, A.; Iijima, Y.; Furuya,
K.; Kuwano, H.; Hata, T. J. Antibiot. 1995, 48, 1188.
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37, 7107. (b) Foote, K. M.; Hayes, C. J.; Pattenden, G. Tetrahedron Lett.
1996, 37, 275. (c) Seth, P. P.; Totah, N. I. Org. Lett. 2000, 2, 2507. (d)
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John, M.; Pattenden, G. Synlett 2001, 3, 365. (f) Mi, B. Y.; Maleczka, R.
E. Org. Lett. 2001, 3, 1491. (g) Chemler, S. R.; Iserloh, U.; Danishefsky,
S. J. Org. Lett. 2001, 3, 2949. (h) Houghton, T. J.; Choi, S.; Rawal, V. H.
Org. Lett. 2001, 3, 3615. (i) Mohr, P. J.; Halcomb, R. L. Org. Lett. 2002,
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a Reagents and conditions: a) CBr4, PPh3, Zn; b) n-BuLi, Et2O, 0 °C
(92% for two steps); c) n-BuLi, THF, -78 °C (88%); d) TBAF; e) TBS-Cl
(94% for two steps); f) Cp2ZrHCl, 40 °C, 12 h; then I2, 0 °C (65%); g)
TBAF (92%); h) TBHP, (-)-DIPT, Ti(O-iPr)4, 4 Å mol. sieves; i) Pyr‚SO3,
DMSO, Et3N (66% for two steps).
(3) Goldring,W.P.D.;Pattenden,G.J.Chem.Soc.,Chem.Commun.2002,1736.
(4) Tori, M.; Uchida, N.; Sumida, A.; Furuta, H.; Asakawa, Y. J. Chem. Soc.,
Perkin Trans. 1 1995, 1513.
The synthesis was completed as shown in Scheme 4. Lithium-
halogen exchange of 9 was performed at -78 °C, and addition of
the resulting vinyllithium reagent to aldehyde 13 gave an intermedi-
ate allylic alcohol which was oxidized to give ketone 14. The TBS
group was then removed to give the corresponding free secondary
alcohol, which cyclized under acidic conditions to install the pyran
ring and provide 15. Alcohol 15 was protected as a triethylsilyl
ether,20 and then the DMB group was removed to give the
corresponding primary alcohol, which spontaneously formed the
hemiacetal and installed the hydrated furan ring. The tertiary
hydroxyl group of the hemiacetal was then protected as a TMS
ether to give 16. To construct the macrocycle, a regioselective
hydroboration was carried out on the terminal olefin of 16 with
9-BBN to give an intermediate alkyl borane, which cyclized using
a modification21 of Johnson’s22 conditions. This reaction illustrates
the mildness of the Suzuki23-25 reaction in that the coupling was
carried out with the sensitive dihydrofuran ring in place. Treatment
with TBAF then removed both silyl groups to give phomactin A
(5) (a) Kowalski, C. J.; Dung, J. J. Am. Chem. Soc. 1980, 102, 7951. (b)
Clive, D. L. J.; Russell, C. G.; Suri, S. C. J. Org. Chem. 1982, 47, 1632.
(6) Reich, H. J.; Chow, F. J. Chem. Soc., Chem. Commun. 1975, 790.
(7) Johnson, C.; Medich, J. J. Org. Chem. 1988, 53, 4131.
(8) Dauben, W.; Michno, D. J. Org. Chem. 1977, 42, 682.
(9) All attempts at direct bromination of 5 failed, presumably due to the
demanding steric environment and electron deficiency of the trisubstituted
olefin.
(10) The MOM group introduced early in the synthesis could not be successfully
removed at an appropriate later stage.
(11) 2-(3,4-Dimethoxybenzyloxy)-3-nitropyridine (DMB-ONPy) was prepared
according to the procedure of Mukaiyama: Nakano, M.; Kikuchi, W.;
Matsuo, J.; Mukaiyama, T. Chem. Lett. 2001, 424.
(12) All attempts at reduction of the ketone to give exclusively the desired
alcohol diastereomer were unsuccessful. Because the two alcohol dia-
stereomers were not easily separated, exclusive reduction to the undesired
diastereomer was carried out, followed by Mitsunobu inversion.
(13) Muto, S.; Nishimura, Y.; Mori, K. Eur. J. Org. Chem. 1999, 2159.
(14) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(15) Elimination of the geminal dibromide and methylation of the resulting
alkyne were both found to be solvent dependent. As a result, the two
reactions were carried out in separate steps.
(16) Attempted hydrozirconation of the TBDPS-protected alcohol resulted in
removal of the silyl-protecting group and decomposition.
(17) (a) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975,
97, 679. (b) Nishizawa, M.; Imagawa, H.; Hyodo, I.; Takeji, M.; Morikuni,
E.; Asoh, K.; Yamada, H. Tetrahedron Lett. 1998, 39, 389.
(18) Gao, Y.; Hanson, R.; Klunder, J.; Ko, S.; Masamune, H.; Sharpless, K.
B. J. Am. Chem. Soc. 1987, 109, 5765.
1
(1). The H and 13C NMR data for synthetic 1 were in agreement
with the data reported for natural phomactin A.1a,26
Scheme 4. Completion of the Total Synthesisa
(19) Parikh, J. R.; Von Doering, E. W. J. Am. Chem. Soc. 1967, 89, 5505.
(20) Suzuki macrocyclization was accomplished on the TES ether of 15.
However, reduction of the ketone to the corresponding allylic alcohol was
observed as an accompanying side reaction during the hydroboration step.
(21) Tl2CO3 was used in place of Cs2CO3. For the use of thallium bases in
Suzuki reactions, see ref 24 and references therein.
(22) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014.
(23) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki,
A. J. Am. Chem. Soc. 1989, 111, 314.
(24) (a) For a review of the B-alkyl Suzuki reaction, see: Chemler, S. R.;
Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544.
(b) Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.; Roush, W.
R. Org. Lett. 2000, 2, 2691.
(25) For recent application of the B-alkyl Suzuki reaction in natural product
synthesis, see ref 2d, and: (a) Chemler, S. R.; Danishefsky, S. J. Org.
Lett. 2000, 2, 2695. (b) Gagnon, A.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2002, 41, 1581. (c) Bauer, M.; Maier, M. E. Org. Lett. 2002, 4,
2205.
(26) In CDCl3 instead of CD3OD, synthetic phomactin A showed 1H NMR
data which were superimposable on those reported for natural Sch 49028
from Phoma sp. It has been suggested that Sch 49028 is, in fact, phomactin
A (1) and not the epoxy cyclic hemiacetal structure reported. See ref 3,
and Chu, M.; Truumees, I.; Gunnarsson, I.; Bishop, W. R.; Kreutner, W.;
Horan, A. C.; Patel, M. G.; Gullo, V. P.; Puar, M. S. J. Antibiot. 1993,
46, 554.
a Reagents and conditions: a) t-BuLi, -78 °C, then 13; b) Dess-Martin
periodinane (45% for two steps); c) TBAF (91%); d) 1% HCl, tert-amyl
alcohol (65%); e) TES-Cl (83%); f) DDQ (87%); g) TMS-OTf, Pyr. 0 °C
(81%); h) 9-BBN, THF, 40 °C; then H2O; Pd(dppf)Cl2, AsPh3, Tl2CO3,
6:3:1 THF:DMF:H2O, rt (37%); i) TBAF (78%).
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