Diazonamide support studies: Stereoselective formation of the C10 chiral center in both the CDEFG and AEFG fragments

Article abstract of DOI:10.1021/ol8014336

(Chemical Equation Presented) The synthesis of both the AEFG macrolactam and the CDEFG bis-indole/tyrosine units found in the marine natural product diazonamide A is presented. Key to the success of the synthesis is the highly stereoselective direct C-arylation of an oxindole by an aryllead(IV) reagent derived from tyrosine.

Full text of DOI:10.1021/ol8014336

ORGANIC
LETTERS
2008
Vol. 10, No. 18
3969-3972
Diazonamide Support Studies:
Stereoselective Formation of the C10
Chiral Center in both the CDEFG and
AEFG Fragments
Jinzhen Lin,† Brian S. Gerstenberger,‡ Nhu Y T. Stessman,§
and Joseph P. Konopelski*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Cruz,
Santa Cruz, California 95064
joek@chemistry.ucsc.edu
Received June 25, 2008
ABSTRACT
The synthesis of both the AEFG macrolactam and the CDEFG bis-indole/tyrosine units found in the marine natural product diazonamide A is
presented. Key to the success of the synthesis is the highly stereoselective direct C-arylation of an oxindole by an aryllead(IV) reagent derived
from tyrosine.
The combination of unusual molecular architecture and high
biological activity found in the marine natural product
diazonamide A (1, original structure, Figure 1)1 has generated
considerable interest from the synthetic organic chemistry
community. Harran’s synthesis of 1 uncloaked the true
structure of diazonamide A as 2 and produced a highly active
synthetic analogue (3).2 To date, there have been three total
syntheses3,4 of this potent cytotoxic compound5 together with
a formal total synthesis and a wealth of synthetic6 methodol-
ogy development.7 Herein, we disclose our synthetic work
D. Y.-K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003, 42, 1753–1758. (c)
Nicolaou, K. C.; Chen, D. Y.-K.; Huang, X.; Ling, T.; Bella, M.; Snyder,
S. A. J. Am. Chem. Soc. 2004, 126, 12888–12896. (d) Nicolaou, K. C.;
Hao, J.; Reddy, M. V.; Rao, P. B.; Rassias, G.; Snyder, S. A.; Huang, X.;
Chen, D. Y.-K.; Brenzovich, W. E.; Giuseppone, N.; Giannakakou, P.;
O’Brate, A. J. Am. Chem. Soc. 2004, 126, 12897–12906
(4) Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew. Chem.,
Int. Ed. 2003, 42, 4961–4966.
.
(5) (a) Cruz-Monserrate, Z.; Mullaney, J. T.; Harran, P. G.; Pettit, G. R.;
Hamel, E. Eur. J. Biochem. 2003, 270, 3822–3828. (b) Cruz-Monserrate,
Z.; Vervoort, H. C.; Bai, R.; Newman, D. J.; Howell, S. B.; Los, G.;
Mullaney, J. T.; Williams, M. D.; Pettit, G. R.; Fenical, W.; Hamel, E.
Mol. Pharmacol. 2003, 63, 1273–1280. (c) Wang, G.; Shang, L.; Burgett,
A. W. G.; Harran, P. G.; Wang, X. Proc. Nat. Acad. Sci. U.S.A. 2007, 104,
2068–2073. (d) Williams, N. S.; Burgett, A. W. G.; Atkins, A. S.; Wang,
X; Harran, P. G.; McKnight, S. L Proc. Nat. Acad. Sci. U.S.A. 2007, 104,
2074–2079.
(6) Cheung, C.-M.; Goldberg, F. W.; Magnus, P.; Russell, C. J.; Turnbull,
R.; Lynch, V. J. Am. Chem. Soc. 2007, 129, 12320–12327.
(7) (a) See ref 5 for a listing of published work. (b) Lachia, M.; Moody,
C. J. Nat. Prod. Rep. 2008, 25, 227–253.
† Present address: Xiamen Doingcom Chemical Company Limited,
Xiamen, PRC.
‡ Present address: Pfizer Global Research and Development, Groton, CT.
§ Present address: Chemistry Department, CSU, Stanislaus, Turlock, CA.
(1) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am.
Chem. Soc. 1991, 113, 2303–2304.
(2) (a) Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed.
2001, 40, 4765–4770. (b) Li, J.; Burgett, A. W. G.; Esser, L.; Amezeua,
C.; Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770–4773.
(3) (a) Nicolaou, K. C.; Bella, M.; Chen, D. Y.-K.; Huang, X.; Ling,
T.; Snyder, S. A. Angew. Chem., Int. Ed. 2002, 41, 3495–3499. (b) Nicolaou,
K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.; Rassias, G.; Huang, X.; Chen,
10.1021/ol8014336 CCC: $40.75
Published on Web 08/15/2008
2008 American Chemical Society

Further simplification leads to 6/7, in which the C10 center
is established via the coupling of 8/9 to aryllead reagent 10.8
Earlier work had shown that the stereocenter of the tyrosine-
derived reagent 10 was too remote from the reaction site to
affect the stereochemical outcome of the coupling reaction.9
However, there was optimism for two reasons. First, Lubell
and Rapoport10 had demonstrated (modest) stereoselectivity
upon R-substitution of enantiomerically pure R′-amino
ketones bearing sterically bulky protection on the amine.
Since we had already documented high cyclic stereoselection
in the aryllead coupling reaction in systems where the
existing stereocenter is two bonds removed from the reaction
site,11 acyclic stereoselection seemed a distinct possibility.
Second, the 8/9 stereochemistry would arise from the amino
acid serine, which is readily available in either enantiomeri-
cally pure form. Since this stereocenter was slated for
destruction in the formation of ring A (oxazole), our quest
was for high diastereospecificity without initial regard to the
absolute chirality at C10.
Figure 1. Nominal and true diazonamide A structures.
Scheme 2. Benzofuranone Approach
on both the nominal and true diazonamide structures. Our
approach has been focused on the C10 center, both the literal
and figurative core of compounds 1-3, and the ability to
form this quaternary carbon in a highly diastereoselective
manner through the direct C-arylation of benzofuranone and
oxindole adducts with an aryllead(IV) reagent derived from
tyrosine.
Scheme 1. Retrosynthesis
Initial work focused on 8 as the coupling partner for 10
toward nominal structure 1. Esterification of commercially
available hydroxyphenylacetic acid 11, followed by selective
ortho-bromination of the phenol,12 yielded 12 (76%, Scheme
2, eq 1). Allyl protection of the phenol was followed by
acylation via CDI activated Boc-Ser(OBn)-OH to give 13
Our analysis (Scheme 1) envisioned advanced AEFG
lactone 4 (original structure) or lactam 5 (true structure)
leading to the target compound through elaboration of the
B, C, and D rings using the functionality at C29 and C16.
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Org. Lett., Vol. 10, No. 18, 2008

(60%). Allyl removal (PdCl2(PPh3)2/Bu3SnH) followed by
treatment of sodium methoxide led to the benzofuranone salt
8-Boc.
Scheme 3. Oxindole Approach
Reaction of 10 with 8-Boc afforded none of the desired
structure 6; only small amounts of unidentifiable compounds
were isolated (Scheme 2). This result inspired two changes
in our synthetic design. The protection group on the serine
residue was changed from -Boc to trityl in the hopes that
the large -CPh3 group would preclude both racemization13
and general degradation. Moreover, an alternative approach
to benzofuranone salt 8 was developed (Scheme 2, eq 2) to
overcome the poor yield of the carbon acylation step in the
production of 8-Boc. Phenol 12 was coupled with Tr-
Ser(OBn)-OH (DCC, 85%) to yield 14, which was reacted
with KH (1 equiv) to initiate a cascade reaction. Intramo-
lecular acyl transfer and subsequent intramolecular lacton-
ization precedes deprotonation of the resulting ꢀ-keto lactone
by the liberated methoxy anion, resulting in formation of
the desired benzofuranone potassium salt 8-Tr. Reaction of
10 with 8-Tr in 1,2-dichloroethane at 40 °C overnight
afforded a single isomer of the desired coupling product 6
in 45% yield from 14. However, our elation was shortlived
due to the revision of the structure of diazonamide A to 2.
Hence, we abandoned this work and moved to a strategy
employing oxindole 9.
Trityl group removal (1% TFA in CH2Cl2) and direct
coupling with Cbz-Val-OH (CIP/HOAt, 89%, 55% from 9)
preceded oxazole formation, which proved challenging. Best
15
results occurred with PPh3/C2Cl6 to give desired product
Lubell and Rapoport10 reported R′-alkylation of R-amino
ketones protected with the N-9-phenylfluorenyl (PhFl) group.
Diastereomeric ratios originated from an equilibrium between
two reactive conformations that, with our structures super-
imposed on the logic of our Berkeley colleagues, results in
cyclic structure A as the major isomer (Figure 2). Reaction
Scheme 4. CDEFG Fragment
Figure 2. Mechanistic interpretation.
of this structure with 10 leads to the desired product.
Experimentally, enolates A/B react with tert-butyl(chlo-
ro)diphenylsilane to afford the expected silyl enol ether (see
the Supporting Information).
The synthesis of oxindoles of type 9 has been reported by
our laboratory14 and relies on the direct acylation of the
requisite oxindole by the stable acid imidazolide formed from
Tr-Ser(OBn)-OH and CDI. Treatment of 9-Bn with NaH and
tyrosine derivative 10 afforded two C10 isomers of desired
compound 15 (7, PG1 ) Bn, PG2 ) Tr, X ) H) in 70%
isolated yield as an approximate 8:1 separable mixture
(major isomer: 62%, Scheme 3).
(8) Elliott, G. I.; Konopelski, J. P. Org. Lett. 2000, 2, 3055–3057.
(9) Konopelski, J. P.; Hottenroth, J. M.; Mo´nzo-Oltra, H.; Ve´liz, E. A.;
Yang, Z.-C. Synlett 1996, 609–11.
Org. Lett., Vol. 10, No. 18, 2008
3971

16 (31% yield, 36% BRSM). Closure of the 12-membered
lactam ring required reductive removal of the benzyl and
-Cbz protection groups to liberate the amino and acid
functionalities. Direct macrolactamization employing Nico-
laou’s procedure3a afforded the desired AEFG macrocycle
in 30% yield for the two steps. Confidence in the C10
stereochemical assignment resulted from the similarity in
yield between our result and that of Nicolaou (36%) for
minimally different compounds (N1-Cbz vs -Boc, C7-
OMOM vs OMe, C16-Br vs H) and Nicolaou’s observation
that the incorrect stereochemistry at C10 yields no product.
The original plan for the synthesis of diazonamide A was
to construct 5 with a halogen substituent at the C7 position
of the indole (C16 in diazonamide numbering). However,
all attempts at removing the Cbz (valine) and benzyl
(tyrosine) protection groups proved fruitless; the halogen was
removed under hydrogenolysis conditions at a greater rate
than acid or free amine formation.
the natural product with suitable functionality to complete
the synthesis. Although the C10 stereochemistry in 22 is not
confirmed, it is assumed that the trityl group again dictates
the outcome of the coupling reaction, as described in Figure 2.
In conclusion, a highly stereoselective route to the C10
quaternary center of diazonamide A has been developed.
Further progress to the total synthesis of 2 is ongoing in this
laboratory and will be reported in due time.
Acknowledgment. We thank the NIH (CA 098878) for
support of this work. Purchase of the 600 MHz NMR used
in these studies was supported by funds from the National
Institutes of Health (S10RR019918) and the National Science
Foundation (CHE-0342912).
Supporting Information Available: Experimental pro-
1
cedures, spectral data, and H and 13C NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Consequently, two modifications were implemented
(Scheme 4). First, the oxindole nitrogen protection group
was changed from -Bn to -MOM. Additionally, the C16-C18
bond was formed early in the synthetic sequence. In the
event, 7-bromo-1-methoxymethyl-1,2-dihydroindol-2-one
(17)14 was transformed to the corresponding boronate ester
(18) and coupled via palladium catalysis with 4-bromo-N,N′-
(bis-tert-butoxycarbonyl)tryptamine (19)16 to afford bisindole
compound 20 (80%). Acylation of the oxindole followed our
published protocol14 to afford 21 in 58% yield. Finally, the
C10 quaternary center is established as before, giving the
desired fragment 22 bearing the CDEFG ring system of
OL8014336
(10) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1988, 110, 7447–
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(11) Konopelski, J. P.; Lin, J.; Wenzel, P. J.; Deng, H.; Elliott, G. I.;
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(12) Pearson, D. E.; Wysong, R. D.; Breder, C. V. J. Org. Chem. 1967,
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(14) Gerstenberger, B. S.; Lin, J.; Mimieux, Y. S.; Brown, L. E.; Oliver,
A. G.; Konopelski, J. P. Org. Lett. 2008, 10, 369–372.
(15) Morwick, T.; Hrapchak, M.; DeTuri, M.; Campbell, S. Org. Lett.
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