An expedient formal total synthesis of (-)-diazonamide A via a powerful, stereoselective O-aryl to C-aryl migration to form the C10 quaternary center

Article abstract of DOI:10.1021/ja0744448

During the course of studies on the synthesis of diazonamide A 1, an unusual O-aryl into C-aryl rearrangement was discovered that allows partial control of the absolute stereochemistry of the C-10 quaternary stereogenic center. Treatment of 30 with TBAF/THF gave the O-tyrosine ethers 31 and 32 (1:1), which on heating each separately in chloroform at reflux rearranged to 33 and 34 in ratios of 84:16 and 56:44, respectively. This corresponds to a 70% yield of the correct C-10 stereoisomer 33 and a 30% yield of the wrong C-10 stereoisomer 34. Attempts to convert 34 into 33 by ipso-protonation and equilibration were unsuccessful. Confirmation of the stereochemical outcome of the rearrangement was obtained by converting 33 into 37, an advanced intermediate in the first synthesis of diazonamide A by Nicolaou et al. It was also found that the success of the above rearrangement is sensitive to the protecting group on both the tryptophan nitrogen atom and the tyrosine nitrogen atom.

Full text of DOI:10.1021/ja0744448

Published on Web 09/19/2007
An Expedient Formal Total Synthesis of (-)-Diazonamide A
via a Powerful, Stereoselective O-Aryl to C-Aryl Migration To
Form the C10 Quaternary Center
Chi-Ming Cheung, Frederick W. Goldberg, Philip Magnus,* Claire J. Russell,
Rachel Turnbull, and Vince Lynch†
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Texas at Austin,
1 UniVersity Station A5300, Austin, Texas 78712-1167
Received July 3, 2007; E-mail: p.magnus@mail.utexas.edu
Abstract: During the course of studies on the synthesis of diazonamide A 1, an unusual O-aryl into C-aryl
rearrangement was discovered that allows partial control of the absolute stereochemistry of the C-10
quaternary stereogenic center. Treatment of 30 with TBAF/THF gave the O-tyrosine ethers 31 and 32
(1:1), which on heating each separately in chloroform at reflux rearranged to 33 and 34 in ratios of 84:16
and 56:44, respectively. This corresponds to a 70% yield of the correct C-10 stereoisomer 33 and a 30%
yield of the wrong C-10 stereoisomer 34. Attempts to convert 34 into 33 by ipso-protonation and equilibration
were unsuccessful. Confirmation of the stereochemical outcome of the rearrangement was obtained by
converting 33 into 37, an advanced intermediate in the first synthesis of diazonamide A by Nicolaou et al.
It was also found that the success of the above rearrangement is sensitive to the protecting group on both
the tryptophan nitrogen atom and the tyrosine nitrogen atom.
Introduction
of diazonamide A. In the first reported total synthesis of
diazonamide A 1 by the Nicolaou group, it was found that
treatment of 8 [1:1 mixture of epimers at C10 (diazonamide
Diazonamide A 1 was isolated from the colonial ascidian
Diazona angulata, collected from the ceilings of caves along
the northwest coast of Siquijor Island in the Philippines. It
exhibits potent in vitro activity against HCT-116 human colon
carcinoma and B-16 murine melanoma cancer cells (IC50 < 15
ng/mL). The original structure, as reported in 1991 by Fenical
and Clardy,1 was corrected in 2001 to 1 by Harran, Figure 1.2
While there has been a large number of research groups involved
in the total synthesis of diazonamide A,3a-k only the Nicolaou4a-d
and Harran5 groups have so far been successful.
Our original photo-Fries rearrangement strategy as applied
to the “old incorrect structure” converted 3 into 4 (76%), Scheme
1.6 Attempted use of this strategy on the “new correct structure”
required an aza photo-Fries rearrangement.7 In the event, it was
found that photolysis of 5 under a variety of conditions did not
give 6; only 5 was recovered unchanged. It was therefore
decided to pursue a different strategy that involved formation
of the C8-C10 bond by nucleophilic displacement of a leaving
group (LG) at C10 as depicted in 2, Figure 1. It was planned to
form the C16-C18 bond by a Suzuki coupling reaction.8
The most significant problem in the synthesis of diazonamide
A is the stereoselective formation of the crucial C10 quaternary
center. Scheme 2 summarizes the results that have addressed
this difficult problem, and subsequently resulted in the synthesis
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288. Poriel, C.; Lachia, M.; Wilson, C.; Davies, J. R.; Moody, C. J. J.
Org. Chem. 2007, 72, 2978-2987. (b) Konopelski, J. P.; Hottenroth, J.
M.; Oltra, H. M.; Veliz, E. A.; Yang, Z.-C. Synlett 1996, 609-611. (c)
Wipf, P.; Methot, J.-L. Org. Lett. 2001, 3, 1261-1264. (d) Vedejs, E.;
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Lett. 2000, 2, 1033-1035. Vedejs, E.; Zajac, M. A. Org. Lett. 2001, 3,
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Sawada, T.; Fuerst, D. E.; Wood, J. L. Tetrahedron Lett. 2003, 44, 4919-
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3525-3528. (g) Boto, A.; Ling, M.; Meek, G.; Pattenden, G. Tetrahedron
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J.; Pattenden, G. Org. Biomol. Chem. 2006, 4, 4193-4205. (h) Chen, X.;
Esser, L.; Harran, P. G. Angew. Chem., Int. Ed. 2000, 39, 937-940. Li, J.;
Chen, X.; Burgett, A. W. G.; Harran, P. G. Angew. Chem., Int. Ed. 2001,
40, 2682-2685. Jeong, S.; Chen, X.; Harran, P. G. J. Org. Chem. 1998,
63, 8640-8641. (i) Nicolaou, K. C.; Snyder, S. A.; Simonsen, K. B.;
Koumbis, A. E. Angew. Chem., Int. Ed. 2000, 30, 3473-3478. Nicolaou,
K. C.; Snyder, S. A.; Giuseppone, N.; Huang, X.; Bella, M.; Reddy, M.
V.; Rao, P. B.; Koumbis, A. E.; Giannakakou, P.; O’Brate, A. J. Am. Chem.
Soc. 2004, 126, 10174-10182. Nicolaou, K. C.; Snyder, S. A.; Huang,
X.; Simonsen, K. B.; Koumbis, A. E.; Bigot, A. J. Am. Chem. Soc. 2004,
126, 10162-10173. (j) Magnus, P.; Kreisberg, J. D. Tetrahedron Lett. 1999,
40, 451-454. Chan, F.; Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000,
41, 835-838. Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000, 41, 831-
834. Kreisberg, J. D.; Magnus, P.; McIver, E. G. Tetrahedron Lett. 2001,
42, 627-629. Magnus, P.; Venable, J. D.; Shen, L.; Lynch, V. Tetrahedron
Lett. 2005, 46, 707-710. Magnus, P.; Turnbull, R. Tetrahedron Lett. 2006,
47, 6461-6464. (k) Ritter, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2002,
41, 2489-2495.
† Author for inquiries concerning the X-ray data.
(1) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem.
Soc. 1991, 113, 2303-2304.
(2) Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed. 2001, 40,
4765-4770. Li, J.; Burgett, A. W. G.; Esser, L.; Amezcua, C.; Harran, P.
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9
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J. AM. CHEM. SOC. 2007, 129, 12320-12327
10.1021/ja0744448 CCC: $37.00 © 2007 American Chemical Society

Total Synthesis of (−)-Diazonamide A
A R T I C L E S
Figure 1. Structure of diazonamide A 1 and crucial disconnections 2.
Scheme 1. Initial Photo-Fries Rearrangement Approach
Scheme 2. Methods Used To Form the C10 Quaternary Center in the Three Syntheses of Diazonamide A
numbering)] with 7 (4 equiv) in the presence of p-TsOH at
83 °C in 1,2-dichloroethane gave 9 (16.5%) (after reintroduction
of the Boc group), and an equal amount of the C10-epimer 10.4a,c
In an attempt to conduct an intramolecular version of this
reaction, 11 was treated under a number of reaction conditions
designed to ionize the tertiary hydroxyl group, but it did not
cyclize to provide 12.9 In the second synthesis of 1, Nicolaou
et al. converted 13 into 14 as a 1:1 mixture of diastereoisomers
in 70% yield.4b,d
In a tyrosine-indole oxidative coupling approach to form the
C10 quaternary center, Harran et al. treated 15 with PhI(OAc)2/
LiOAc/CF3CH2OH at -20 °C to give 16 (20-25%), and its
9
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A R T I C L E S
Cheung et al.
Scheme 3. Synthesis of the Oxazole 21 and Isatin 24 Components
Scheme 4. Formation of Macrocyclic Ethers 31 and 32
C10 epimer 17 (7-8%), along with products from other
nonproductive oxidative pathways.5
In this Article, we describe a serendipitous solution to this
problem that involves a O-aryl to C-aryl rearrangment that
enables the construction of the C8-C10 bond stereoselectively
and in high yield and provides a correlation with an advanced
intermediate in the “first” Nicolaou synthesis of diazonamide
A.4a,c
Results and Discussion
(4) (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.; H, X.; Chen, 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.
The known valine derived oxazole 21 was prepared by the
Meyers and Williams procedures.10 (S)-N-t-Butoxycarbonyl
valine serine methyl ester 18 was dehydrated (Burgess reagent)11
(9) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II; Wiley-VCH:
Weinheim, 2003; p 569.
(5) Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew. Chem., Int. Ed.
2003, 42, 4961-4966.
(10) Downing, S. V.; Aguilar, E.; Meyers, A. I. J. Org. Chem. 1999, 64, 826-
831. Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron
Lett. 1997, 38, 331-334.
(6) Magnus, P.; Lescop, C. Tetrahedron Lett. 2001, 42, 7193-7196.
(7) Carlsson, D. J.; Gan, L. H.; Wiles, D. M. Can. J. Chem. 1975, 53, 2337-
2344. Abdel-Malik, M. M.; De Mayo, P. Can. J. Chem. 1984, 62, 1275-
1278.
(11) Burgess, E. M.; Penton, H. R.; Taylor, E. A.; Williams, W. M. Org. Synth.
Coll. Vol. VI 1988, 788-790. Atkins, G. M.; Burgess, E. M. J. Am. Chem.
Soc. 1968, 90, 4744-4745.
(8) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
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12322 J. AM. CHEM. SOC. VOL. 129, NO. 40, 2007

Total Synthesis of (−)-Diazonamide A
A R T I C L E S
Scheme 5. O- to C-Rearrangement of 31 and 32 into 33 and 34
Table 1
to give 19 (68%), which was treated with BrCCl3/DBU to
provide 20 (79%). Base hydrolysis of 20 gave 21 (100%),
Scheme 3.
entry, starting
material
conditions
time
product (33:34)
1, 31
2, 32
3, 31
4, 32
5, 31
6, 32
7, 31
8, 32
9, 31
10, 32
11, 31
12, 32
solid, -20 °C
3 weeks 96:4 (42% conv.)a
3 weeks 33:67 (27% conv.)b
The second component we required was 7-bromoisatin 23.4c
The classical isatin synthesis using the condensation of 2-bro-
moaniline with chloral to give 22 was not possible because
chloral hydrate is no longer commercially available. However,
the equivalent 2,2,2-trichloro-1-ethoxyethanol (Acros 34653
CAS [515-83-3]) is the most convenient replacement. Treatment
of 2-bromoaniline with 2,2,2-trichloro-1-ethoxy-ethanol/Na2SO4
gave 22 (91%), which was dehydrated using concentrated H2-
SO4 resulting in 23 (81%).12 Protection of 23 as the N-
methoxymethyl derivative 24 was accomplished by treatment
of 23 in tetrahydrofuran at 25 °C with Et3N (5.0 equiv)/TMSCl
(5.0 equiv) (heated at reflux for 2 h), followed by cooling the
mixture to 0 °C and addition of methoxymethyl chloride
(MOMCl, 5.0 equiv) to give 24 (84%).13
For the reasons indicated in ref 14, we decided to attempt to
convert 21 into its derived trianion 21a and couple it to 24, and
thus preserve the correct carboxylate oxidation level throughout
the entire sequence. The acid 21 was treated with t-BuLi (3.4
equiv) in THF in the presence of HMPA (3.4 equiv) at -78 °C
to generate the trianion 21a (as judged by its subsequent reaction
with 24), Scheme 4.14 Addition of 7-bromo-N-methoxymeth-
ylisatin 24 to the trianion 21a (followed by workup) and
treatment of the crude reaction mixture with TMSCHN2 or
CH2N2 gave 25 (35-50%). The quinolone derivative 26 was
isolated in some runs of this reaction as a byproduct, which
presumably was formed from the reaction of remaining 24 with
TMSCHN2 or CH2N2.
solid, -20 °C
solid, 83 °C
solid, 83 °C
6 h
6 h
80:20
18:82
CH2Cl2, -20 °C
CH2Cl2, -20 °C
CH2Cl2, 21 °C
CH2Cl2, 21 °C
CH2Cl2, AcOH, 21 °C
CH2Cl2, AcOH, 21 °C
CHCl3, reflux
3 weeks 96:4 (12% conv.)c
3 weeks 38:62 (4% conv.)d
7 days
7 days
5 days
5 days
6 h
6 h
6 h
6 h
6 h
82:18
55:45
80:20
53:47
84:16
56:44
70:30
58:42
49:51
49:51
53:47
58:42
67:33
61:39
66:34
62:38
CHCl3, reflux
13, 31 + 32 CHCl3, reflux
14, 31 + 32 (CF3)2CHOH, 55 °C
15, 31 + 32 DMSO, 55 °C
16, 31 + 32 DMSO, 3 mol % TFA, 21 °C 6 h
17, 31 + 32 CH3CN, 55 °C 6 h
18, 31 + 32 CH3CN, 3 mol % TFA, 21 °C 6 h
19, 31 + 32 EtOH, 55 °C
6 h
6 h
20, 31 + 32 EtOH, 3 mol % TFA, 21 °C
21, 31 + 32 CH2Cl2, 3 mol % TFA, 55 °C 6 h
22, 31 + 32 CH2Cl2, cat aq HBF4
6 h
a 58% returned starting material (31:32 ) 78:22). b 63% returned starting
material (31:32 ) 20:80). c 88% returned starting material (31:32 ) 76:
24). d 96% returned starting material (31:32 ) 38:62). All of the ratios were
determined by analytical HPLC.
steps) as a 1:1 mixture of diastereomers. The t-hydroxy
functionality in 29 was converted into the chloride 30 (67%)
by treatment with SOCl2/collidine. When 30 was exposed to
standard silyl deprotection conditions (TBAF/THF at 0 °C), it
was cleanly converted into a 1:1 mixture (94%) of O-aryl ethers
31 and 32, which were separable by chromatography, Scheme
4.15 The 1H NMR data for 31 and 32 did not allow us to assign
the C10 stereochemistry, and we were unable to obtain crystals
of either isomer that were suitable for X-ray crystallography.
For some time, we thought that when 31 and 32 were heated
separately in chloroform at reflux (61 °C) it resulted in the
Removal of the Boc-group from 25 (TFA/CH2Cl2/0 °C) gave
27, which was coupled (EDC/HOBt/DMF at 25 °C) with the
N-Cbz/OSiPri3 tyrosine derivative 28 to give 29 (52% over two
(12) Newman, M. S.; Logue, M. W. J. Org. Chem. 1971, 36, 1398-1401.
(13) Klebe, J. F. In Silylation in Organic Synthesis. AdVances in Organic
Chemistry; Taylor, E. C., Ed.; Wiley-Interscience: New York, 1972; pp
119-135.
(14) The Nicolaou synthesis reduces 20 to the derived alcohol and selectively
O-benzylates (J. Am. Chem. Soc. 2004, 126, 12888-12896, Scheme 6, p
12893). Neither NaHMDS nor LiHMDS worked in our hands; consequently,
we examined maintaining the carboxylate oxidation level through the direct
use of 21 and the formation of the trianion 21a.
(15) For references to azaxylylene intermediates formed from 1,4-elimination,
see: Ly, T.-M.; Laso, N. M.; Zard, S. Z. Tetrahedron 1998, 54, 4889-
4898. Corey, E. J.; Steinhagen, H. Angew. Chem., Int. Ed. 1999, 38, 1928-
1931. Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068-5069.
Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677-680. Avemaria, F.;
Vanderheiden, S.; Bra¨se, S. Tetrahedron 2003, 59, 6785-6796.
9
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A R T I C L E S
Cheung et al.
Scheme 6. Correlation with the First Nicolaou Synthesis of Diazonamide A
formation of only 33.16 Eventually, through a series of events
that involved repeating all of this work and discovering a TLC
solvent system that revealed that a mixture of 33 and 34 was
being formed, we realized that the transformation of 31 and 32
was stereoselective in favor of 33, but not stereoconvergent in
that both 31 and 32 were not converted into the same
stereoisomer 33, but a mixture of both 33 and 34, Scheme 5
and Table 1.
and 34 in ratios of 84:16 and 56:44, respectively. This
corresponds to a 70% yield of 33 and a 30% yield of 34. In
more polar solvents that would be expected to favor dissociation
of the C-O bond, entries 14-21, the ratio of 33 to 34 varies
from 49:51 to 67:33. Finally, exposure of 34 to a variety of
reaction conditions (TFA/CH2Cl2, TFA/(CF3)2CHOH, etc.) that
have the potential to convert 34 into 33 via ipso-protonation17
did nothing.
The overall trends that are apparent from the data in Table 1
are that: (a) 31 produces more of 33 than does 32; (b) 32 is
less selective in the rearrangement than 31, and as the temper-
ature is increased from 21 to 61 °C the amount of 33 increases,
and it becomes the major isomer; and (c) dissociating solvents
tend to convert 31 and 32 to equal amounts of 33 and 34.18
The equilibration of 31 into 32 and vice versa must be slower
than their conversion into 33 and 34, respectively. Both 31 and
32 can convert into 33 and 34, the difference being that 31 f
33 involves dissociation to a tight ion-pair (Scheme 9) and
formation of the new carbon-carbon bond without bond
rotation, whereas the conversion of 31 f 34 involves dissocia-
tion of the C-O bond, rotation, and recombination of the
dissociated ions to give the inverted product 34.
The assignment of the stereochemistry at C10 in 33 is based
on its subsequent conversion into 37, which is an advanced
intermediate in Nicolaou’s first synthesis of diazonamide A 1,
Scheme 6.4a,c The C10 stereochemistry in 34 is based on the
comparison of its spectral data with 44 (Scheme 7) whose
structure was established by X-ray crystallography. Therefore,
from the principle of least motion19 we can assign the C10
stereochemistry of 31 and 32 as shown in Scheme 5.
In the solid phase at -20 °C, both 31 and 32 are converted
into 33 and 34 in ratios of 96:4 and 33:67, respectively. Even
though we started with pure 31 and pure 32, the recovered ethers
consisted of a mixture of 31 and 32 in ratios of 78:22 and 20:
80, respectively, entries 1 and 2. Carrying out the same reaction
of 31 and 32 in the solid phase at 83 °C allowed complete
conversion into 33 and 34 in ratios of 80:20 and 18:82,
respectively, entries 3 and 4.
In solution at -20 °C in dichloromethane, 31 and 32 are
partially converted into 33 and 34, entries 5 and 6, whereas at
21 °C, complete conversion takes place within 7 days to give
33 and 34 in ratios of 82:18 and 55:45, respectively, entries 7
and 8. The above rearrangement in dichloromethane is complete
in 5 days if a catalytic amount of acetic acid is present, entries
9 and 10, and gives 33 and 34 in almost exactly the same ratio
as in the nonacid-catalyzed version.
The most practical method of converting 31 and 32 into the
correct stereoisomer 33 is heating the ethers in chloroform at
reflux (61 °C) for 6 h, entries 11 and 12, which results in 33
(16) Bould, L. Studies on the synthesis of tetracycline. Ph.D. Thesis; Imperial
College, London, 1968; pp 91 and 153. In the above thesis, the conversion
of 56 into 57 is described. The text (p 93) describes the yield of 57 as
20%. However, the experimental section (p 153) converts 56 (125 mg)
into 57 (37 mg), corresponding to a 29.6% yield. In 1968, Magnus was a
Ph.D. student working next to Bould, and as a consequence knew about
the transformation of 56 into 57. This information initiated the notion (36
years later!) that this type of reaction could be used for the construction of
the C-10 quaternary center in diazonamide A.
As alluded to above, we decided that the most expeditious
way to confirm the structure of 33 was to convert 33 into a
known compound that had been itself converted into diazona-
(17) Goldberg, F. W.; Magnus, P.; Turnbull, R. Org. Lett. 2005, 7, 4531-4534.
(18) Reichardt, C. SolVents and SolVent Effects in Organic Chemistry; VCH:
New York, 1988.
(19) Rice, F. O.; Teller, E. J. Chem. Phys. 1938, 6, 489-496. Hine, J. AdV.
Phys. Org. Chem. 1977, 15, 1-61. “A spontaneous reaction will yield a
product which has a similar spatial arrangement of the atoms rather than a
very different one even if energetically favorable.” Isaacs, N. Physical
Organic Chemistry; Longman Group Ltd.: Harlow, U.K., 1995; pp 123-
124.
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Total Synthesis of (−)-Diazonamide A
A R T I C L E S
Scheme 7. Stereoselective O- to C-Rearrangement of 41 and 42 into 43 and 44, Respectively
Scheme 8
mide A. The simplest way to achieve this structural correlation
was to convert 33 into 37, an advanced intermediate in
Nicolaou’s4a,c first synthesis of diazonamide A, Scheme 6. To
establish the above proposed correlation, the phenolic hydroxyl
group in 33 was converted into its derived methoxymethyl ether
for 37 (J. Am. Chem. Soc. 2004, 126, 12888-12896, Scheme
1
7, p 12893, compound 43), H NMR (500 MHz), 13C NMR
(125 MHz), IR, HRMS, and optical rotation, lit.4c [R]20D -177.0
(c ) 0.57, MeOH), [R]20 -180.7 (c ) 0.7, MeOH) (within
D
2.1%) clearly established the structure of 37, and thus the
remarkable stereoselective conversion of 31 and 32 into 33.
Since 37 has been converted into diazonamide A 1 in Nicolaou’s
first synthesis,4a,c this constitutes a formal total synthesis of 1.
While the work described so far has the tyrosine nitrogen
atom protected as the benzyloxycarbonyl derivative (Cbz), we
i
35 by treatment with MeOCH2Cl/NPr2 Et in dichloromethane
at 0 °C, Scheme 6. Reduction of the methyl ester functionality
in 35 was achieved by exposure of 35 to LiBH4/THF to give
36 (75%), which was converted into 37 by treatment with n-Bu4-
NI/NaH/BnBr in DMF/THF at 0 °C (89%). Comparison of data
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A R T I C L E S
Cheung et al.
Figure 2. View of 44 showing the atom labeling scheme. Displacement ellipsoids are scaled to the 30% probability level. The methyl hydrogen atoms have
been removed for clarity.
Scheme 9. Mechanism of O-Ar to C-Ar Rearrangement
Table 2
consisted of a mixture of 41 and 42 in ratios of 84:16 and 8:92,
respectively, entries 1 and 2.
entry, starting
material
conditions
time
product (43:44)
In solution at -20 °C in dichloromethane, 41 is partially (2%)
converted into 43 and 44 (46:54), entry 3, whereas under the
same reaction conditions 42 remained unchanged, entry 4. At
21 °C in dichloromethane, 41 and 42 are completely converted
within 7 days to give 43 and 44 in ratios of 62:38 and 66:34,
respectively, entries 5 and 6. The above rearrangement in
dichloromethane is complete in 5 days if a catalytic amount of
acetic acid is present, entries 7 and 8, and gives 43 and 44 in
ratios of 47:53 and 58:42.
1, 41
2, 42
3, 41
4, 42
5, 41
6, 42
7, 41
8, 42
solid, -20 °C
3 weeks
3 weeks
3 weeks
3 weeks
7 days
7 days
5 days
5 days
6 h
77:23 (18% conv.)a
13:87 (48% conv.)b
46:54 (2% conv.)c
0% conv.d
62:38
66:34
47:53
58:42
65:35
solid, -20 °C
CH2Cl2, -20 °C
CH2Cl2, -20 °C
CH2Cl2, 21 °C
CH2Cl2, 21 °C
CH2Cl2, AcOH, 21 °C
CH2Cl2, AcOH, 21 °C
CHCl3, reflux
9, 41 + 42
a 82% returned starting material (41:42 ) 84:16). b 52% returned starting
material (41:42 ) 8:92). c 98% returned starting material (41:42 ) 90:10).
d 100% returned starting material (41:42 ) 4:96). All of the ratios were
determined by analytical HPLC.
The most practical method of converting 41 and 42 into the
correct stereoisomer 43 is heating the ethers in chloroform at
reflux (61 °C) for 6 h, entry 9, which results in 43 and 44 (6:
35). Exposure of 44 to a variety of reaction conditions (TFA/
CH2Cl2, TFA/(CF3)2CHOH, etc.) did not produce 43.
also explored t-butoxycarbonyl (Boc) protection. Treatment of
27 with 3820 under standard amide coupling reaction conditions
gave 39 (73% from 25), Scheme 7. The derived chloride 40 on
exposure to n-Bu4NF (TBAF)/THF at 0 °C resulted in clean
conversion into the phenolic ethers 41 and 42 (1:1, 95%). The
separated ethers 41 and 42 were subjected to a number of
reaction conditions, Table 2, to give 43 and 44. The trends are
similar to those seen for the Cbz series (Scheme 5, Table 1).
The structure of 44 was unequivocally established by X-ray
crystallography, Figure 2.
It was also discovered that the formation of the 14-membered
phenolic ether ring requires a protecting group on the tryptophan
nitrogen atom. In contrast to the above results, the unprotected
oxindole substrate 45 on exposure to TBAF/THF at 0 °C
produced a complex mixture, and none of the desired phenolic
ether 46 could be detected, Scheme 8. The nature of the
protecting group on the tyrosine nitrogen atom was also crucial.
As alluded to above, both the N-Cbz and the N-Boc derivatives
30 and 40 cyclized to give the phenolic ethers 31/32 (Scheme
4) and 41/42 (Scheme 7), respectively, whereas the N-Nos
protected adduct 47 on exposure to TBAF/THF at 0 °C resulted
in a complex mixture, and none of the desired phenolic ether
In the solid phase at -20 °C, both 41 and 42 are converted
into 43 and 44 in ratios of 77:23 and 13:87, respectively. Even
though we started with pure 41 and pure 42, the recovered ethers
(20) Wasserman, H. H.; Zhang, R. Tetrahedron 2002, 58, 6277-6284.
9
12326 J. AM. CHEM. SOC. VOL. 129, NO. 40, 2007

Total Synthesis of (−)-Diazonamide A
A R T I C L E S
48 was observed. Presumably, the pyramidal N-Nos prevents
47 from adopting a conformation that can result in 48.
We have studied the mechanism of the O-aryl to C-aryl
rearrangement on simple oxindoles and have made the following
observations.17 Heating 49 at 80 °C results in 53 (R ) H),
Scheme 8, whereas treatment of 49 with a catalytic amount of
CF3CO2H in benzene at 25 °C gave 55 (R ) H). Both the
thermal and the acid-catalyzed rearrangment exhibit crossover
when carried out in the presence of another phenol. Treatment
of 53 with a catalytic amount of CF3CO2H in benzene at 25 °C
cleanly converted it into the p-isomer 55.
This fortuitous rearrangement has some analogy in the
O-arylglycoside to C-arylglycoside conversion,21 and the Lewis
acid/Bronsted acid-catalyzed conversion of benzyl ethers into
2-hydroxydiphenylmethane derivatives.22 Also, there is an
unpublished thermal rearrangement of an O-cresyl ether into
an C-cresol derivative, which, in fact, provided the motivation
to pursue the rearrangement chemistry described in Scheme 5.16
Acknowledgment. The NIH (CA RO1 50512) and the Welch
Chair (F-0018) are thanked for their support of this research.
Professor K. C. Nicolaou is thanked for spectra of 37.
There appears to be two mechanisms operating. Under neutral
thermal conditions, 49 (R ) H) dissociates to 50 (R ) H), which
forms 51 (R ) H) (π-complex or ion-pair) and converts into
the o-cyclohexa-2,5-dienone 52 (R ) H), which tautomerizes
to give 53 (R ) H). In the presence of acid, the partially
dissociated adduct 50 (R ) H) can completely ionize to give
54 (R ) H), which gives the thermodynamically more stable
product 55 (R ) H). ipso-Protonation of 53 (R ) H) leads to
52 (R ) H) and eventually 55 (R ) H), thus providing further
evidence that acid catalysis promotes the formation of the more
stable rearrangement product. In the NMe series, treatment of
N-methyl-3-chloro-3-phenyloxindole with PhOH/Cs2CO3/CH2-
Cl2 at 25 °C gave 53 (R ) Me) directly, presumably via 49 (R
) Me). The rearrangement of 31/32 into 33 and likewise 41/42
into 43 most probably proceeds via the dissociative pathway
through a π-complex analogous to 51.
Supporting Information Available: Complete experimental
details and compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA0744448
(21) Booma, C.; Balasubramanian, K. K. Tetrahedron Lett. 1995, 36, 5807-
5810. Pinhey, J. T.; Xuan, P. T. Aust. J. Chem. 1988, 41, 69-80. Rousseau,
C.; Martin, O. R. Org. Lett. 2003, 5, 3763-3766. Ramesh, M. G.;
Balasubramanian, K. K. Tetrahedron Lett. 1992, 33, 3061-3064. Matsu-
moto, T.; Hosoya, T.; Suzuki, K. Synlett 1991, 709-711.
(22) Dewar, M. J. S.; Puttnam, N. A. J. Chem. Soc. 1959, 4080-4086, 4086-
4090, 4090-4095. de Mayo, P. Molecular Rearrangements. Part 1,
Aromatic Rearrangements; Interscience: New York, 1963; pp 313-318.
Tarbell, D. S.; Petropoulos, J. C. J. Am. Chem. Soc. 1952, 74, 244-248.
Hart, H.; Elia, A. R. J. Am. Chem. Soc. 1954, 76, 3031-3032. Sprung, M.
M.; Wallis, E. S. J. Am. Chem. Soc. 1934, 56, 1715-1720.
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