Total synthesis of hamigerans: Part 1. Development of synthetic technology for the construction of benzannulated polycyclic systems by the intramolecular trapping of photogenerated hydroxy-o-quinodimethanes and synthesis of key building blocks

Article abstract of DOI:10.1002/1521-3773(20011001)40:19<3675::AID-ANIE3675>3.0.CO;2-G

A streamlined and general method for the construction of benzannulated systems such as I involves the intramolecular Diels - Alder reaction of photochemically generated hydroxy-o-quinodimethanes, for example, II. The method was optimized to set the stage

Full text of DOI:10.1002/1521-3773(20011001)40:19<3675::AID-ANIE3675>3.0.CO;2-G

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OMe OH
Total Synthesis of Hamigerans: Part 1.
OH
O
R1
R2
R1
R2
X
Development of Synthetic Technology for the
Construction of Benzannulated Polycyclic
Systems by the Intramolecular Trapping of
Photogenerated Hydroxy-o-quinodimethanes
and Synthesis of Key Building Blocks**
Me
Me
Me
Me
H
Y
R3
II
I
Scheme 1. Proposed o-enolquinodimethane route to the hamigerans.
K. C. Nicolaou,* David Gray, and Jinsung Tae
A recent report[1] disclosed the structures of a series of
compounds isolated from the poecilosclerid sponge Hamigera
tarangaensis Bergquist & Fromont (family Anchinoidae,
syn. Phorbasidae) from the Hen and Chicken Islands off the
coast of New Zealand. Termed hamigerans (e.g. 1 ± 4), these
natural products contain a unique carbon skeleton in which
chemical enolization of benzophenone. The few reports on
this reaction have typically involved mechanistic studies and
very simple substrates and/or rather special conditions.[6] In an
effort to develop a streamlined and general method for the
synthesis of benzannulated systems such as those found in the
hamigerans, we undertook a systematic investigation of this
process. In this and the following communication,[7] we wish to
describe the details of our explorations in this area which led
to the development of a general and practical entry into such
systems (Scheme 2), and its application to the total synthesis
of the hamigerans 1 ± 4 and their analogues.
OH
O
11
OH O
O
OH
11
X
Br
O
10
OMe
Me
10
Me
9
9
5
5
Me
Me
H
H
6
6
X
1: X = H: debromohamigeran A
2: X = Br: hamigeran A
3: X = H: hamigeran B
4: X = Br: 4-bromohamigeran B
a substituted aromatic nucleus is fused onto a [4.3.0]
carbocyclic system that contains three or four stereogenic
centers and features an isopropyl group. The biological
properties of these compounds range from moderate cytotox-
icity (e.g. 4-bromohamigeran B (4)) against P-388 leukemia
cells to strong antiviral activity (hamigeran B (3)) against
herpes and polio viruses. Despite their relatively small size,
the hamigerans offer both a challenge and an opportunity for
the development of new synthetic technologies and chemical
biology studies. In contemplating potential synthetic routes to
these compounds, we considered the possibility of employing
an intramolecular trapping strategy that involves the photo-
chemically generated hydroxy-o-quinodimethane species II to
form the benzannulated system I (Scheme 1). With a few
notable exceptions,[2, 3] there are only scant examples of
the potential use of this reaction in total synthesis,[4]
despite the early work by Yang and Rivas[5] on the photo-
Scheme 2. General strategy for the synthesis of benzannulated systems
from substituted benzaldehydes by the photogeneration and trapping of
hydroxy-o-quinodimethanes. A) Intermolecular variant. B) Intramolecular
variant.
With the ultimate goal of applying the developed technol-
ogy to complex molecule construction, we sought to include in
our studies a diverse and polyfunctional collection of sub-
strates for the intended photo-enolization-based reaction
(Scheme 2). Thus, it was observed that a wide variety of
dienophiles, including vinyl ketones,[8] acrylate esters,[9] acryl-
onitriles, and acroleins[4b] reacted with the electron-rich o-
methylbenzaldehyde 7 (Table 1, entries 4 ± 8) to afford a series
of benzannulated systems in generally good yields. An initial
exploration of the generality of the intermolecular Diels ±
Alder reaction of the photochemically generated hydroxy-o-
quinodimethanes (Scheme 2A) proved to be quite promising,
except for the fact that some of the employed dienophiles
showed an unacceptable propensity to photo-induced poly-
merization. We fine-tuned the reaction conditions and found
that these reactions could be made quite efficient and
practical (Table 1) by employing an excess of the polymer-
izable dienophiles, by performing the reaction in dilute
[*] Prof. Dr. K. C. Nicolaou, D. Gray, Dr. J. Tae
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (‡1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] This work was financially supported by the National Institutes of
Health (USA) and The Skaggs Institute for Chemical Biology, and
grants from Abbott, Amgen, ArrayBiopharma, Boehringer-Ingel-
heim, Glaxo, Hoffmann-La Roche, DuPont, Merck, Pfizer, and
Schering Plough.
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Table 1. Synthesis of benzannulated systems by the intermolecular trap-
ping of hydroxy o-quinodimethanes (see Scheme 2A).[a]
Table 2. Synthesis of benzannulated tricycles by the intramolecular trap-
ping of hydroxy-o-quinodimethanes (see Scheme 2B).[a]
Entry Aldehyde
Dienophile Product
t
Yield
Entry Aldehyde
Product
t
Yield
[h] [%]
[min] [%]
OH
O
H
O
OH
O
9
O
O
O
O
OEt
25
1
2
12 55
H
5
H
OEt
1
2
3
45
90
45
95
83
95
H
H
H
18
O
O
OH
O
OH
OH
8
8
72
71
H
6
CN
H
CN
O
10
H
OH
O
O
O
H
26
19
O
3
4
H
6
O
H
11
H
OEt
27
H
OEt
MeO
O
MeO HO
OMe
O
O
O
H
7
2
4
2
2
4
2
83
82
89
75
84
88
20
21
OMe
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
O
O
MeO
MeO
OH
OH
O
H
MeO 12
O
O
O
O
H
H
H
H
MeO
MeO
OH O
O
O
O
O
4
5
6
7
20
20
20
60
90
H
7
5
6
7
8
9
H
28
13
MeO
MeO
O
11
MeO HO
OEt
Me
OEt
O
O
H
10
90[b]
88[c]
75
Me
H
7
5
H
Me
9
H
6
29
HO
HO
HO
OH
22
23
MeO
MeO
MeO 14
O
OH
11
O
MeO
MeO
OH
OEt
30
CN
O
EtO
CN
10
H
7
Me
5
9
H
6
15
MeO
MeO
OH
O
MeO OH
O
HO
OMe
O
MeO
H
7
H
H
OMe
OMe
Me
H
MeO
O
MeO
OH
16
31
OH
24
O
O
[a] O-alkyl benzaldehydes (0.5 ± 1 mmol) were dissolved in deoxygenated
toluene or benzene (0.02m) in a pyrex flask and irradiated at ambient
temperature with a 450-W Hanovia lamp at a distance of 5 cm. Products
were obtained as separable mixtures of isomers, which reflected the E:Z
ratios of the starting olefins. The starting material and product shown are
the major isomers (stereochemistry assigned by NMR spectroscopy).
[b] Starting olefin: E/Z >20:1; product: C10 epimers >20:1. [c] Starting
olefin: Z/E >20:1; product: C10 epimers ꢀ3:1.
H
8
F
F
17
[a] O-alkyl benzaldehyde (1 mmol) and olefin (5 ± 20 equiv) were dissolved
in deoxygenated toluene (0.025m) in a pyrex flask and irradiated at
ambient temperature with a 450-W Hanovia lamp at a distance of 10 cm.
Products were obtained as separable mixtures of isomers in the following
ratios, by entry number: 1) ꢀ 4:1; 2) ꢀ 4:1; 3) ꢀ 8:1; 4) ꢀ 3:1; 5) ꢀ 8:4:1;
6) ꢀ 6:1; 7) ꢀ 7:1; 8) ꢀ 9:3:1; 9) ꢀ 6:1. The product shown is the major
isomer (stereochemistry assigned by NMR spectroscopy).
A powerful extension of this methodology would be its
intramolecular variant. This proposition assumed special
priority in light of the many foreseeable applications of such
synthetic technology. To test this, a rapid entry into a series of
ortho-alkyl-substituted benzaldehydes was devised and em-
ployed to deliver substrates 18 ± 24 (Table 2, entries 1 ± 7).
When these aldehydes were exposed to ultraviolet light (450-
W Hanovia lamp, pyrex filter) at ambient temperature, a
remarkably fast, stereoselective, and high-yielding ring clo-
sure took place in each case to furnish the tricycles 25 ± 31
(Table 2, entries 1 ± 7). These examples demonstrate that both
[4.4.0] (Table 2, entries 1 ± 3) and [4.3.0] bicyclic systems
(Table 2, entries 4 ± 7) can be fused onto the aromatic nucleus,
and that the newly generated fusion in the cyclization product
toluene solution, and by using ordinary pyrex vessels (as
opposed to quartz glass). We also noted that in going from the
parent 2-methylbenzaldehyde (5; Table 1, entry 1) to more
substituted substrates, the efficiency of the reaction improved
substantially (Table 1, entries 2 ± 9). Interestingly, the more
electron-rich benzaldehydes (Table 1, entries 2 ± 8) proved to
be excellent substrates in this reaction as did commercially
available 3-fluoro-2-methylbenzaldehyde (8). The latter re-
acted with methyl vinyl ketone to afford the corresponding
bicyclic fluoride 17 in high yield under the developed photo-
lytic conditions (Table 1, entry 9).
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has a trans-fused stereochemistry. Furthermore, the three
contiguous substituents that extend from the benzylic position
(OH, electron-withdrawing group, and H or Me) were found
to be syn to one another when di- or trisubstituted E olefins
were employed (Table 2, entries 1 ± 5). Also notable is the
ability of this process to deliver quaternary centers (Table 2,
entries 3, 5 ± 7), including two such centers in adjacent
positions (Table 2, entry 7). Furthermore, some interesting
stereochemical aspects of this process are evident (Table 2,
entries 5 and 6). When (E)-22 was subjected to the reaction,
the product with the all-syn stereochemistry at C9, C10, and
C11 (29; Table 2, entry 5; for selected data, see Table 3) was
obtained as the major product together with the isomeric
compound 30 in which the ester group is anti to the two
neighboring substituents (>20:1 ratio). An endo approach of
the dienophile towards the hydroxy-o-quinodimethane ac-
counts for this stereochemical outcome. Surprisingly, how-
ever, when pure (Z)-23 was employed, a mixture of the same
two products (29/30 ꢀ1:3) was formed, with stereoisomer 30
now predominating. This observation requires an exo mode of
approach of the incoming dienophile (to explain the forma-
tion of the major product 30 from 23) and a Z to E
isomerization under the irradiation conditions (to account
for the formation of the all-syn isomer 29). Molecular
modeling confirms the highly strained nature of both the
exo approach for the E isomer 22 and the endo arrangement
for the Z isomer 23, thus precluding the formation of the C5 ±
C9 syn junction which would require transition states
associated with such modes of interaction.
Having established the reaction as a reliable and efficient
synthetic process and further defined its scope and generality,
we then proceeded to the second phase of the program, which
had as its ultimate aim the possible application of the
intramolecular version of the developed technology to the
total synthesis of the hamigerans. To this end, two cyclization
precursors were designed, one in which the isopropyl group at
the C6 position of the targeted structure (45, Scheme 3A) was
already installed prior to ring closure, and another in which
this position was occupied by a protected oxygen functionality
(48, Scheme 3B). The latter functionality was chosen so as to
serve as a handle to introduce the isopropyl group after
cyclization, and to facilitate the desired epimerization at C5
(given the results of the model studies which led to the
undesired C5 ± C9 junction).
The construction of these two substrates is summarized in
Scheme 3. Treatment of benzamide 32 with two equivalents of
tBuLi in the presence of TMEDA (for abbreviations of
reagents and protecting groups, see legends in schemes) led to
the deep red colored dianion, which opened terminal
epoxide 33 to afford secondary alcohol 34 in 69% yield
(Scheme 3A).[10] For the isopropyl substrate, the commercial-
ly available racemic epoxide (Æ)-33 was utilized, whereas for
the protected alcohol (Scheme 3B), enantiomerically en-
riched (>99% ee) epoxide (S)-33, which was obtained by
using the Jacobsen hydrolytic kinetic resolution method with
the S,S cobalt catalyst,[11] was used (see below). Acid-induced
(pTsOH) intramolecular attack of the newly generated
alcohol at the amide group of 34 led to d-lactone 35 in 91%
yield.[10] Compound 35 was then reduced with LiAlH4, the
Scheme 3. Synthesis of cyclization substrates 45 and 48. Reagents and
conditions: a) tBuLi (2.2 equiv), TMEDA (2.0 equiv), 78 ! 208C, then
33 (1.0 equiv), THF, 78 !08C, 2 h, 69%; b) pTsOH (2.0 equiv), toluene,
reflux, 2 h, 91%; c) LiAlH4 (2.0 equiv), THF, 258C, 30 min, 91%; d) TBSCl
(1.1 equiv), Et3N (2.0 equiv), 258C, 12 h, 89%; e) SO3 ´ py. (3.0 equiv), Et3N
(6.0 equiv), DMSO/CH2Cl2 (1:1), 08C, 2 h, 94%; f) iPrMgCl (2.0 equiv),
CeCl3 (2.0 equiv), 78 !08C, 1 h, 94%; g) SOCl2, py, CH2Cl2, 608C,
15 min, 80%; h) PdCl2 (0.1 equiv), Cu(OAc)2 (2.0 equiv), DMA/H2O
(10:1), O2 (1 atm), 258C, 12 h, 80%; i) 10% Pd/C, H2 (1 atm), EtOAc,
258C, 2 h, 92%; j) (MeO)2 P(O)CH2COOMe (3.0 equiv), NaH (3.0 equiv),
THF, 608C, 3 h, 94% (mixture of E/Z isomers, ca. 3:1); k) HF ´ py
(4.0 equiv), THF, 258C, 20 min, 91%; l) SO3 ´ py (3.0 equiv), Et3N
(6.0 equiv), DMSO/CH2Cl2 (1:1), 08C, 2 h, 86%; m) MOMCl (2.0 equiv),
iPr2NEt (6.0 equiv), CH2Cl2, 258C, 4 h, 83%; n) same procedure as steps h,
j, and k above, similar yields; o) same procedure as step l above, 88%.
TMEDA ˆ N,N,N',N'-tetramethylethylenediamine. pTsOH ˆ p-toluene-
sulfonic acid, TBS ˆ tert-butyldimethylsilyl, py ˆ pyridine, DMA ˆ N,N-
dimethylacetamide, MOM ˆ methoxymethyl.
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resulting diol was selectively monosilylated (TBSCl/Et3N,
89% yield), and the secondary alcohol was oxidized (SO3 ´ py/
DMSO) to afford ketone 38 in 94% yield. Reaction of ketone
38 with iPrMgCl required prior addition of CeCl3 to the
Grignard reagent to generate the less basic cerium species,
which reacted smoothly with the substrate to afford tertiary
alcohol 39 in 94% yield. Elimination of the tertiary hydroxy
group from 39 was effected regioselectively towards the
aromatic nucleus by the action of SOCl2/py at 608C, leading
to olefin 40, which was subjected to Wacker oxidation (PdCl2,
Cu(OAc)2, H2O, O2) to afford the expected methyl ketone 41
as the major product (80% yield). Hydrogenation (Pd/C) of
the remaining double bond led to compound 42 in 92% yield.
Reaction of ketone 42 with (MeO)2P(O)CH2COOMe/NaH
furnished the E-a,b-unsaturated ester 43 as the major
product, together with its Z isomer (ca. 3:1) in 94% total
yield. The silyl protecting group was then removed from 43
under carefully controlled conditions to afford the corre-
sponding benzyl alcohol 44 (91% yield), which was smoothly
oxidized to the targeted aldehyde 45 by treatment with
SO3 ´ py/DMSO (86% yield).
hydroxy-o-quinodimethane species, which were subsequently
trapped by dienophiles in either inter- or intramolecular
Diels ± Alder fashion. The present technology holds consid-
erable potential in the construction of complex molecules, as
demonstrated by the accommodation of a diverse range of
functional groups and its application to the total synthesis of
the hamigerans described in the following communication.[7]
Received: June 7, 2001 [Z17243]
[1] K. D. Wellington, R. C. Cambie, P. S. Rutledge, P. R. Bergquist, J. Nat.
Prod. 2000, 63, 79 ± 85.
[2] a) G. Quinkert, H. Stark, Angew. Chem. 1983, 95, 651 ± 669; Angew.
Chem. Int. Ed. Engl. 1983, 22, 637 ± 655; b) G. A. Kraus, Y. Wu, J. Org.
Chem. 1992, 57, 2922 ± 2925. These examples, however, involved
ketone substrates as precursors of the hydroxy-o-quinodimethanes.
[3] a) K. Hashimoto, M. Horikawa, H. Shirahama, Tetrahedron Lett. 1990,
31, 7047 ± 7050; b) W. Oppolzer, K. Keller, Angew. Chem. 1972, 84,
712 ± 714; Angew. Chem. Int. Ed. Engl. 1972, 11, 728 ± 730; c) G. A.
Kraus, L. Chen, Synth. Commun. 1993, 14, 2041 ± 2049.
[4] a) K. C. Nicolaou, D. Gray, Angew. Chem. 2001, 113, 783 ± 785;
Angew. Chem. Int. Ed. 2001, 40, 761 ± 763; b) G. A. Kraus, G. Zhao, J.
Org. Chem. 1996, 61, 2770 ± 2773.
The enantioselective synthesis of the second required
aldehyde 48 (Scheme 3B) started with epoxide (S)-33 and
proceeded through hydroxy silyl ether 37 (obtained as
described above, Scheme 3A). Compound 37 was protected
as its MOM ether (MOMCl/iPr2NEt, 83% yield) and then
carried through the same sequence as described for the
preparation of racemic 45 to furnish, in similar yields, benzyl
alcohol 47 (for selected data, see Table 3), which was oxidized
[5] N. C. Yang, C. Rivas, J. Am. Chem. Soc. 1961, 83, 2213.
[6] a) P. G. Sammes, Tetrahedron 1976, 32, 405 ± 422, and references
therein; b) J. L. Charlton, M. M. Alauddin, Tetrahedron 1987, 43,
2873 ± 2889, and references therein; c) A. C. Weedon in The Chemistry
of Enols (Ed.: Z. Rappoport), Wiley, New York, 1990, pp. 615 ± 621,
and references therein; d) F. Nerdel, W. Brodowski, Chem. Ber. 1968,
101, 1398 ± 1406; e) M. Pfau, S. Combrisson, J. E. Rowe, N. D. Heindel,
Tetrahedron 1978, 34, 3459 ± 3468; f) R. Haag, J. Wirz, P. J. Wagner,
Helv. Chim. Acta 1977, 60, 2595 ± 2607; g) T. J. Connolly, T. Durst,
Tetrahedron 1997, 47, 15969 ± 15982.
[7] K. C. Nicolaou, D. Gray, J. Tae, Angew. Chem. 2001, 113, 3791 ± 3795;
Angew. Chem. Int. Ed. 2001, 40, 3679 ± 3683, following communica-
tion.
Table 3. Selected data for compounds 29 and 47.
[8] G. Kanai, N. Miyaura, A. Suzuki, Chem. Lett. 1993, 845 ± 848.
[9] a) J. L. Charlton, Tetrahedron Lett. 1989, 30, 3279 ± 3282; b) J. L.
Charlton, G. Plourde, K. Koh, A. S. Secco, Can. J. Chem. 1989, 67,
574 ± 579.
[10] M. Watanabe, M. Sahara, S. Furukawa, R. Billedeau, V. Snieckus,
Tetrahedron Lett. 1982, 23, 1647 ± 1650.
29: colorless solid; Rf ˆ 0.3 (silica gel, hexane/EtOAc 1:1); IR (film): nÄmax
ˆ
3386, 2935, 1715, 1453, 1174, 1034 cm 1; 1H NMR (CDCl3, 600 MHz): d ˆ
7.48 (d, J ˆ 7.4 Hz, 1H), 7.22 ± 7.12 (m, 3H), 4.98 (t, J ˆ 7.0 Hz, 1H), 4.18 ±
4.08 (m, 2H), 3.92 (m, 1H), 3.63 (d, J ˆ 7.4 Hz, 1H), 3.59 (m, 1H), 2.94 (d,
J ˆ 7.0 Hz, 1H), 2.45 (m, 1H), 2.29 (d, J ˆ 10.5 Hz, 1H), 2.09 (m, 1H), 1.86
(dd, J ˆ 11.6, 8.1 Hz, 1H), 1.68 (m, 1H), 1.58 ± 1.45 (m, 2H), 1.12 (t, J ˆ
7.5 Hz, 3H), 0.55 (s, 3H); 13C NMR (CDCl3, 150 MHz): d ˆ 173.2, 139.0,
137.3, 127.3, 127.3, 126.4, 124.3, 67.9, 67.2, 60.6, 56.5, 52.0, 44.8, 39.8, 38.0,
[11] I. OꢁNeil, E. Cleator, J. M. Southern, N. Hone, D. J. Tapolczay, Synlett
2000, 695 ± 697.
‡
21.1, 16.2, 14.2; HR-MS (MALDI): calcd for C18H24O4 [M‡Na ]: 327.1567;
found: 327.1562
47: colorless solid; Rf ˆ 0.5 (silica gel, hexane/EtOAc 1:1); [a]2D2 ˆ ‡5.27
(c ˆ 0.168, CHCl3); IR (film): nÄmax ˆ 3465, 2944, 1716, 1646, 1610, 1581,
1456, 1221, 1149, 1097, 1034 cm 1; 1H NMR (CDCl3, 400 MHz): d ˆ 6.62 (s,
1H), 6.58 (s, 1H), 5.68 (s, 1H), 4.77 (m, 1H), 4.60 (m, 1H), 4.51 (d, J ˆ
7.0 Hz, 1H), 4.34 (d, J ˆ 7.0 Hz, 1H), 3.82 (s, 3H), 3.78 (m, 1H), 3.67 (s,
3H), 3.06 (s, 3H), 2.94 (m, 2H), 2.74 (m, 1H), 2.30 (s, 3H), 2.24 (m, 1H),
2.14 (s. 3H), 1.74 (m, 2H); 13C NMR (CDCl3, 100 MHz): d ˆ 167.1, 159.7,
158.0, 138.6, 138.4, 125.3, 123.3, 115.3, 109.7, 95.5, 78.1, 55.9, 55.5, 55.4, 50.8,
39.7, 36.4, 32.3, 29.0, 21.5; HR-MS (MALDI): calcd for C20H30O6
‡
[M‡ Na ]: 389.1934; found: 389.1936
with SO3 ´ py/DMSO to deliver the targeted intermediate 48 in
enantiomerically enriched form.
In summary, a highly efficient and direct approach to
benzannulated systems has been developed by employing
suitable aromatic aldehydes as starting materials and light as a
reagent, and proceeding through a cascade reaction sequence
that involved initial photo-enolization to afford reactive
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Angew. Chem. Int. Ed. 2001, 40, No. 19