Dynamic stereochemistry transfer in a transannular aldol reaction: Total synthesis of hypocrellin A

Article abstract of DOI:10.1002/anie.200800734

(Chemical Equation Presented) A dynamic approach: The key step in the total synthesis of hypocrellin A involves a potentially biomimetic 1,8-diketone aldol reaction, which constructs the seven-membered ring. The helical configuration is established first

Full text of DOI:10.1002/anie.200800734

Angewandte
Chemie
DOI: 10.1002/anie.200800734
Natural Product Synthesis
Dynamic Stereochemistry Transfer in a Transannular Aldol Reaction:
Total Synthesis of Hypocrellin A**
Erin M. OꢀBrien, Barbara J. Morgan, and Marisa C. Kozlowski*
Hypocrellin A (1), shiraiachrome A (2), hypocrellin B (3),
and hypocrellin (4) are members of a growing class of natural
products called perylenequinones (Scheme 1). Hypocrellin A,
perylenequinones have attracted considerable attention
because of their potent biological activity, including light-
induced activity against tumor cell lines,[3,4] antiviral activity,[5]
and immunotherapeutic properties,[6] and elegant approaches
to the calphostins have been reported.[7] The more architec-
turally complex perylenequinones are exciting targets for
photodynamic cancer therapy (PDT)[3,4,8] but have not
succumbed to total syntheses. Notably, hypocrellin A (1)
with a seven-membered ring that contains two stereogenic
centers, one of which is quaternary, remains a challenging
synthetic target. Herein, we report the first total synthesis of
hypocrellin A (1) through a dynamic stereochemistry transfer
reaction.
There has been much confusion in the literature regarding
the naming of these structurally distinct members of the
perylenequinone natural products.[9] One contributing factor
lies in the tautomerization available within the perylenequi-
none moiety (1 and 1·taut; Scheme 1). The major tautomer of
each perylenequinone varies depending on the planarity of
the naphthalene core and the strength of the intramolecular
hydrogen bonds.[9,10] For hypocrellin A (1), the two tautomers
are present in almost equal amounts. A second issue centers
on atropisomerization of the helical configuration in the
perylenequinone. Although the structurally related calphos-
tins are atropisomerically stable, the additional seven-mem-
bered ring in hypocrellin A lowers the atropisomerization
barrier. As a result, hypocrellin A exists as an equilibrium
mixture of atropisomers (1 and 1·atrop),[11] with 1 favored
(Scheme 2).
Scheme 1. Hypocrellin A and related perylenequinone natural products.
M and P are the helical configurations, taut=tautomer.
shiraiachrome A, and hypocrellin B are isolates of Shiraia
bambusicola.[1] Interestingly, a different source, Hypocrella
bambusae, gave rise to hypocrellin (4), the enantiomer of
hypocrellin A (1), along with the racemic hypocrellin B.[2] The
[*] E. M. O’Brien, B. J. Morgan, Prof. M. C. Kozlowski
Department ofChemistry, Roy and Diana Vagelos Laboratories
University ofPennsylvania
Philadelphia, PA 19104-6323 (USA)
Fax: (+1)215-573-7165
E-mail: marisa@upenn.edu
Homepage: http://www.sas.upenn.edu/chem/
[**] We are grateful to the NIH CA-109164 for financial support and to
Eli Lilly (E.M.O.), Novartis (B.J.M.), and the American Chemical
Society, Division ofOrganic Chemistry sponsored by Organic
Syntheses (B.J.M.) for graduate fellowships. Special thanks go to
Quest Pharmaceuticals for providing a sample of hypocrellin.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Proposed dynamic stereochemistry transfer (DST) reaction
to give hypocrellin A. atrop=atropisomer.
Angew. Chem. Int. Ed. 2008, 47, 6877 –6880
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6877

Communications
Given the facile atropisomerization of 1, it is unclear
which stereochemistry elements are established first in the
biosynthesis, that is, the helical axis or the stereocenters of the
seven-membered ring. For the synthesis of hypocrellin A, our
research group envisioned a potentially biomimetic, dynamic
stereochemistry transfer (DST) reaction (Scheme 2).[12] Such
DST reactions that satisfy the following requirements are
rare: 1) there is a directing stereocenter that is not involved in
any bond-forming or bond-breaking processes; 2) diastereo-
control occurs from this directing stereocenter in the for-
mation of a new stereocenter; and 3) a loss of the integrity in
the original directing stereocenter occurs subsequent to the
transformation.
To implement this plan, the helical configuration, as found
in enantiomerically pure perylenequinone 5, would be
synthesized first. The helical configuration would be used to
direct the stereochemistry of an intramolecular 1,8-diketone
aldol cyclization that forms the seven-membered ring and
establishes the key centrochiral stereocenters, including the
quaternary center (Scheme 2). From a biosynthetic view-
point, such an ordering explains the genesis of all the
perylenequinone compounds, including the calphostins and
elsinochromes, from a common precursor similar to 5.[13]
Helically chiral perylenenquinone 5 would in turn be
synthesized from axially chiral 6.
Scheme 3. Reagents and conditions: a) ICl, AcOH, 85%; b) SOCl2,
benzene; NaCH(CO2Me)2, THF; c) CH3SO3H, P2O5; d) Ac2O, pyridine,
40% (over 3 steps); e) K2CO3, MeOH, CH2Cl2, 87%; f ) (R,R)-11
(20 mol%), CH3CN, RT, 80%, 81% ee (>99% ee, EtOAc/hexanes
trituration); g) MeI, NaH, DMF, 94%; h) allylB(pin), [Pd(PPh3)4]
(20 mol%), CsF, toluene, 96%. allylB(pin)=allylboronic acid pinacol
ester, DMF=N,N-dimethylformamide.
Previous synthetic approaches toward less complex per-
ylenequinone natural products (calphostins) have employed
oxidative coupling reactions of enantiopure, chiral 2-naph-
thols; unfortunately, low diastereoselection was usually
observed, with the undesired atropdiastereomer predominat-
ing.[7] As such, it seems unlikely that the biosynthetic route to
these compounds relies on a similar diastereoselective
coupling. The fact that certain enzymes exhibit enantioselec-
tivity in the oxidative coupling of 2-naphthol[14] provides
support for an enantioselective oxidative coupling of an
achiral naphthol as a possible biogenesis. In our approach we
employed such an enantioselective oxidative coupling of 9,
which was readily prepared in five steps from commercially
available 7 (Scheme 3). The enantioselective biaryl coupling
with our copper diaza-cis-decalin catalyst (11)[15] further
highlights the utility of this method, and gave 6 with 81% ee
(> 99% ee after one trituration) and good yield. Deacylation
of the C4,C4’-positions and subsequent methylation of the
free hydroxy groups on the naphthalene ring was followed by
a highly efficient Suzuki coupling reaction (96%) to install
the C7,C7’ allyl groups, which afforded 10.
With a viable route to large quantities of enantiopure
biaryl 10, our attention turned to the synthesis of diketone
perylenequinone intermediate 5 (Scheme 2). Hydroxylation
at the C5,C5’-positions was accomplished in 73% yield
followed by benzylation to give dibenzyl ether 12
(Scheme 4). Wacker oxidation of 12 to the diketone 13
proceeded smoothly (75%). Protection of 13 as the bisketal
was required because of the basic nature of the subsequent
steps. An anionic displacement reaction was necessary to
cleave the unreactive C3,C3’ esters; the use of NaCN
provided 14 in quantitative yield. Standard methods to
conduct aromatic decarboxylations require high temperature
(namely, copper/quinoline, 1808C),[16] which would racemize
Scheme 4. Reagents and conditions: a) PhI(OCOCF3)2, (CF3)2CHOH;
then aq NaOH, 73%; b) BnBr, nBu4NI, NaH, DMF, 78%; c) PdCl2,
CuCl, H2O, DMF, 75%; d) HC(OEt)3, HOCH2CH2OH, cat. TsOH, 90%;
e) NaCN, DMSO, H2O, 1108C, 100%; f) Pd(OCOCF3)2, Ag2CO3, 5%
DMSO/DMF, 708C; then NaBH4, 60%; g) H2, Pd/C, MeOH, 100%;
h) MnO2, NaOH, THF, EtOH, 88%. Bn=benzyl, DMSO=dimethyl
sulfoxide, Ts=para-toluenesulfonyl.
6878 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 6877 –6880

Angewandte
Chemie
the enantioenriched biaryl substrate 14. To circumvent this
problem we developed a new palladium-mediated decarbox-
ylation that takes place at 708C and provided 15 without
racemization.[17] After debenzylation of 15, cyclization to
perylenequinone 16 proved unexpectedly difficult with
MnO2,[7c,d] and gave rise to a hydroperylenequinone. How-
ever, addition of NaOH to facilitate deprotonation allowed
smooth conversion into 16.
Surprisingly, ketal hydrolysis of perylenequinone 16 was
accompanied by decomposition. The sensitivity of the per-
ylenequinone to acid was avoided by reducing 16 to the
corresponding perylene (16b) and then treating with [PdCl2-
(CH3CN)2]in acetone. Subsequent exposure to air oxidized
the deprotected intermediate to furnish 5 (Scheme 5). With
This approach requires that the helical configuration be
sufficiently stable during the aldol reaction, even though it
atropisomerizes freely thereafter. To investigate this pro-
posal, silazide bases were chosen to effect deprotonation as
they give predominantly Z enolates.[21]
After considerable optimization of the base, solvent,
additive, and temperature, we discovered that aldol cycliza-
tion of 5 proceeded smoothly using LiN(SiMe2Ph)2 at À1058C
and provided the requisite seven-membered ring (Scheme 5).
The resultant adduct was treated with MgI2,[,7b,e,f] which
selectively removed the C4,C4’ methyl ethers, to yield the
natural form of hypocrellin A (1:1·atrop) as the major product
(syn/anti 10:1; syn diastereomer 92% ee). Spectroscopic data
from our synthetic 1:1·atrop were identical to that of
hypocrellin (4) from natural sour-
ces, with the exception of the
absolute configuration, as deter-
mined by direct comparison. The
minor diastereomer 2 was sepa-
rated by chromatography, and
1H NMR spectroscopic analysis
showed that it corresponds to shir-
aiachrome A, a natural product
also isolated from Shiraia bambu-
sicola.[1] Interestingly, in the case of
shiraiachrome A, the atropiso-
meric equilibrium after the aldol
reaction favors the opposite M hel-
ical configuration even though it
originally arose from the same
P helical configuration of
5 as
hypocrellin A.
In summary, we have com-
pleted the first total synthesis of
hypocrellin A in 19 steps (1.6%
overall yield; average 82% per
step). Key methods that were
Scheme 5. Reagents and conditions: a) Na2S2O4, benzene; then [PdCl2(CH3CN)2] (20 mol%),
(CH3)2CO, 89%; b) LiN(SiMe2Ph)2, THF, À1058C, 74% (d.r. 10:1); c) MgI2, Et2O, 57%.
key intermediate 5 in hand, the crucial intramolecular
diketone aldol cyclization was investigated. To the best of
our knowledge, the type of 1,8-diketone aldol reaction that we
proposed to use had not been employed previously outside of
bridged or macrocyclic architectures.[18,19]
developed to enable this synthetic venture include: 1) a
catalytic enantioselective coupling of highly functionalized
naphthols;[15] 2) a low temperature aromatic decarboxylation
protocol;[17] and 3) a 1,8-diketone aldol reaction to establish
the seven-membered ring. In the aldol reaction, the two newly
Nonetheless, we hypothesized that such an aldol reaction
must be involved in the biosynthesis of the hypocrellins.
Encouragingly, the desired product of this aldol reaction
corresponds to structure 1, which is the most stable of the
rapidly equilibrating atropisomeric (1·atrop; Scheme 2) and
tautomeric (1·taut; Scheme 1) forms.[11] Furthermore, molec-
ular modeling studies indicated that a Z enolate geometry of 5
would give rise to the syn aldol product, which corresponds to
hypocrellin A (1), whereas the E enolate would produce the
anti product, which corresponds to shiraiachrome A (2) via
closed chairlike transition states. Analysis of the relevant
transition states also revealed that the helical configuration of
5 would expose one diastereoface of the ketone, thus resulting
in the required S tertiary alcohol configuration of both 1 and
2. Simple MM2*[20] calculations reveal that of the two possible
Z enolate transition states, transition state A, which corre-
sponds to the configuration of 1, is lower in energy (Figure 1).
Figure 1. MM2* calculated Z enolate transition states. M=Li.
Angew. Chem. Int. Ed. 2008, 47, 6877 –6880
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6879

Communications
an, Jr., Drugs Aging 1999, 15, 49 – 68; f) A. M. Rouhi, Chem.
Eng. News 1998, 76(44), 22 – 26.
formed centrochiral stereocenters of the seven-membered
ring were dictated by the stable perylenequinone helical
configuration and the enolate geometry. After the aldol
reaction, however, the helical configuration was labile as
observed for the natural product (4:1 mixture of atropisom-
ers). As such, we have shown that a dynamic stereochemical
transfer is a viable approach here. The efficiency of this
strategy will enable the synthesis of related structures and
exploration of their biological chemistry and PDT properties.
[9]Here, we employ the names and structural assignments sug-
gested by: S. Mazzini, L. Merlini, R. Mondelli, L. Scagloni, J.
Chem. Soc. Perkin Trans. 2 2001, 409 – 416. Note: SciFinder
indexes hypocrellin and hypocrellin A as identical compounds
with the absolute configuration of hypocrellin.
[10]A. Arnone, L. Merlini, R. Mondelli, G. Nasini, E. Ragg, L.
Scaglioni, U. Weiss, J. Chem. Soc. Perkin Trans. 2 1993, 1447 –
1454.
[11]A. Smirnov, D. B. Fulton, A. Andreotti, J. W. Petrich, J. Am.
Chem. Soc. 1999, 121, 7979 – 7988.
Received: February 13, 2008
Published online: May 27, 2008
[12]For related examples involving axial to central chirality transfer,
see: a) K. Ohmori, M. Kitamura, K. Suzuki, Angew. Chem. 1999,
111, 1304 – 1307; Angew. Chem. Int. Ed. 1999, 38, 1226 – 1229;
b) M. Kitamura, K. Ohmori, T. Kawase, K. Suzuki, Angew.
Chem. 1999, 111, 1308; Angew. Chem. Int. Ed. 1999, 38, 1229 –
1232; c) K. Ohmori, M. Tamiya, M. Kitamura, H. Kato, M.
Oorui, K. Suzuki, Angew. Chem. 2005, 117, 3939 – 3942; Angew.
Chem. Int. Ed. 2005, 44, 3871 – -3874; d) A. Joncour, A. Dꢀcor, S.
Thoret, A. Chiaroni, O. Baudoin, Angew. Chem. 2006, 118, 4255;
Angew. Chem. Int. Ed. 2006, 45, 4149 – 4152; e) G. Stavrakov, M.
Keller, B. Breit, Eur. J. Org. Chem. 2007, 5726 – 5733; f) A. J. B.
Lapierre, S. J. Geib, D. P. Curran, J. Am. Chem. Soc. 2007, 129,
494 – 495; for a general review of chirality transfer within biaryl
systems, see: g) G. Bringmann, A. J. Price Mortimer, P. A.
Keller, M. J. Gresser, J. Garner, M. Breuning, Angew. Chem.
2005, 117, 5518 – 5563; Angew. Chem. Int. Ed. 2005, 44, 5384 –
5427.
[13]For reviews of the perylenequinone natural products, see: a) G.
Bringmann, C. Gꢁnther, M. Ochse, O. Schupp, S. Tasler, Prog.
Chem. Org. Nat. Prod. 2001, 82, 1 – 249; b) U. Weiss, L. Merlini,
G. Nasini, Prog. Chem. Org. Nat. Prod. 1987, 52, 1 – 71.
[14]a) M. Sridhar, S. K. Vadivel, U. T. Bhalerao, Tetrahedron Lett.
1997, 38, 5695 – 5696; b) M. Takemoto, Y. Suzuki, K. Tanaka,
Tetrahedron Lett. 2002, 43, 8499 – 8501.
[15]a) X. Li, J. Yang, M. C. Kozlowski, Org. Lett. 2001, 3, 1137 –
1140; b) X. Li, J. B. Hewgley, C. A. Mulrooney, J. Yang, M. C.
Kozlowski, J. Org. Chem. 2003, 68, 5500 – 5511; c) C. A. Mul-
rooney, X. Li, E. S. Divirgilio, M. C. Kozlowski, J. Am. Chem.
Soc. 2003, 125, 6856 – 6857; d) E. S. DiVirgilio, E. C. Dugan,
C. A. Mulrooney, M. C. Kozlowski, Org. Lett. 2007, 9, 385 – 388;
e) M. C. Kozlowski, E. C. Dugan, E. S. DiVirgilio, K. Maksi-
menka, G. Bringmann, Adv. Synth. Catal. 2007, 349, 583 – 594.
[16]Examples of copper-catalyzed decarboxylation of aryl acids:
a) M. Nakajima, I. Miyoshi, K. Kanayama, S.-I. Hashimoto, M.
Noji, K. Koga, J. Org. Chem. 1999, 64, 2264 – 2271; b) T. Cohen,
R. A. Schambach, J. Am. Chem. Soc. 1970, 92, 3189 – 3190.
[17]J. Dickstein, C. A. Mulrooney, E. M. OꢂBrien, B. J. Morgan,
M. C. Kozlowski, Org. Lett. 2007, 9, 2441 – 2444.
Keywords: biaryls·cyclization·dynamicstereochemicaltransfer·
.
natural products · total synthesis
[1]a) T. Kishi, S. Tahara, M. Tsuda, C. Tanaka, S. Takahashi, Planta
Med. 1991, 57, 376 – 379; b) H. Wu, X. F. Lao, Q. W. Wang, R. R.
Lu, J. Nat. Prod. 1989, 52, 948 – 951 (hypocrellin A is called
shiraiachrome B here, see Ref. [9]).
[2]W. S. Chen, Y. T. Chen, X. Y. Wang, E. Friedrichs, H. Puff, E.
Breitmaier, Liebigs Ann. Chem. 1981, 1880 – 1885.
[3]For reviews, see: a) J. W. Lown, Can. J. Chem. 1997, 75, 99 – 119;
b) Z. Diwu, Photochem. Photobiol. 1995, 61, 529 – 539.
[4]a) M. Olivo, M. Ali-Seyed, Int. J. Oncol. 2007, 30, 537 – 548;
b) J. B. Maxhimer, R. M. Reddy, J. Zuo, G. W. Cole, Jr., D. S.
Schrump, D. M. Nguyen, J. Thoracic and Cardiovascular Surg.
2005, 129, 53 – 63; c) Z. Xiao, C. B. Hansen, T. M. Allen, G. G.
Miller, R. B. Moore, J. Pharm. Pharm. Sci. 2005, 8, 536 – 543;
d) B. Guo, S. L. Hembruff, D. J. Villeneuve, A. F. Kirwan, A. M.
Parissenti, Breast Cancer Res. Treat. 2003, 82, 125 – 141; e) L. Ma,
H. Tai, C. Li, Y. Zhang, Z.-H. Wang, W.-Z. Ji, World J.
Gastroenterol. 2003, 9, 485 – 490; f) S. M. Ali, M. Olivo, Int. J.
Oncol. 2002, 21, 1229 – 1237; g) S. M. Ali, M. Olivo, G. Y. Yuen,
S. K. Chee, Int. J. Oncol. 2001, 19, 633 – 643; h) A. L. Vanden-
bogaerde, W. S. Delaey, A. M. Vantieghem, B. E. Himpens, W. S.
Merlevede, P. A. De Witte, Photochem. Photobiol. 1998, 67,
119 – 125; i) J. Zhang, E.-H. Cao, J.-F. Li, T.-C. Zhang, W.-J. Ma,
J. Photochem. Photobiol. B 1998, 43, 106 – 111.
[5]a) J. Hirayama, K. Ikebuchi, H. Abe, K.-W. Kwon, Y. Ohnishi,
M. Horiuchi, M. Shinagawa, K. Ikuta, N. Kamo, S. Sekiguchi,
Photochem. Photobiol. 1997, 66, 697 – 700; b) J. B. Hudson, V.
Imperial, R. P. Haugland, Z. Diwu, Photochem. Photobiol. 1997,
65, 352 – 354.
[6]B. Leveugle (Altachem Pharma Ltd., Edmonton, CA),
EP1357944, 2002.
[7]a) C. A. Broka, Tetrahedron Lett. 1991, 32, 859 – 862; b) F. M.
Hauser, D. Sengupta, S. A. Corlett, J. Org. Chem. 1994, 59,
1967 – 1969; c) R. S. Coleman, E. B. Grant, J. Am. Chem. Soc.
1994, 116, 8795 – 8796; d) R. S. Coleman, E. B. Grant, J. Am.
Chem. Soc. 1995, 117, 10889 – 10904; e) C. A. Merlic, C. C.
Aldrich, J. Albaneze-Walker, A. Saghatelian, J. Am. Chem. Soc.
2000, 122, 3224 – 3225; f) C. A. Merlic, C. C. Aldrich, J. Alba-
neze-Walker, A. Saghatelian, J. Mammen, J. Org. Chem. 2001,
66, 1297 – 1309.
[18]For selected examples, see: a) Y. Miyahara, J. Org. Chem. 2006,
71, 6516 – 6521; b) S. Davies, R. L. Sheppard, A. D. Smith, J. E.
Thomson, Chem. Commun. 2005, 3802 – 3804; c) E. Piers, K. A.
Skupinska, D. J. Wallace, Synlett 1999, 1867 – 1870.
[19]There is one report of an acyclic intramolecular aldol to yield the
seven-membered ring through a reductive aldol reaction of the
enone aldehyde: T. G. Baik, A. L. Luis, L. C. Wang, M. J.
Krische, J. Am. Chem. Soc. 2001, 123, 5112 – 5113.
[20]W. C. Still, MacroModel, V4.0, V5.0, V6.0, V6.5; Columbia
University.
[21]M. Gaudemar, M. Bellassoued, Tetrahedron Lett. 1989, 30,
2779 – 2782.
[8]a) N. Lane, Sci. Am. 2003, 288, 38 – 45; b) D. E. J. G. J. Dolmans,
D. Fukumura, R. K. Jain, Nat. Rev. Cancer 2003, 3, 380 – 387;
c) C. Hopper, Lancet Oncol. 2000, 1, 212 – 219; d) D. E. Brund-
ish, W. G. Love, IDrugs 2000, 3, 1487 – 1508; e) J. S. McCaugh-
6880 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 6877 –6880