Total synthesis of zaragozic acid C: Implementation of photochemical C(sp3)-H acylation

Article abstract of DOI:10.1021/jacs.6b13263

Zaragozic acid C (1) was isolated as a potent squalene synthase inhibitor. The 2,8-dioxabicyclo[3.2.1]octane core of 1 is decorated with the three hydroxycarbonyl (C³,4,5), two hydroxy (C4,7), one acyloxy (C6), and one alkyl (C1) groups. Instal

Full text of DOI:10.1021/jacs.6b13263

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Communication
Total Synthesis of Zaragozic Acid C: Implementation
of Photochemi-cal C(sp3)–H Acylation
Takahiro Kawamata, Masanori Nagatomo, and Masayuki Inoue
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 16 Jan 2017
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Total Synthesis of Zaragozic Acid C: Implementation of Photochemi-
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Takahiro Kawamata, Masanori Nagatomo, Masayuki Inoue*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Supporting Information Placeholder
tetrasubstituted C=C bond,7c,g,j,8a the addition of a carbon nucleo-
ABSTRACT: Zaragozic acid C (1) was isolated as a potent squa-
lene synthase inhibitor. The 2,8-dioxabicyclo[3.2.1]octane core of
1 is decorated with the three hydroxycarbonyl (C3,4,5), two hy-
phile to the C=O bond,7a,b,d,e,f,h alkylation of a trisubstituted -
alkoxy anion,7b,d,f,i or pericyclic reaction.7e,8b Here we disclose the
design and execution of a novel strategy for the total synthesis of 1.
Specifically, photochemical C(sp3)–H functionalization was de-
vised as the key transformation for securing the cumbersome C4,5-
stereochemical relationship.
droxy (C4,7), one acyloxy (C6), and one alkyl (C1) groups. Instal-
lation of the contiguous C4- and C5-fully-substituted carbons pre-
sents a formidable synthetic challenge. Our approach to addressing
this problem utilized a two-step photochemical C(sp3)-H acylation.
Persilylated D-gluconolactone 4 was derivatized into 3 with the 1,2-
diketone moiety at the C5-tetrasubstituted center. Norrish-Yang
cyclization of 3 under violet LED irradiation followed by oxidative
opening of the resultant -hydroxy-cyclobutanone regio- and ste-
reoselectively transformed the electron-rich tertiary C(sp3)-H bond
at C4 to the C(sp3)-C bond to produce a densely functionalized 2.
A subsequent series of judicious functional group transformations
from 2 gave rise to the targeted 1. The present total synthesis pro-
vides a guide for designing site-selective C(sp3)-H functionaliza-
tion of architecturally complex molecules with multiple oxygen
functionalities.
Scheme 1. Synthetic Plan of Zaragozic Acid C, and Site- and
Stereoselective C(sp3)-H Acylationa
Zaragozic acid C (1, Scheme 1A) is a representative example of a
family of natural products, zaragozic acids1 and squalestatins.2
These compounds constitute a class of potent inhibitors of mam-
malian squalene synthase (Ki = 29–78 pM).3 Squalene synthase
plays a key role in catalyzing the conversion of presqualene pyro-
phosphate into squalene at the last branching point of cholesterol
biosynthesis, and thus zaragozic acids/squalestatins are considered
to be promising lead structures for the development of cholesterol-
lowering drugs. Recent findings of other diverse pharmacologi-
cally important activities has spurred renewed interest in these mol-
ecules. Several members act as nanomolar inhibiters of ras farnesyl
protein transferase, which is a useful property for antitumor
agents.4 Moreover, these compounds protect neurons against the
toxic effects of prions and amyloid- peptides,5 and inhibit dengue
virus replication and hepatitis C virus production.6
Zaragozic acid C (1) is characterized by a hydrophilic 2,8-dioxa-
bicyclo[3.2.1]octane-4,6,7-trihydroxy-3,4,5-tricarboxylic
acid
core with an array of six stereogenic centers, and hydrophobic C6-
acyloxy and C1-alkyl side-chains. The two adjacent fully-substi-
tuted carbons at C4 and C5 within the densely oxygenated core rep-
resent further challenge for its chemical synthesis. Inspired by the
complex architecture and potential benefits for human medicine,
various creative strategies and tactics have been tested, ultimately
resulting in 10 total7 and 3 formal syntheses8 of 1 and congeners.9
These syntheses constructed the unusually hindered oxygen-based
tetrasubstituted C4- and C5-centers by osmylation of a tri- or
The direct transformation of C(sp3)-H bonds to C(sp3)-C bonds
enables new strategic disconnections during the planning of a syn-
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thetic route.10 Our retrosynthesis of 1 was based on photochemi-
only 26% yield with 36% of remaining 3. Use of a UV (365 nm)
cally induced C(sp3)–H acylation, which we previously reported
(Scheme 1A).11 Photo-induced Norrish-Yang cyclization of 1,2-
diketone 3,12,13 followed by oxidative ring-opening, would substi-
tute the tertiary C4–H with the -hydroxyacyl group of 2. As 2
possesses the C4,5,6,7-stereocenters of 1, C3-reduction, C8,9-oxi-
dation, C1-acetal reorganization, and C6–OH acylation would
transform 2 to the target 1. Retrosynthetically, the key precursor 3
would be traced back to commercially available persilylated D-glu-
conolactone 4, which shares the C6,7-stereochemistry with 3. In
this approach, 1 was to be assembled from four structurally simple
components; carboxylic acid A, C1-lipid tail B,14 C5-side-chain C,
and pyranose 4.
LED as an alternative higher energy light resulted in a complex
mixture of products, and the UV light was assumed to cause the
degradation of the non-conjugated ketone of product 13 (max=333
nm, Figure S2).19 UV-vis analyses of the substrates revealed that
the max values of D (407 nm), G (413 nm), and 3 (405 nm) were
comparable, whereas the UV-vis spectral bandwidth of 3 was sig-
nificantly narrower than that of D and G, presumably due to the
fixed conformation of the 1,2-diketone moiety of the more substi-
tuted 3. Accordingly, the inefficient Norrish-Yang cyclization of 3
can be attributed to its lower absorptivity at the blue light region
(460 nm). Based on these data and considerations, we decided to
use a violet (405 nm) LED that matches max of 3 to attain this cru-
cial transformation. After optimization of the flow rate (50
L/min), the cis-fused bicycle 13 was produced as the sole isomer
in 85% yield based on the 1H NMR analysis. Because of its chem-
ical instability, 13 was treated with Pb(OAc)4 in MeOH without
purification, giving rise to ketoester 2 in 62% yield over two steps.
Hence, the tertiary C4–H of 3 was effectively converted to the -
hydroxyacyl group of 2 by linking the hindered bond within the
highly complex environment.
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The presumed Norrish-Yang cyclization of 3 involves -hydrogen
abstraction by a photogenerated C3-oxyl radical, and thus the reac-
tion at C6–H could compete with that at C4–H. We envisioned
controlling the regioselectivity between C4–H and C6–H by low-
ering the electron-donating hyperconjugative effect of the C6-oxy-
gen atom with its protective group.10a To explore this possibility, a
proof-of-concept study was performed prior to the total synthesis
(Scheme 1B). Differentially protected diketones D and G14 were
prepared and separately irradiated with a blue light (460 nm)-emit-
ting diode (LED) in benzene. As a result, cyclobutanone formation
occurred to furnish E and H, which were in turn subjected to oxi-
dative cleavage, leading to F and I, respectively. While the same
cis-stereoselectivity for E and H would originate from the lower
strain energy of the 6/4-cis-fused system compared to that of the
trans-counterpart, the protective groups would influence the site-
selectivity. The electrophilic oxyl radical reacted with the electron-
rich ethereal methine C(sp3)–H bond of D, and the electron-with-
drawing Bz group of G switched the site-selectivity, resulting in
functionalization at the methylene (reactivity order: CHOTBS >
CH2 > CHOBz). According to these model studies, the key precur-
sor 3 was designed to have the reactive ethereal C4-H bond, and
the less reactive BzO-substituted C6-H bond.
Regio- and stereoselective conversion from 3 to 13 under mild and
neutral conditions exemplified the power and reliability of the Nor-
rish-Yang cyclization. In this reaction, the input of 405 nm light
allows for selective excitation of the 1,2-diketone structure of 3.
The thus generated 1,2-biradical K abstracts the proximal ethereal
C4–H bond selectively over not only the BzO-substituted C6–H
bond, but also the potentially reactive ethereal C9–H bond.20 The
resultant 1,4-biradical L undergoes facile C–C bond formation by
avoiding the steric repulsion between the C8- and C9-bulky sub-
stituents to afford 13 with complete control of the C3,4-stereocen-
ters. The stereochemistry of C3-OH of 13 was confirmed by the
NOE experiment.
Contiguous tetrasubstituted carbon centers at C4 and C5 of 2 were
successfully established on the pyranose format. Next, stereoselec-
tive reduction of the C3-ketone and oxidation at the C8 and C9 po-
sitions from 2 generated 17, which has the entire stereochemistry
and carboskeleton of 1. To introduce the C3-stereocenter, various
reductants and additives were screened. Consequently, the reagent
combination of LiAlH4 and LiI21 realized chemo- and stereoselec-
tive reduction of the C3-ketone of 2.22 The stereoselectivity of the
C3-reduction would come from the -face reaction of LiAlH4 to the
lithium-chelated cis-decalin-like structure M. Under the same re-
action conditions, regioselective removal of the Bz group at the pri-
mary C8–OH and attack of the C3-oxygen atom on the C10-car-
bonyl group proceeded to furnish cis-fused lactone 14 with the two
intact Bz groups. Simultaneous detachment of the Bn and TMS
groups from 14 was then realized by conducting hydrogenolysis
(H2, Pd/C) in the presence of HCl, resulting in the formation of triol
15. The two primary hydroxy groups at C8 and C9 of 15 were ox-
idized together by applying AZADOL, NaClO2 and NaOCl to pro-
duce dicarboxylic acid 16,23 and ensuing treatment with TMSCHN2
gave bis-methylester 17.
Synthesis of 3 from gluconolactone derivative 4 required intro-
duction of the C1-alkyl and C5-alkynyl chains, placement of the
appropriate protective groups, and oxidation of the alkyne to the
1,2-diketone (Scheme 2). First, the alkyl lithium that was prepared
from iodide B and t-BuLi attached on the C1-lactone of 4. The
adduct was subsequently treated with MeSO3H in MeOH to form
the C1-methyl acetal and to remove all the TMS groups, leading to
tetraol 5. Cyclic acetal formation between the C5– and C9–OHs of
5, and benzoylation of the C6– and C7–OHs of 6 provided the dif-
ferentially protected 7. NaBH3CN15 and HCl then regioselectively
converted the benzylidene acetal of 7 to the C7-benzyl ether of 8.
The liberated C5-hydroxy group of 8 was in turn oxidized with cat-
alytic AZADOL16 in the presence of NaOCl to afford the C5-ke-
tone of 9. The lithium acetylide, generated via deprotonation of
three-carbon unit C, was selectively added from the -face to in-
stall the correct C5-tetrasubstituted stereocenter of 10, as lithium-
chelated intermediate J would block the -face approach of the nu-
cleophile. The desilylated primary C8–OH of 10 and the tertiary
C5–OH of 11 were capped with the Bz and TMS groups, respec-
tively, resulting in the formation of 12. Preparation of 1,2-diketone
3 was completed by oxidation of internal alkyne 12 by the action
of a catalytic amount of RuO2 and stoichiometric NaIO4.17
We next investigated the pivotal photochemical C(sp3)-H func-
tionalization using the highly oxygenated substrate 3. In doing so,
a microflow reactor was selected over a batch reactor, because light
penetration can be achieved more effectively in a fixed microreac-
tion space, and the continuous microflow conditions are easily ap-
plied to a large scale reaction.18 Similar to the conversion of D and
G in Scheme 1B, blue LED light was employed to 3. Although the
Norrish-Yang cyclization occurred regio- and stereoselectively at
C4, the desired C4,5-cis-fused cyclobutanone 13 was obtained in
The 5/6-cis-fused ring system of 17 was then altered to the 2,8-
dioxabicyclo[3.2.1]octane core of 20 via transacetalization. Before
doing so, the TBDPS group at the C4’-hydroxy group of 17 was
exchanged with the more robust benzyl group of 19.24 Treatment
of 17 with HF·pyridine led to desilylated 18, the resultant C4’–OH
of which was benzylated with benzyl trichloroacetimidate and
TMSOTf,25 affording 19 with concomitant acidic C1-epimerization.
The following ring-reorganization necessitated detachment of C4–
OH and MeOH from the C1-position of 19, methanolysis of C8-
lactone, and attachment of C3–OH and C5–OH to the C1-position.
This complicated cascade reaction was realized in a single step by
use of MeSO3H. When 19 was subjected to 0.2 M MeSO3H/MeOH
at 100 °C for 24 h, the core structure 20 was obtained with the loss
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Scheme 2. Total Synthesis of Zaragozic Acid Ca
4
5
6
7
8
9
Li
O
R2O
OBn
f.
BnO
Y
TMSO
b. PhCH(OMe)2
(+)-CSA
R1
O
X
O
R1
O
C
5
9
9
d. NaBH3CN
n-BuLi
O
O
4
5
1
7
4
5
1
7
BzO
R1
OMe
OMe
OR2
OMe
OBz
5
6
6
R2O
OR2
Ph
O
BzO
OR2
OR2
OBz
e.
4: R2 = TMS, X = O
a. B (I-R1), t-BuLi;
MeSO3H/MeOH
6: R2 = H
8: Y = H, OH
9: Y = O
OTMS
J
c. BzCl
5: R2 = H, X = R1, OMe
7: R2 = Bz
HO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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N
; i-PrOH/H2O
AZADOL, NaOCl
R1
i. RuO2·H2O
BnO
OBn
TMS
9
O
R1
Bn
O
j. violet LED
(405 nm)
OTMS
BzO
H
O
BzO
O
O
O
OBn
4
NaIO4
6
6
BzO
R1
BzO
R1
OMe
OBz
OMe
OBz
5
7
10
4
4
9 O
10
6
O
O
3
H
H
microflow
50 L/min
O
R4
O
OBz
O 3
8
MeO
8
MeO
H
OBz
3
OBz O
TMS
H
H
chemoselective
O
OBz
OR3
OBz
C(sp3)–H functionalization
10: R3 = H, R4 = H
11: R3 = Bz, R4 = H
12: R3 = Bz, R4 = TMS
L
K
3 ( max = 405 nm)
g. BzCl
h. TMSOTf
NOE
HO
H
OBn
OBn
8
OR5
O
Bz
H
O
O
OBn
O
HO
9
9
k. Pb(OAc)4
MeOH
Li
O
R1
O
R1
OMe
OBz
R1
3O
E
BzO
MeO
Al
H
8
l. LiAlH4, LiI
H
BzO
3
4
5
3
4
5
H
OTMS
R1
O
OMe
OBz
OMe
OBz
5
O
6
6
10
MeO
62% (2 steps)
O
O
OBz
O
R4
O
OBz
O
BzO
OBz
H
OBz
E = CO2Me
H
TMS
TMS
14: R4 = TMS, R5 = Bn
15: R4 = H, R5 = H
2
M
13 ( max = 333 nm)
m. H2, Pd/C, aq. HCl
n. AZADOL, NaClO2, NaOCl
8
R6O2C
R2O
OH
7
CO2Me
9CO2R6
MeO2C
r. MeSO3H
MeOH
6
OR7
4'
4'
O
Ph
O
Ph
p. HF·pyridine
8
3
8
5
1
4
5
1
7
1
R6O2C
O
OMe
OBz
O
O
OMe
OBz
OR7
OTBDPS
5
O
4'
4
6
Ph
R6O2C
O
3
CO2R6
HO
HO
O
HO
OBz
OBz
20: R2 = Bz, R6 = Me, R7 = Bn
21: R2 = H, R6 = H, R7 = Bn
22: R2 = H, R6 = t-Bu, R7 = Bn
23: R2 = H, R6 = t-Bu, R7 = H
18: R7 = H (C1- / -OMe)
q. BnOC(=NH)CCl3
TMSOTf
16: R6 = H
s. NaOH
t. t-BuOC(=Ni-Pr)NHi-Pr
u. H2, Pd/C
o. TMSCHN2
19: R7 = Bn (C1- -OMe)
17: R6 = Me
O
Ph
O
OR8
R2O
OR8
7
6
OAc
Ph
OAc
v. Ac2O
y. A, DCC, DMAP
R6O2C
R6O2C
t-BuO2C
t-BuO2C
O
O
4'
Ph
O
O
CO2R6
CO2t-Bu
HO
HO
24: R2 = Ac, R8 = Ac
25: R2 = H, R8 = H
26: R2 = H, R8 = Boc
27: R6 = t-Bu, R8 = Boc
zaragozic acid C (1): R6 = H, R8 = H
w. K2CO3, MeOH
x. Boc2O
z. CF3CO2H
aReagents and conditions: a) B, t-BuLi, hexane/Et2O, –78 oC; MeSO3H, MeOH, –78 to 0 oC; b) PhCH(OMe)2, (+)-10-camphorsulfonic acid (CSA),
MeCN, 0 oC, 64% (2 steps); c) benzoyl chloride (BzCl), 4-dimethylaminopyridine (DMAP, 5 mol%), pyridine, rt, 93%; d) NaBH3CN, 4 M HCl in
dioxane, 4 Å MS, THF, 0 oC, 84%; e) 2-hydroxy-2-azaadamantane (AZADOL) (5 mol%), KBr (10 mol%), 1.2 M aqueous NaOCl, saturated aqueous
o
NaHCO3/CH2Cl2, rt; f) C, n-BuLi, hexane/Et2O, –78 to 0 C; i-PrOH/H2O, rt; g) BzCl, pyridine, rt, 76% (3 steps); h) trimethylsilyl trifluoro-
methanesulfonate (TMSOTf), pyridine, CH2Cl2, rt, 86%; i) RuO2·H2O (30 mol%), NaIO4, MeCN/CCl4/H2O, rt, 72%; j) violet (405 nm) LED, benzene,
25 °C, 50 L/min, 85% (NMR yield); k) Pb(OAc)4, MeOH/benzene, rt, 62% (2 steps); l) LiAlH4, LiI, Et2O, –78 °C, 65%; m) H2, Pd/C, 1 M aqueous
HCl, MeOH, rt; n) AZADOL (20 mol%), NaClO2, NaOCl, MeCN/pH 7 buffer, rt; o) trimethylsilyldiazomethane (TMSCHN2), MeOH/benzene, rt,
75% (3 steps); p) HF·pyridine, MeCN, rt, 95%; q) BnC(=NH)CCl3, TMSOTf, CH2Cl2, 0 °C, 85%; r) 0.2 M MeSO3H in MeOH, 100 °C, 40%; s) 1
M aqueous NaOH/1,4-dioxane, 80 °C; t) t-BuOC(=Ni-Pr)NHi-Pr, CH2Cl2, rt, 39% (2 steps); u) H2, Pd/C, MeOH, rt, 84%; v) Ac2O, DMAP, CH2Cl2,
0 °C, 87%; w) 0.2% K2CO3 in MeOH, 0 °C, 88%; x) di-tert-butyl dicarbonate (Boc2O), 4-pyrrolidinopyridine, Et3N, CH2Cl2, 0 °C, 100%; y) A,
N,N’-dicyclohexylcarbodiimide (DCC), DMAP, CH2Cl2, rt, 70%; z) CF3CO2H, CH2Cl2, rt, 100%.
of the C7O-Bz group in 40% yield. Noteworthy is that Lewis acids,
weaker or stronger Brønsted acids (e.g., CF3CO2H, TsOH, H2SO4,
HCl, La(OTf)3, Sc(OTf)3, Table S2) were ineffective for the trans-
formation or detrimental to the product.
lation of C4'–OH of 23 to produce 25 was realized by peracetyla-
tion of the three hydroxy groups, and methanolysis of the two ace-
tyl groups at the C6- and C7-oxygen atoms of 24. Lastly, selective
Boc protection of the C7–OH of diol 25 with Boc2O and 4-pyrrol-
idinopyridine (25→26), condensation between C7–OH and car-
boxylic acid A using DCC and DMAP (26→27), and removal of
the three t-Bu and one Boc groups with CF3CO2H (27→1) deliv-
ered the target molecule, zaragozic acid C (1). All the spectral and
physical data of 1, including 1H NMR, 13C NMR, []D and HRMS
data, matched in all respects with those of naturally occurring 1.1
In the final 8 steps from 20, the surrounding functional groups
were adjusted to yield zaragozic acid C (1). Basic hydrolysis of the
one Bz group and the three methyl esters of 20 gave 21, the tricar-
boxylic acids of which were converted to the tris-t-Bu-esters of 22
with N,N'-diisopropyl-O-tert-butylisourea.26 Then, a reaction se-
quence established by Hashimoto7d and Carreira7a was applied to
22 to finish the total synthesis of 1. Hydrogenolysis of the benzyl
group of the side-chain of 22 gave triol 23. Regioselective acety-
In summary, we accomplished the total synthesis of bioactive za-
ragozic acid C (1) in 26 steps from persilylated D-gluconolactone
4. Application of the two nucleophiles generated from B and C
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K.; Shirasago, Y.; Suzuki, T.; Aizaki, H.: Hanada, K.; Wakita, T.; Nishijima,
M.; Fukasawa, M. J. Virol. 2015, 89, 2220.
furnished 3, which possess the same carbon numbers and C5,6,7-
stereochemistry as the core of 1. Then, selective photoactivation
of the 1,2-diketone moiety of 3, followed by the oxidative C–C
bond cleavage reaction regio- and stereoselectively transferred the
-hydroxyacyl group at the C4-position of 2, thereby constructing
the contiguous fully-substituted C4,5-carbons. Subsequent stere-
oselective reduction of the C3-ketone, transacetalization into the
characteristic 2,8-dioxabicyclo[3.2.1]octane core, and attachments
of the C4’O-acetyl group and the C6O-acyl chain converted 2 to 1.
Among the variety of selective reactions, a special feature of the
present synthesis is the Norrish-Yang cyclization from 3 to 13. The
strategically placed electron-withdrawing Bz group decreased the
reactivity of the proximal C6–H, permitting selective functionali-
zation of the electron-rich ethereal C4–H bond. Moreover, violet
LED irradiation under the microflow system improved the effi-
ciency and scalability of the transformation without any additional
reagents. Hence, the present photochemical C(sp3)–H functionali-
zation allowed access to the unique molecular structure that are dif-
ficult to be obtained by conventional polar reactions, and thus sim-
plified the synthetic scheme to 1. The substrate design principle
employed here for site- and stereoselective C(sp3)-H functionaliza-
tion would have broad applications in the total synthesis of other
structurally complex natural products and pharmaceuticals with
multiple oxygen functionalities.
7. Zaragozic acid C (1): (a) Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc.
1995, 117, 8106. (b) Evans, D. A.; Barrow, J. C.; Leighton, J. L.; Ro-
bichaud, A. J.; Sefkow, M. J. Am. Chem. Soc. 1994, 116, 12111. (c) Arm-
strong, A.; Barsanti, P. A.; Jones, L. H.; Ahmed, G. J. Org. Chem. 2000,
65, 7020. (d) Nakamura, S.; Sato, H.; Hirata, Y.; Watanabe, N.; Hash-
imoto, S. Tetrahedron 2005, 61, 11078. (e) Hirata, Y.; Nakamura, S.;
Watanabe, N.; Kataoka, O.; Kurosaki, T.; Anada, M.; Kitagaki, S.; Shiro,
M.; Hashimoto, S. Chem. Eur. J. 2006, 12, 8898. (f) Nicewicz, D. A.; Sat-
terfield, A. D.; Schmitt, D. C.; Johnson, J. S. J. Am. Chem. Soc. 2008, 130,
17281. Zaragozic acid A: (g) Nicolaou, K. C.; Yue, E. W.; La Greca, S.;
Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis,
F. Chem. Eur. J. 1995, 1, 467. (h) Caron, S.; Stoermer, D.; Mapp, A. K.;
Heathcock, C. H. J. Org. Chem. 1996, 61, 9126. (i) Tomooka, K.; Kiku-
chi, M.; Igawa, K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew. Chem.,
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Eur. J. 2011, 17, 3335.
10
11
12
13
14
15
16
17
18
19
20
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23
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25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
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58
59
60
8. Formal total synthesis of zaragozic acid A or C: (a) Freeman-Cook, K.
D.; Halcomb, R. L. J. Org. Chem. 2000, 65, 6153. (b) Bunte, J. O.; Cuz-
zupe, A. N.; Daly, A. M.; Rizzacasa, M. A. Angew. Chem., Int. Ed. 2006,
45, 6376. See also reference 7j.
9. For reviews on the synthesis of zaragozic acids, see: (a) Nadin, A.; Ni-
colaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 1622. (b) Armstrong,
A.; Blench, T. J. Tetrahedron 2002, 58, 9321.
10. For recent reviews on the application of C(sp3)–H functionalization for
natural product synthesis, see: (a) Newhouse, T.; Baran, P. S. Angew.
Chem., Int. Ed. 2011, 50, 3362. (b) Gutekunst, W. R.; Baran, P. S. Chem.
Soc. Rev. 2011, 40, 1976. (c) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K.
Angew. Chem., Int. Ed. 2012, 51, 8960.
ASSOCIATED CONTENT
Supporting Information
Characterization data for all new compounds, and experimental
procedures. This material is available free of charge via the Internet
at http://pubs.acs.org.
11. (a) Kamijo, S.; Hoshikawa, T.; Inoue, M. Tetrahedron Lett. 2010, 51,
872. (b) Yoshioka, S.; Nagatomo, M.; Inoue, M. Org. Lett. 2015, 17, 90.
12. (a) Yang, N. C.; Yang, D.-D. H. J. Am. Chem. Soc. 1958, 80, 2913. (b)
Urry, W. H.; Trecker, D. J. J. Am. Chem. Soc. 1962, 84, 118.
13. For recent applications of the Norrish-Yang photocyclization, see: (a)
Herrera, A. J.; Rondón, M.; Suárez, E. J. Org. Chem. 2008, 73, 3384. (b)
Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59. For reviews, see:
(c) Bach, T.; Hehn, J. P. Angew. Chem., Int. Ed. 2011, 50, 1000. (d) Chen,
C. Org. Biomol. Chem. 2016, 14, 8641. (e) Kärkäs, M. D.; Porco, J. A. Jr.;
Stephenson, C. R. J. Chem Rev. 2016, 116, 9683. (f) Ravelli, D.; Protti, S.;
Fagnoni, M. Chem Rev. 2016, 116, 9850.
14. See Supporting Information for the preparation of A, B, D and G.
15. Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97.
16. Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am. Chem.
Soc. 2006, 128, 8412.
17. (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936. (b) Zibuck, R.; Seebach, D. Helv. Chim. Acta.
1988, 71, 237.
18. (a) Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett 2008, 151.
For reviews, see: (b) Sugimoto, A.; Fukuyama, T.; Sumino, Y.; Takagi,
M.; Ryu, I. Tetrahedron 2009, 65, 1593. (c) Ley, S. V.; Fitzpatrick, D. E.;
Myers, R. M.; Battilocchio, C.; Ingham, R. J. Angew. Chem., Int. Ed.
2015, 54, 10122.
19. Norrish-type I fragmentation proceeds from the cyclobutanone struc-
ture. (a) Norrish, R. G. W. Trans. Faraday Soc. 1937, 33, 1521. (b) Yates,
P. Pure. Appl. Chem. 1968, 16, 93. (c) Coyle, J. D. Chem. Soc. Rev. 1972,
1, 465.
20. -Hydrogen abstraction at C7 or C9 by the activated C10-ketone would
be inhibited, because the reaction requires large conformational reorganiza-
tion.
21. Mori, Y.; Huhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron Lett.
1988, 29, 5419.
AUTHOR INFORMATION
Corresponding Author
inoue@mol.f.u-tokyo.ac.jp
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This research was financially supported by the Funding Program
for a Grant-in-Aid for Scientific Research (A) (26253003) to M.I.,
and a Grant-in-Aid for Scientific Research (C) (16K08156) to M.N.
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