Total Synthesis of Tetarimycin A, (±)-Naphthacemycin A9, and (±)-Fasamycin A: Structure-Activity Relationship Studies against Drug-Resistant Bacteria

Article abstract of DOI:10.1021/acs.joc.8b00802

Making use of a reductive olefin coupling reaction and Michael-Dieckmann condensation as two key operations, we have completed a concise total synthesis of tetarimycin A, (±)-naphthacemycin A₉, and (±)-fasamycin A in a highly convergent and pra

Full text of DOI:10.1021/acs.joc.8b00802

Subscriber access provided by READING UNIV
Article
The Total Synthesis of Tetarimycin A, (±)-
9
Naphthacemycin A and (±)-Fasamycin A. Structure-Activity
Relationship Studies against Drug-Resistant Bacteria
Jing-Kai Huang, Tsai-Ling Yang Lauderdale, Chun-Cheng Lin, and Kak-Shan Shia
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00802 • Publication Date (Web): 22 May 2018
Downloaded from http://pubs.acs.org on May 22, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
The Total Synthesis of Tetarimycin A, (±)ꢀNaphthacemycin A9 and
(±)ꢀFasamycin A. StructureꢀActivity Relationship Studies against
DrugꢀResistant Bacteria
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
JingꢀKai Huang,†,‡ TsaiꢀLing Yang Lauderdale,§ ChunꢀCheng Lin,*,† and KakꢀShan
Shia*,‡
†Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan, R.O.C.
‡Institute of Biotechnology and Pharmaceutical Research; §National Institute of Infectious Diseases and
Vaccinology, National Health Research Institutes, Miaoli County 35053, Taiwan, R.O.C.
ABSTRACT: Making use of
a reductive olefin coupling reaction and
MichaelꢀDieckmann condensation as two key operations, we have completed a
concise total synthesis of tetarimycin A, (±)ꢀnaphthacemycin A9 and (±)ꢀfasamycin A
in a highly convergent and practical protocol. Synthetic procedures thus developed
have also been applied to providing related analogues for structureꢀactivity
relationship studies, thereof coming to a conclusion that the free hydroxyl group at
Cꢀ10 is essential for exerting inhibitory activities against a panel of Gramꢀpositive
bacteria, including drugꢀresistant strains VRE and MRSA.
INTRODUCTION
A rapid increase in multidrugꢀresistant bacteria and slow development of new
antibiotics have posed a great threat to global public health.1 What’s even worse,
infection caused by methicillinꢀresistant Staphylococcus aureus (MRSA) has become
one of the most serious problems in hospitals due to its high mortality rate.2 Though a
few antibiotics, including vancomycin, linezolid, tigecycline and daptomycin, are
claimed to be clinically effective against MRSA infections, however, drugꢀresistant
strains have been observed in recent years.3 Thus, developing new antibiotics against
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 42
1
2
3
4
5
6
7
8
9
these multidrugꢀresistant bacteria is urgently demanded in the modern society. As
illustrated in Figure 1, a class of natural products possessing a gemꢀdimethyl
tetracyclic carbon skeleton has been reported to show potent antiꢀMRSA activities.4
Among them, fasamycin A and B were found to inhibit the FabF enzyme associated
with the biosynthesis of type II fatty acid (FASII) in bacteria.5 Other congeners (e.g.,
naphthacemycin A9) not only showed activities against various MRSA strains, but
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
also could overcome β
ꢀlactam resistance in a regimen combining with imipenem.4g
Above biological features make this family of natural products become a potential hit
and/or lead for further structural modifications to pursue novel antibiotics for
infectious diseases, especially those in unmet medical needs.
Figure 1. Structures of tetarimycin A and its congeners.
Recently, the total synthesis of tetarimycin A (1) and its congener (±)ꢀnaphthacemycin
A9 (6) have been achieved, respectively, by Shia and Sunazuka.6 Although these
synthetic sequences proved to be feasible, however, from the synthetic point of view,
they remained lengthy, laborious and lacking of economic benefits.7 Herein, we wish
to report a general approach to construct linear gemꢀdimethyl tetracyclic skeletons,
common in the titled natural products, in a more concise and practical manner. More
importantly, both targeted products and related analogues could be rapidly synthesized
to generate a library for structureꢀactivity relationship (SAR) analysis against a panel
of Gramꢀpositive bacterial strains usually causing serious infections, including MSSA,
MRSA and VRE. Results and discussion are presented as follows.
ACS Paragon Plus Environment

Page 3 of 42
The Journal of Organic Chemistry
1
2
3
RESULTS AND DISCUSSION
4
5
6
7
8
9
Natural products 1 and 6 are structurally common in A, B, C and D rings with a
major difference in E ring (methyl vs aryl). Target molecules 2 and 6 are structurally
quite similar but possess a different oxidation state in C ring (phenol vs
pꢀbenzoquinone) as well as A ring (Cl vs H). Retrosynthetic analyses of these
congeners are briefly illustrated in Figure 2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
Figure 2. Retrosynthetic analyses of natural products 1, 2 and 6
It is envisioned that the linear tetracyclic nucleus might be constructed through the
tandem MichaelꢀDieckmann condensation of fragments 9 and 10.8 Subsequently, the
pꢀbenzoquinone or phenol moiety in C ring should be achieved through either an
oxidation or aromatization transformation. Lactone 10 could be readily prepared by a
SuzukiꢀMiyaura coupling reaction of triflate 11 with boronic ester 12aꢀb or
methylboronic acid 12c, which are commercially available or easily synthesized via
documented procedures.9 Enone 9 is proposed to be synthesized via a reductive olefin
coupling between benzylꢀprotected 13 and methyl acrylate followed by intramolecular
FriedelꢀCrafts acylation.10 Indeed, based on our previous synthetic routes (Scheme 1;
details outlined in Scheme S1), key fragment 9 was synthesized via a sequence of 10
steps in low yields (13~23%).6a Lengthy and laborious procedures made it difficult to
achieve final products and related analogues in a sufficient amount for various
bioactive tests and pharmacokinetic studies. Therefore, we decided to design a more
concise sequence for enones 9aꢀb starting from 13aꢀb, which are commercially
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 42
1
2
3
4
5
available or readily prepared according to synthetic procedures reported in the
literature.11
6
7
Scheme 1. Preparation of Enones 9aꢀb via the Lengthy FirstꢀGeneration Route
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
Since constructing the essential quaternary carbon center of intermediates 17aꢀb was
critical for the subsequent intramolecular FriedelꢀCrafts acylation, efforts on
screening optimal coupling reaction conditions were intensively made. As listed in
Table 1, an initial attempt to undergo free radical coupling using Fe(acac)3 (30 mol%)
and PhSiH3 (3 equiv.) in one pot resulted in 17a (entry 1) in low yield (38%).10a
However, when Fe(acac)3 was reduced to 10 mol% along with a slow addition of
PhSiH3 (3 equiv.) over 30 min (entry 4), the desired product could be obtained up to
58% yield. Further reducing the amount of PhSiH3 from 3.0 to 1.5 equiv. and
extending its addition time from 0.5 to 5 h via a syringe pump resulted in a high yield
of 17a (Table 1, entry 5, 91%). With compound 17a in hand, the gemꢀdimethyl
tetralone 18a (Scheme 2) was readily prepared in 95% yield via a threeꢀstep sequence,
involving the formation of carboxylic acid under basic hydrolysis followed by
FriedelꢀCrafts acylation with TFAA and basic hydrolysis of the overꢀreactive product
“enol trifloroacetate”.12
Table 1. Screening optimal conditions for reductive olefin coupling
ACS Paragon Plus Environment

Page 5 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Oxidation of 18a with DDQ in refluxing toluene afforded α,βꢀunsaturated tetralone 9a
in 82% yield.13 Following a similar synthetic sequence (Scheme 2), enone 9b was
obtained in an overall yield of 63% starting from 17b.
Scheme 2. Preparation for BenzylꢀProtected Enone 9aꢀb
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
The newly designed 5ꢀstep sequence (71%) for tetralone 9a is apparently much more
concise than the 10ꢀstep one (23%) originally applied to the total synthesis of
tetarimycin A.6a With this significant improvement in building the AꢀB ring, we then
moved forward to construct the CꢀE fragments. According to Scheme 3, boronic esters
12aꢀb, intended to establish the E ring existing in natural products 2 and 6, were
synthesized via a twoꢀstep sequence starting from 19aꢀb in good yields (73~80%).
Scheme 3. Preparation of Boronic Esters 12aꢀb
Lactones 10aꢀc, serving as precursors for Hauser donors, could be prepared in a more
general synthetic route according to Scheme 4. Benzyl alcohol 14a could undergo
VilsmeierꢀHaack formylation in a regioselective manner with concomitant
chlorination to give formyl benzylchloride 21 in high yield (93%).14 Selective
demethylation of 21 was achieved under treatment with boron trichloride to afford
oꢀhydroxybenzaldehyde,15 which was subjected to Pinnick oxidation followed by
intramolecular lactonization to give lactone 22 in 88% over two steps. Under standard
conditions, compound 22 was further converted to the corresponding triflate 11 in
high yield (95%), which was then reacted with 12aꢀc via SuzukiꢀMiyaura coupling to
afford sterically crowded biphenyl lactones 10aꢀb and methyl lactone 10c in excellent
yields (92~98%).16
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 42
1
2
3
Scheme 4. Synthesis of Lactones 10aꢀc via SuzukiꢀMiyaura Coupling
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
Based on 10c, lactone 10d was readily prepared via deprotection with BBr3 followed
by protection with BnBr in 73% over two steps. To approach natural products 1 and 6
as well as their related analogues to establish a library for the structureꢀactivity
relationship (SAR) analysis. Hauser donors 24aꢀb and 24d were then prepared
according to Scheme 5. The lactone ring of compounds 10aꢀb and 10d was first
opened up by treatment with diethylamine in the presence of AlMe3 ascatalyst to form
the corresponding amide benzyl alcohols,17 which without purification were oxidized
by MnO2 to give amide aldehyde 23aꢀb and 23d, respectively, in good to excellent
yields (72~96%) over two steps. The aldehyde moiety thus formed was subjected to
1,2ꢀaddition with TMSCN followed by protonation with HOAc to give cyanohydrin
by which intramolecular lactonization rapidly occurred to afford the corresponding
cyanophthalides 24aꢀb and 24d in 75~95% yields.18
Scheme 5. Preparation of Hauser Donors 24aꢀb and 24d
ACS Paragon Plus Environment

Page 7 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
According to Scheme 6, the desired pꢀquinone motif in the Cꢀring could be efficiently
constructed via HauserꢀKraus annulation to give the corresponding pꢀhydroquinone
intermediate 25, which without purification was subjected to hydrogenolysis under
Pd/C followed by oxidation with DDQ to accomplish targets tetarimycin A (1) and
(±)ꢀnaphthacemycin A9 (6) in 57 and 63% yields, respectively, over three steps.
Indeed, compound 25 was found to be partially oxidized to its pꢀquinone counterpart
upon exposure to air in the crude residue.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
Scheme 6. Completed Synthesis of Tetarimycin A and (±)ꢀNaphthacemycin A9
OBn O
OBn O
OH
R
R
O
LiHMDS
O
+
THF, 0 oC to rt
BnO
BnO
OR'
OR'
NC
OH
24a, R = aryl, R' = Me
24d, R = Me, R' = Bn
9a
25
OMe
OH
O
O
OMe
1. Pd/C, H2 (1 atm)
EtOAc
OH
O
O
O
2. DDQ, EtOAc
HO
OH
HO
OMe
O
tetarimycin A (1)
(
-naphthacemycin A9 (6)
24d
from
63% (3 steps)
from 24a 57% (3 steps)
Similarly, following aforementioned synthetic strategies with minor peripheral
modifications, structurally related analogues 26~35 were prepared for SAR studies
against a panel of Gramꢀnegative/positive bacterial strains as listed in Table 2.
Table 2. SAR of tetarimycin A (1) and (±)ꢀnaphthacemycin A9 (6) against different
bacterial strains.
a
b
Organism
MIC (ꢀg/mL) of Compound
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 42
1
2
3
Vc
1
26 27 28 29 30 31 32 33 34
6
35
4
Escherichia coli
5
6
ATCC 25922
>8 >8 >8 >8 >8 >8 >8 >8 >8 >8 >8 >8 >8
Staphylococcus aureus
ATCC 29213 (MSSA)
ATCC 43300 (MRSA)
M056 (MSSA)
7
8
9
>8 >8
>8 >8
>8 >8
>8 >8
>8 >8
>8 >8
>8 >8
>8 >8
4
4
4
4
4
8
8
4
4
4
4
2
2
2
2
2
8
8
4
4
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
N216 (MRSA)
Enterococcus faecalis
ATCC 51299 (VRE)
>8 >8
>8 >8
4
8
2
4
>8
2
2
2
<0.5
a
E. coli, Gramꢀnegative bacteria; S. aureus and E. faecalis,Gramꢀpositive bacteria; ATCC, American Type Culture Collection;
M056 and N216, clinical isolates; MSSA, methicillinꢀsusceptible S. aureus; MRSA, methicillinꢀresistant S. aureus; VRE,
vancomycinꢀresistant enterococci. b MIC, minimum inhibitory concentration. c V = Vancomycin.
The current SAR study reveals that the hydroxyl group at Cꢀ10 is less tolerated than
that on Cꢀ18. As demonstrated by natural product 1 and its analogue 28 (Table 2),
both exhibited equally potent activity against MSSA, MRSA and VRE strains at a low
MIC value (1 or 2 ꢀg/mL) even if the free Cꢀ18 hydroxyl group was blocked. In sharp
contrast, a complete loss of activity was observed once the Cꢀ10 hydroxyl group was
blocked as exemplified by compounds 26, 27 and 29. In addition, keeping the
molecule in a coplanar manner appeared important to show inhibitory activity against
bacteria in that when the Cꢀ8 hydroxyl group was transformed to the methoxy,
compound 30 (MIC > 8 ꢀg/mL) resulted in a complete loss of activity against all
strains tested. This inference is further supported by the fact that when the Cꢀ8
hydroxyl group of 30 is eliminated, inhibitory activities of resulting compounds 31
(MIC = 4 ꢀg/mL) and 32 (MIC = 1 or 2 ꢀg/mL) can be recovered by 2 to 4ꢀfold.
Compound 31 relative to 32 also suggests that the Cꢀ18 position is in favor of
lipophilic interactions (e.g., Van der Waals attraction). To our surprise, compound 33,
as fully blocked with the acetyl group, exhibited a moderate activity (MIC = 4 ꢀg/mL)
against ATCC 29213 and N216 strains. These unexpected outcomes may be ascribed
to the partial hydrolysis of the acetate functionality at Cꢀ10 during assays. More
importantly, as compared to natural 1, compound 34 (MIC < 0.5 ꢀg/mL) with an
additional chlorine atom at Cꢀ11 displayed a dramatic improvement in activity against
a VRE strain (ATCC 51299), indicating that structural modifications of this position
might lead to the identification of a potential agent against VRE strains. Natural
product 6 with slightly weaker bioactivities than 28 implied that a bulky hydrophobic
ACS Paragon Plus Environment

Page 9 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
group might not be necessary for Cꢀ1 position. All tested compounds in Table 2
possess a MIC > 8 ꢀg/mL against a Gramꢀnegative strain (ATCC 25922) and thus, we
tentatively assume that natural products 1 and 6, and their structurally related
analogues could be Gramꢀpositiveꢀspecific inhibitors. Mechanistically, tetarimycin A
(1) and (±)ꢀnaphthacemycin A9 (6) are supposed to inhibit an enzyme called FabF in
that it has been identified as a molecular target of their congeners fasamycins A and B
by Brady.5 Since fasamycin A (2) possesses a phenol unit rather than pꢀbenzoquinone
in the C ring, instead of cyanophthalides for performing HauserꢀKraus annulation,
homophthalate compounds 39aꢀb were then elaborated to carry out traditional
MichaelꢀDieckmann condensation (Scheme 7).19 Commercially available 16b and
diethyl malonate dissolved in THF were first treated with NaH to deprotonate diethyl
malonate followed by addition of a second base LDA to form benzyne in situ.
Malonate enolate was then reacted with benzyne to afford diester 36 in 46% yield
along with an inevitable side product formed via addition of diisopropylamine to
benzyne.20 Selective demethylation could take place under treatment with BCl3 to give
phenol 37 (89%), which was converted to triflate 38 in 98% yield under standard
conditions followed by coupling with 12aꢀb to yield compounds 39aꢀb in 95% and
86%, respectively.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
Scheme 7. Preparation of 39aꢀb for MichaelꢀDieckmann Condensation
O
OH
O
OMe
OMe
diethyl malonate
NaH, then LDA
Cl
BCl3
EtO
EtO
EtO
EtO
DCM, 0 o
89%
C
THF, 0 o
46%
C
OMe
OMe
OMe
37
36
16b
O
O
OMe
OEt
O
OR
via
Na
O
OMe
OTf
OEt
OR
2 mol% Pd2(dba)3
8 mol% SPhos
O
O
EtO
EtO
2M Na2CO3(aq)
,
12a-b EtO
Tf2O, pyridine
DCM, 0 o
98%
C
OMe
OMe
39a, R = Me 95%
39b, R = Bn 86%
toluene
sealed 150 o
C
O
EtO
O
38
With Michael donor 39b and acceptor 9b in hand, a 4ꢀstep synthetic sequence
(Scheme 8), involving MichaelꢀDieckmann condensation with lithium base, basic
hydrolysis with KOH(aq), decarboxylation with DBU and aromatization with DDQ,
was carried out to give intermediate 40 in an overall yield of 35%.19c Finally, full
deprotection of compound 40 could be fulfilled under treatment with BBr3 to achieve
the first total synthesis of (±)ꢀfasamycin A (2) in 76% yield, which was first isolated
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 42
1
2
3
and reported by Brady in 2011.4d In a similar synthetic manner, analogues 41ꢀ45 listed
4
5
in Table 3 were also synthesized for SAR analysis.
6
7
8
Scheme 8. Completed Synthesis of (±)ꢀFasamycin A
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
In general, compounds with a phenol C ring (Table 3) are inferior to those with a
pꢀbenzoquinone unit (Table 2) in showing activities against bacterial strains examined.
As natural product 2 was compared to analogue 34 (Table 2), it clearly indicated that
replacing the methyl group with a crowded 1,3ꢀdiphenol unit at Cꢀ1 position was
totally unfavorable, resulting in an almost loss of activities (MIC ≥ 8 ꢀg/mL) against
all strains tested, with the exception that a moderate activity (MIC = 2 ꢀg/mL) against
VRE (ATCC 51299) was observed, presumably due to the halogen effect (Cl) at Cꢀ11
position. Analogues 41ꢀ43 (MIC = 2~4 ꢀg/mL) in comparison with parental 2 (MIC =
2~8 ꢀg/mL) again supported that a hydrophobic group (e.g., a methoxy moiety) at
Cꢀ18 could enhance antiꢀbacterial potency. When the free hydroxyl group of the E
ring was fully blocked, compounds 44 and 45 (MIC = 8 ꢀg/mL) thus obtained with a
dramatic drop in activities suggested that a bulky hydrophobic group at Cꢀ1 was
inappropriate.
ACS Paragon Plus Environment

Page 11 of 42
The Journal of Organic Chemistry
1
2
3
Table 3. SAR of (±)ꢀfasamycin A (2) against different bacterial strains.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
b
a
MIC (ꢀg/mL) of Compound
Organism
Vc
2
41
42
43
44
45
Escherichia coli
ATCC 25922
>8
>8
>8
>8
>8
>8
>8
Staphylococcus aureus
ATCC 29213 (MSSA)
ATCC 43300 (MRSA)
M056 (MSSA)
>8
8
4
4
4
4
4
4
4
4
>8
8
>8
>8
>8
>8
1
1
1
1
8
2,4 2,4
>8
>8
N216 (MRSA)
8
2
2
Enterococcus faecalis
ATCC 51299 (VRE)
2
4
4
4
4
>8
>8
a
E. coli, Gramꢀnegative bacteria; S. aureus and E. faecalis,Gramꢀpositive bacteria; ATCC, American Type Culture Collection;
M056 and N216, clinical isolates; MSSA, methicillinꢀsusceptible S. aureus; MRSA, methicillinꢀresistant S. aureus; VRE,
vancomycinꢀresistant enterococci. b MIC, minimum inhibitory concentration. c V = Vancomycin.
CONCLUSION
We have completed a concise total synthesis of tetarimycin A, (±)ꢀnaphthacemycin A9
and (±)ꢀfasamycin A in a highly convergent and practical protocol, mainly making use
of a reductive olefin coupling in the early stage and MichaelꢀDieckmann condensation
in the late stage as two key operations. Based on the current SAR studies, several
important conclusions could be derived as follows: 1) the free hydroxyl group at Cꢀ10
is structurally required for displaying antiꢀbacterial activities; 2) a pꢀbenzoquinone
unit in the C ring is superior to the corresponding phenol unit; 3) the free hydroxyl
group at Cꢀ18 is structurally modifiable and preferable to the lipophilic functionality;
4) the Cl atom at Cꢀ11 has a particularly beneficial effect against the VRE strain; 5)
the Eꢀring shows preference to having a smaller hydrophobic group rather than a
bulky one.
EXPERIMENTAL SECTION
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 42
1
2
3
4
5
6
7
8
9
Chemistry General. All reactions were performed under nitrogen unless otherwise
stated. All solvents and reagents were employed as received without further
purification. Analytical thin layer chromatography was performed on SiO2 60 Fꢀ254
plates and flash column chromatography was carried out using SiO2 60 (particle size
0.040ꢀ0.055 mm, 230–400 mesh). Visualization was performed under UV irradiation
at 254 nm followed by staining with aqueous potassium permanganate and charring
by heat gun. Infrared spectra (IR) were recorded on a FTꢀIR spectrometer and
expressed in cmꢀ1. 1H NMR spectra were recorded at 400 MHz and 13C NMR spectra
at 100 MHz. Chloroformꢀd was used as the solvent and TMS (δ = 0.00 ppm) as an
internal standard (δ = 77.00 for 13CꢀNMR). Acetoneꢀd6 was used as the solvent (δ =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
2.05 for HꢀNMR, δ = 29.29 for 13CꢀNMR). DMSOꢀd6 was used as the solvent (δ =
1
1
13
2.50 for HꢀNMR, δ = 39.51 for CꢀNMR). Chemical shifts are reported as δ values
in ppm as referenced to TMS. Multiplicities are recorded as s (singlet), d (doublet), t
(triplet), q (quartet), quint (quintet), dd (doublet of doublets), dt (doublet of triplets),
td (triplet of doublets), qd (quartet of doubles), tt (triplet of triplets), ddd (doublet of
doublet of doublets), m (multiplet), br (broad). Coupling constants (J) are expressed
in Hz. HRMS was obtained on a triple quadrupole mass analysis using electrospray
ionization (ESI) source or a double quadrupole mass analysis using electron impact
(EI) source, and spectral data were recorded as m/z values. Melting points were
measured using an Electrothermal instrument.
Methyl 4ꢀ(3,5ꢀbis(benzyloxy)phenyl)ꢀ4ꢀmethylpentanoate (17a). To a stirred
solution of styrene 13a (1.7 g, 5.0 mmol) methyl acrylate (1.3 g, 15.0 mmol) and cat.
Fe(acac)3 (176 mg, 0.50 mmol) in EtOH/ethylene glycol (20 mL/5 mL), which was
degassed with argon, was added phenylsilane (812 mg, 7.50 mmol) over 5 h via
syringe pump at 60 . After reaction was complete, the solvent was evaporated to
give the crude residue, which was purified by chromatography on silical gel with
EtOAc/nꢀhexane (1:20) followed by EtOAc/nꢀhexane (1:10) to afford ester 17a (1.9 g,
91%) as a colorless oil: IR (CH2Cl2 cast, cmꢀ1) νmax 3064, 3032, 2952, 2871, 1736,
1
1593, 1454, 1434, 1158; H NMR (CDCl3, 400 MHz): δ 1.27 (s, 6H), 1.92 (dd, J =
10.8, 6.8 Hz, 2H), 2.04 (dd, J = 10.8, 6.8 Hz, 2H), 3.61 (s, 3H), 5.02 (s, 4H), 6.47 (t, J
= 2.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 2H), 7.31ꢀ7.44 (m, 10H); 13C NMR (CDCl3, 100
MHz): δ 28.6, 29.9, 37.5, 38.8, 51.4, 70.0, 98.8, 105.8, 127.6, 127.9, 128.5, 136.9,
150.6, 159.8, 174.3; HRMS (ESI) m/z: [M + Na]+ calcd. for C27H30O4Na 441.2036,
found: 441.2038.
Methyl
4ꢀ(3,5ꢀbis(benzyloxy)ꢀ2ꢀchlorophenyl)ꢀ4ꢀmethylpentanoate
(17b).
According to the synthetic procedures similar to compound 17a, ester 17b (12.3 g,
68% yield) was prepared from styrene 13b (14.6 g, 40.0 mmol) as a colorless oil: IR
(CH2Cl2 cast, cmꢀ1) νmax 3064, 3032, 2951, 2927, 2874, 1736, 1592, 1579, 1434,
ACS Paragon Plus Environment

Page 13 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1169; 1H NMR (CDCl3, 400 MHz): 1.45 (s, 6H), 2.01 (dd, J = 11.6, 8.4 Hz, 2H), 2.35
(dd, J = 11.6, 8.4 Hz, 2H), 3.61 (s, 3H), 5.00 (s, 2H), 5.08 (s, 2H), 6.55 (d, J = 2.8 Hz,
1H), 6.61 (d, J = 2.8 Hz, 1H), 7.33ꢀ7.47 (m, 10H); 13C NMR (CDCl3, 100 MHz): δ
28.3, 30.2, 34.6, 39.5, 51.4, 70.2, 71.0, 99.7, 108.1, 115.0, 127.0, 127.5, 127.8, 128.1,
128.5, 128.6, 136.4, 136.4, 145.7, 155.5, 157.2, 174.2; HRMS (ESI) m/z: [M + H]+
calcd. for C27H30ClO4 453.1827, found: 453.1836.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
6,8ꢀBis(benzyloxy)ꢀ4,4ꢀdimethylꢀ3,4ꢀdihydronaphthalenꢀ1(2H)ꢀone (18a). To a
stirred solution of ester 17a (12.6 g, 30.0 mmol) in MeOH (60 mL) was added
NaOH(aq) (4 N, 10 mL, 40.0 mmol) at room temperature under N2. The resulting
mixture was then stirred at reflux temperature under N2 for 3 h. After reaction was
complete, the solvent was evaporated to give the crude residue, which was neutralized
with 5% HCl(aq) to pH~4. EtOAc (60 mL x 2) was then added to extract water layer.
The combined organic extracts were washed with water and brine, dried over MgSO4,
filtered and concentrated to give the corresponding acid (12.1 g, quantity). To a stirred
solution of acid in dry DCM (120 mL), which was degassed with argon, was added
TFAA (9.5 g, 45.0 mmol) at 0 under N2. The resulting mixture was then stirred at
room temperature under N2 for 3 h. After reaction was complete, the NaOH(aq) (4 N,
12 mL, 48.0 mmol) in MeOH (60 mL) was added to quench and hydrolyze the
overreacted product enol trifloroacetate at 0 . The solvent of resutling mixture was
evaporated, and extracted with EtOAc (60 mL x 2). The combined organic extracts
were washed with water and brine, dried over MgSO4, filtered and concentrated to
give the crude residue, which was recrystallized with diethyl ether and nꢀhexane to
afford tetralone 18a (11.0 g, 95% yield over 2 steps) as a white solid: mp = 114–
115 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3032, 2961, 2926, 2864, 1670, 1595, 1568, 1324,
1
1157; H NMR (CDCl3, 400 MHz): δ 1.33 (s, 6H), 1.93 (t, J = 6.8 Hz, 2H), 2.68 (t, J
= 6.8 Hz, 2H), 5.08 (s, 2H), 5.14 (s, 2H), 6.48 (d, J = 2.2 Hz, 1H), 6.59 (d, J = 2.2 Hz,
1H), 7.29ꢀ7.43 (m, 8H), 7.58 (d, J = 7.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ
29.7, 34.8, 36.4, 36.6, 70.0, 70.5, 98.7, 104.1, 115.9, 126.6, 127.5, 127.6, 128.2, 128.4,
128.6, 136.0, 136.6, 156.7, 161.0, 163.0, 196.0; HRMS (ESI) m/z: [M + H]+ calcd. for
C26H27O3 387.1955, found: 387.1956.
6,8ꢀBis(benzyloxy)ꢀ5ꢀchloroꢀ4,4ꢀdimethylꢀ3,4ꢀdihydronaphthalenꢀ1(2H)ꢀone
(18b). According to the synthetic procedures similar to compound 18a, tetralone 18b
(18.8 g, 71% yield over 2 steps) was prepared from ester 17b (12.0 g, 26.5 mmol) as a
white solid: mp = 105–106 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3031, 2959, 2932, 2868,
1682, 1576, 1309, 1226; 1H NMR (CDCl3, 400 MHz): 1.63 (s, 6H), 1.99 (t, J = 6.4 Hz,
2H), 2.62 (t, J = 6.4 Hz, 2H), 5.09 (s, 2H), 5.11 (s, 2H), 6.53 (s, 1H), 7.30ꢀ7.52 (m,
13
10H); C NMR (CDCl3, 100 MHz): δ 26.7, 36.8, 36.9, 40.4, 70.8, 71.3, 99.0, 115.1,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 42
1
2
3
4
5
6
7
8
9
118.1, 126.8, 127.0, 127.8, 128.2, 128.6, 128.7, 135.7, 136.4, 150.8, 158.5, 159.1,
196.4; HRMS (ESI) m/z: [M + H]+ calcd. for C26H26ClO3 421.1565, found: 421.1577.
6,8ꢀBis(benzyloxy)ꢀ4,4ꢀdimethylnaphthalenꢀ1(4H)ꢀone (9a). To a stirred solution of
tetralone 18a (3.9 g, 10.0 mmol) in dry toluene (50 mL) was added DDQ (2.4 g, 10.5
mmol) in one portion. The resulting mixture was then stirred at reflux temperature
under N2 for 2 h. After reaction was complete, the reaction mixture was filtrated with
celite, and quenched with saturated NaHCO3(aq) (20 mL) and extracted with EtOAc
(50 mL). The organic extract was washed with saturated NaHCO3(aq) and brine, dried
over MgSO4, filtered and concentrated to give the crude residue, which was purified
by chromatography on silical gel with DCM/nꢀhexane (1:1) followed by DCM/EtOAc
(10:1) and further recrystallized with diethyl ether and nꢀhexane to afford enone 9a
(3.2 g, 82% yield) as a white solid: mp = 139–140 ; IR (CH2Cl2 cast, cmꢀ1) νmax
3064, 3032, 2966, 2929, 2875, 1659, 1633, 1597, 1455, 1322, 1169; 1H NMR (CDCl3,
400 MHz): δ 1.42 (s, 6H), 5.09 (s, 2H), 5.18 (s, 2H), 6.24 (d, J = 10.0 Hz, 1H), 6.55 (d,
J = 2.4 Hz, 1H), 6.66 (d, J = 10.0 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 7.25ꢀ7.63 (m, 10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
13
H); C NMR (CDCl3, 100 MHz): δ 30.4, 37.8, 70.0, 70.5, 99.2, 104.7, 114.9, 126.5,
127.4, 127.5, 128.1, 128.2, 128.4, 128.6, 135.9, 136.6, 152.8, 154.6, 161.1, 162.2,
183.7; HRMS (EI) m/z: [M] calcd. for C26H24O3 384.1725, found: 384.1729.
6,8ꢀBis(benzyloxy)ꢀ5ꢀchloroꢀ4,4ꢀdimethylnaphthalenꢀ1(4H)ꢀone (9b). According to
the synthetic procedures similar to compound 9a, enone 9b (3.8 g, 90% yield) was
prepared from tetralone 18b (4.2 g, 10.0 mmol) as a white solid: mp = 117–118 ; IR
(CH2Cl2 cast, cmꢀ1) νmax 2959, 2935, 2867, 1587, 1430, 1314, 1209; 1H NMR (CDCl3,
400 MHz): δ 1.73 (s, 6H), 5.14 (s, 4H), 6.18 (d, J = 10.4 Hz, 1H), 6.60 (d, J = 10.4 Hz,
1H), 6.63 (s, 1H), 7.31ꢀ7.45 (m, 8H), 7.55 (d, J = 7.6 Hz, 2H); 13C NMR (CDCl3, 100
MHz): δ 25.0, 39.1, 70.9, 71.3, 99.6, 114.7, 116.7, 125.3, 126.8, 127.0, 127.7), 128.2,
128.5, 128.7), 135.6, 136.4, 148.9, 155.8, 158.0, 159.6, 184.1; HRMS (ESI) m/z: [M
+ Na]+ calcd. for C26H23ClO3Na 441.1228, found: 441.1228.
2ꢀ(2,4ꢀDimethoxyꢀ6ꢀmethylphenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane (12a).
To a stirred solution of compound 19a (4.1 g, 26.6 mmol) in THF (133 mL) was
added NBS (5.0 g, 27.9 mmol) portionwise at room temperature. The resulting
mixture was then stirred at room temperature under N2 for 15 h. After reaction was
complete, the reaction mixture was quenched with 5% Na2S2O3(aq) (30 mL) and
extracted with EtOAc (50 mL). The organic extract was washed with saturated
NaHCO3(aq) and brine, dried over MgSO4, filtered and concentrated to give the crude
residue, which was purified by chromatography on silical gel to afford the
corresponding bromobenzene. To a stirred solution of the intermediate bromobenzene
(5.9 g, 25.5 mmol) in dry THF (51 mL) at ꢀ78
was added nꢀBuLi (2.5 M in
nꢀhexane, 10.2 mL, 25.5 mmol) dropwise under N2. After the reaction mixture was
ACS Paragon Plus Environment

Page 15 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
stirred at ꢀ78 under N2 for 30 mins, the boric ester 20 (5.0 g, 26.8 mmol) was added
in one portion. Then the reaction mixture was allowed to react at room temperature
under N2 for 30 min. After reaction was complete, the reaction mixture was quenched
with sat. NH4Cl(aq) (20 mL) at 0 and extracted with EtOAc (50 mL). The organic
extract was washed with water and brine, dried over MgSO4, filtered and concentrated
to give the crude residue, which was purified by chromatography on silical gel to
afford boronic ester 12a (5.4 g, 73% yield over 2 steps) as a colorless oil: IR (CH2Cl2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
cast, cmꢀ1) νmax 2977, 2937, 2838, 1604, 1579, 1455, 1515, 1201, 1146; H NMR
1
(CDCl3, 400 MHz): δ 1.37 (s, 12H), 2.34 (s, 3H), 3.74 (s, 3H), 3.78 (s, 3H), 6.22 (d, J
= 2.0 Hz, 1H), 6.29 (d, J = 2.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 22.0, 24.6,
54.9, 55.3, 83.2, 94.9, 106.3, 144.2, 161.7, 164.3; HRMS (ESI) m/z: [M + Na]+ calcd.
for C15H23BO4Na 301.1582, found: 301.1581.
2ꢀ(2,4ꢀBis(benzyloxy)ꢀ6ꢀmethylphenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane
(12b). According to the synthetic procedures similar to compound 12a, boronic ester
12b (10.3 g, 80% yield over 2 steps) was prepared from compound 19b (9.1 g, 30.0
mmol) as a white solid: mp = 113–114 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3064, 3032,
1
2977, 2929, 2867, 1601, 1575, 1372, 1338, 1159, 1144; H NMR (CDCl3, 400 MHz):
δ 1.29 (s, 12H), 2.35 (s, 3H), 4.98 (s, 2H), 5.03 (s, 2H), 6.37 (d, J = 1.6 Hz, 1H), 6.40
(d, J = 1.6 Hz, 1H), 7.28ꢀ7.47 (m, 10H); 13C NMR (CDCl3, 100 MHz): δ 22.2, 24.8,
69.8, 70.1, 77.2, 83.4, 97.1, 107.9, 127.5, 127.6, 127.9, 128.2, 128.5, 137.0, 137.3,
144.7, 161.0, 163.6; HRMS (ESI) m/z: [M + Na]+ calcd. for C27H31BO4Na 453.2208,
found: 453.2207.
2ꢀ(Chloromethyl)ꢀ4,6ꢀdimethoxybenzaldehyde (21). To a stirred dry DMF (12 mL)
at 0
was added POCl3 (5.6 mL, 60 mmol) dropwise under N2. After the reaction
mixture was stirred at room temperature for 30 mins, benzyl alchol 14a (7.1 g, 42.2
mmol) was added at 0 . Then the reaction mixture was allowed to react at 75
under N2 for 2 h. The reaction mixture was added portionwise to stirred ice water (50
mL) to quench the reaction. NaOH(aq) was then added to neturalize the reaction
mixture to pH~7. EtOAc (60 mL x 2) was then added to extract water layer. The
combined organic layer was washed with water and brine, dried over MgSO4, filtered
and concentrated to give the crude residue, which was recrystallized with EtOAc and
nꢀhexane to afford benzaldehyde 21 (8.5 g, 93% yield) as a white solid:14 mp = 70–
71 ; 1H NMR (CDCl3, 400 MHz): δ 3.90 (s, 6H), 5.05 (s, 2H), 6.44 (s, 1H), 6.76 (s,
1H), 10.46 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 44.8, 55.6, 56.0, 97.6, 107.5,
115.9, 142.3, 165.0, 165.3, 189.9.
7ꢀHydroxyꢀ5ꢀmethoxyisobenzofuranꢀ1(3H)ꢀone (22). To a stirred solution of 21
(9.7 g, 45.2 mmol) in dry DCM (180 mL) at 0 was added BCl3 (1M in DCM, 60
mL, 60 mmol) under N2. After stirred at room temperature for 7 h, the reaction was
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 42
1
2
3
4
5
6
7
8
9
quenched with ice water at 0 . The organic layer was washed with sat. NaHCO3(aq)
and water, dried over MgSO4, filtered and concentrated to give the crude phenol,
which without purification was oxidized by pinnick reaction. To a stirred solution of
the intermediate phenol (8.8 g, 43.9 mmol) NaH2PO4 (15.6 g, 130 mmol) and
2ꢀmethylꢀ2ꢀbutene (13 mL) in THF/tBuOH/H2O (80 mL/80 mL/40 mL) was added
NaClO2 (11.8 g, 130.6 mmol) portionwise at 0 . After stirred at room temperature
for 3 h, THF (80 mL x 2) was added to extract the reaction mixture. The combined
organic layer was washed with brine, dried over MgSO4, filtered and concentrated to
give the crude residue, which was recrystallized with THF and nꢀhexane to afford
compound 22 (7.1 g, 88% yield over 2 steps) as a white solid:21 mp = 183–185 ; 1H
NMR (d6ꢀDMSO, 400 MHz): δ 3.79 (s, 3H), 5.17 (s, 2H), 6.39 (d, J = 2.0 Hz, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
13
6.58 (d, J = 2.0 Hz, 1H); C NMR (d6ꢀDMSO, 100 MHz): δ 55.8, 68.4, 98.4, 101.4,
104.4, 151.6, 157.9, 165.8, 168.4.
6ꢀMethoxyꢀ3ꢀoxoꢀ1,3ꢀdihydroisobenzofuranꢀ4ꢀyl trifluoromethanesulfonate (11).
To a stirred solution of phenol 22 (7.0 g, 38.9 mmol) and pyridine (20 mL) in dry
DCM (40 mL) at 0 was slowly added trifluoromethanesulfonic anhydride (12.1 g,
42.9 mmol) under N2. After stired at room temperature for 2 h, reaction was quenched
with ice water. The aqueous layer was separated and extracted with DCM (50 mL x 2).
The organic portions were combined, washed with 5% HCl(aq), and water, dried over
MgSO4, filtered and concentrated to give the crude residue, which was recrystallized
with EtOAc and nꢀhexane to afford compound 11 (11.5 g, 95% yield) as a white solid:
mp = 141–142 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3112, 3055, 2986, 2951, 2850, 1757,
1
1625, 1426, 1226, 1197; H NMR (CDCl3, 400 MHz): δ 3.94 (s, 3H), 5.28 (s, 2H),
6.90 (s, 1H), 6.69 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 56.6, 68.8, 106.1, 110.1,
110.8, 118.7 (q, JFꢀC = 319 Hz), 146.7, 151.1, 166.0, 166.2; HRMS (ESI) m/z: [M +
Na]+ calcd. for C10H7F3O6SNa 334.9808, found: 334.9808.
Ethyl
2ꢀ(2ꢀEthoxyꢀ2ꢀoxoethyl)ꢀ4ꢀmethoxyꢀ6ꢀ(((trifluoromethyl)sulfonyl)oxy)benzoate
(38). According to the synthetic procedures similar to compound 11, triflate 38 (6.1 g,
98% yield) was prepared from phenol 37 (4.2 g, 14.9 mmol) as a white solid:22 mp =
60–62 ; 1H NMR (CDCl3, 400 MHz): δ 1.25 (t, J = 7.2 Hz, 3H), 1.38 (t, J = 7.2 Hz,
3H), 3.85 (s, 3H), 3.89 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H), 4.37 (q, J = 7.2 Hz, 2H), 6.75
(d, J = 2.6 Hz, 1H), 6.83 (d, J = 2.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 13.9,
14.1, 40.1, 55.9, 61.2, 62.0, 107.1, 117.0, 118.6 (q, JFꢀC = 319 Hz), 119.0, 138.1,
148.8 , 161.5, 164.4, 170.2.
7ꢀ(2,4ꢀDimethoxyꢀ6ꢀmethylphenyl)ꢀ5ꢀmethoxyisobenzofuranꢀ1(3H)ꢀone (10a). To
a stirred solution of triflate 11 (3.36 g, 10.8 mmol) and boronic ester 12a (6.0 g, 21.6
mmol) in toluene(60 mL) was added cat. Pd2(dba)3 (198 mg, 0.20 mmol), Sphos (369
ACS Paragon Plus Environment

Page 17 of 42
The Journal of Organic Chemistry
1
2
3
4
5
mg, 0.90 mmol) and 2M Na2CO3(aq) (22 mL). After degass with argon for 30 mins, the
reaction vial was sealed and then allowed to react at 150
under N2 for 2 h. The
reaction mixture was diluted with EtOAc (40 mL) and filtrated with celite. The layers
were separated, and the aqueous layer was extracted with EtOAc (50 mL). The
organic portions were combined, washed with water and brine, dried over MgSO4,
filtered and concentrated to give the crude residue, which was purified by
chromatography on silical gel to afford biphenyl lactone 10a (3.3 g, 98% yiled) as a
white solid: mp = 147–148 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3059, 3001, 2939, 2841,
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
1
1756, 1608, 1594, 1478, 1465, 1337, 1213, 1201, 1154; H NMR (CDCl3, 400 MHz):
δ 2.05 (s, 3H), 3.67 (s, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 5.22 (s, 2H), 6.41 (d, J = 2.4
Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 3.0 Hz, 1H), 6.88 (d, J = 3.0 Hz, 1H);
13C NMR (CDCl3, 100 MHz): δ 20.2, 54.9, 55.4, 55.5, 67.9, 95.8, 104.6, 106.2, 116.3,
117.9, 118.8, 137.5, 139.1, 149.7, 157.6, 160.0, 163.9, 169.3; HRMS (ESI) m/z: [M +
Na]+ calcd. for C18H18O5Na 337.1046, found: 337.1048.
7ꢀ(2,4ꢀBis(benzyloxy)ꢀ6ꢀmethylphenyl)ꢀ5ꢀmethoxyisobenzofuranꢀ1(3H)ꢀone (10b).
According to the synthetic procedures similar to compound 10a, biphenyl lactone 10b
(2.2 g, 92% yield) was prepared from triflate 11 (1.6 g, 5.1 mmol) and boronic ester
12b (4.3 g, 10.0 mmol) as a white solid: mp = 139–140 ; IR (CH2Cl2 cast, cmꢀ1) νmax
3063, 3031, 2937, 2875, 1755, 1607, 1477, 1454, 1337, 1213, 1153; 1H NMR (CDCl3,
400 MHz): δ 2.08 (s, 3H), 3.88 (s, 3H), 4.94 (d, J = 13.0 Hz, 1H), 4.97 (d, J = 13.0 Hz,
1H), 5.04 (s, 2H), 5.16 (d, J = 15.2 Hz, 1H), 5.22 (d, J = 15.2 Hz, 1H), 6.53 (d, J = 2.2
Hz, 1H), 6.56 (d, J = 2.2 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H),
7.12ꢀ7.46 (m, 10 H); 13C NMR (CDCl3, 100 MHz): δ 20.5, 55.7, 68.0, 70.0, 70.3, 98.4,
104.9, 107.8, 116.8, 118.7, 119.0, 126.8, 127.4, 127.7, 128.0, 128.2, 128.6, 136.9,
137.2, 137.9, 139.5, 149.6, 157.0, 159.4, 164.0, 169.6; HRMS (ESI) m/z: [M + Na]+
calcd. for C30H26O5Na 489.1672, found: 489.1675.
5ꢀMethoxyꢀ7ꢀmethylisobenzofuranꢀ1(3H)ꢀone (10c). According to the synthetic
procedures similar to compound 10a, methylated lactone 10c (838 mg, 94% yield)
was prepared from triflate 11 (1.6 g, 5.1 mmol) and boronic acid 12c (599 mg, 10.00
mmol) as a white solid: mp = 172–173 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3017, 2980,
1
2950, 2842, 1741, 1616, 1604, 1308, 1146; H NMR (CDCl3, 400 MHz): δ 2.64 (s,
3H), 3.88 (s, 3H), 5.18 (s, 2H), 6.73 (s, 1H), 6.78 (s, 1H); 13C NMR (CDCl3, 100
MHz): δ 17.4, 55.6, 68.4, 103.5, 115.7, 117.3, 141.2, 149.8, 164.2, 170.9; HRMS (EI)
m/z: [M] calcd. For C10H10O3: 178.0630, found: 178.0632.
Ethyl
3ꢀ(2ꢀEthoxyꢀ2ꢀoxoethyl)ꢀ2',4',5ꢀtrimethoxyꢀ6'ꢀmethylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀ
carboxylate (39a). According to the synthetic procedures similar to compound 10a,
biphenyl diethyl homophthalate 39a (794 mg, 95% yield) was prepared from triflate
38 (829 mg, 2.00 mmol) and boronic ester 12a (1.4 g, 5.0 mmol) as a white solid: mp
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 42
1
2
3
4
5
6
7
8
9
= 84–85 ; IR (CH2Cl2 cast, cmꢀ1) νmax 2979, 2938, 2839, 1735, 1713, 1602, 1498,
1465, 1318, 1277, 1201, 1155; 1H NMR (CDCl3, 400 MHz): δ 0.88 (t, J = 7.2 Hz, 3H),
1.23 (t, J = 7.2 Hz, 3H), 2.02 (s, 3H), 3.66 (s, 3H), 3.72 (d, J = 16.4 Hz, 1H), 3.81 (s,
3H), 3.82 (s, 3H), 3.92 (q, J = 7.2 Hz, 2H), 3.93 (d, J = 16.4 Hz, 1H), 4.14 (q, J = 7.2
Hz, 2H), 6.34 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H),
6.80 (d, J = 2.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 13.4, 14.0, 20.4, 40.0, 55.1,
55.6, 60.1, 60.6, 95.7, 105.8, 115.2, 115.4, 122.9, 126.5, 134.9, 138.1, 139.3, 157.5,
159.5, 160.0, 168.2, 171.0; HRMS (ESI) m/z: [M + Na]+ calcd. for C23H28O7Na
439.1727, found: 439.1725.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
Ethyl
2',4'ꢀBis(benzyloxy)ꢀ3ꢀ(2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ5ꢀmethoxyꢀ6'ꢀmethylꢀ[1,1'ꢀ
biphenyl]ꢀ2ꢀcarboxylate (39b). According to the synthetic procedures similar to
compound 10a with reaction carried out for 15 h instead, biphenyl diethyl
homophthalate 39b (2.0 g, 86% yield) was prepared from triflate 38 (829 mg, 2.00
mmol) and boronic ester 12b (2.6 g, 6.1 mmol) as a colorless oil: IR (CH2Cl2 cast,
cmꢀ1) νmax 3064, 3032, 2979, 2930, 2870, 1733, 1716, 1602, 1498, 1464, 1316, 1275,
1
1201, 1154; H NMR (CDCl3, 400 MHz): δ 0.82 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2
Hz, 3H), 2.04 (s, 3H), 3.78 (d, J = 16.4 Hz, 1H), 3.80 (s, 3H), 3.91 (qd, J = 7.2, 1.6 Hz,
2H), 3.92 (d, J = 16.4 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.93 (s, 2H), 5.03 (s, 2H),
6.44 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.64 (d, J = 2.6 Hz, 1H), 6.80 (d, J
= 2.6 Hz, 1H), 7.16ꢀ7.43 (m, 10H); 13C NMR (CDCl3, 100 MHz): δ 13.5, 14.1, 20.4,
40.1, 55.2), 60.2, 60.7, 70.0, 70.1, 98.3, 107.6, 115.1, 115.7, 123.9, 126.5, 126.5,
127.3, 127.5, 127.9, 128.2, 128.5, 135.0, 137.0, 137.3, 138.3, 139.6, 156.5, 158.6,
160.1, 168.3, 171.1; HRMS (ESI) m/z: [M + Na]+ calcd. for C35H36O7Na 591.2353,
found: 591.2351.
5ꢀ(Benzyloxy)ꢀ7ꢀmethylisobenzofuranꢀ1(3H)ꢀone (10d). To a stirred solution of
methylꢀprotecting lactone 10c (2.8 g, 15.7 mmol) in dry DCM (15 mL) was added
BBr3 (4.0 g, 1.52 mL, 16.0 mmol) at 0 under N2. The mixture was then allowed to
react at room temperature under N2 for 6 h. After reaction was complete, ice water (10
mL) was added to quench the reaction. DCM was then evaporated to give the crude
residue,which was dissolved in THF/EtOAc (30 mL/20 mL) and filtrated with celite
to remove bronic acid. The organic layer was washed with saturated NaHCO3(aq) and
brine, dried over MgSO4, filtered and concentrated to give the crude residue. To a
stirred solution of the crude residue in DMF (10 mL) was added K2CO3 (2.2 g, 16.0
mmol) and benzyl bromide (2.7 g, 15.8 mmol) dropwise. The mixture was then
allowed to react at room temperature under N2 for 2 h. After reaction was complete,
water (20 mL) was added to quench the reaction. The aqueous layer was separated
and extrated with DCM (45 mL). The organic extract was washed with water (15 mL
x 3) and brine, dried over MgSO4, filtered and concentrated to give the crude residue,
ACS Paragon Plus Environment

Page 19 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
which was recrystallized with diethyl ether and nꢀhexane to afford benzylꢀprotecting
lactone 10d (2.9 g, 73% yield over 2 steps) as a white solid: mp = 144–145 ; IR
(CH2Cl2 cast, cmꢀ1) νmax 3062, 3032, 2946, 2874, 1754, 1599, 1448, 1340, 1155,
1033; 1H NMR (CDCl3, 400 MHz): δ 2.64 (s, 3H), 5.13 (s, 2H), 5.17 (s, 2H), 6.79 (s,
1H), 6.88 (s, 1H), 7.36ꢀ7.42 (m, 5H); 13C NMR (CDCl3, 100 MHz): δ 17.4, 68.4, 70.3,
104.4, 116.0, 118.1, 127.3, 128.2, 128.7, 135.8, 141.3, 149.8, 163.3, 170.8; HRMS
(EI) m/z: [M] calcd. for C16H14O3 254.0943, found: 254.0950.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
N,NꢀDiethylꢀ3ꢀformylꢀ2',4',5ꢀtrimethoxyꢀ6'ꢀmethylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarboxamid
e (23a). To a stirred solution of diethyl amine (1.5 g, 20.5 mmol) in dry toluene (20
mL) was added AlMe3 (2M in toluene, 10 mL, 20 mmol) dropwise at 0 under N2.
After stirred at room temperature for 30 min, lactone 10a (3.1 g, 9.9 mmol) was added
in one portion. The reaction mixture was then heated to reflux under N2 for 15 h.
After cooling, 5% HCl(aq) (20 mL) was slowly added at 0 to quench the reaction.
The aqueous layer was separated and extrated with EtOAc (30 mL x 2). The
combined organic layer was washed with water and brine, dried over MgSO4, filtered
and concentrated to give the crude residue. The crude residue was dissolved in dry
DCM (50 mL) and MnO2 (8.7 g, 100.1 mmol) was added in one portion. The mixture
was then reacted at room temperature for 10 h. After reaction was complete, the
reaction mixture was filtrated with celite and concentrated to give the crude residue,
which was purified by chromatography on silical gel with EtOAc/nꢀhexane (1:2)
followed by EtOAc/nꢀhexane (1:1) to afford atropisomeric mixture aldehyde 23a (3.7
g, 96% yield over 2 steps) as a white solid: mp = 123–125 ; IR (CH2Cl2 cast, cmꢀ1)
νmax 3057, 2968, 2935, 2841, 2753, 1762, 1697, 1628, 1605, 1498, 1458, 1429, 1317,
1201, 1153; 1H NMR (CDCl3, 400 MHz), major one: δ 0.72 (t, J = 6.8 Hz, 3H), 0.92
(t, J = 6.8 Hz, 3H), 2.10 (s, 3H), 2.80 (sext, J = 6.8 Hz, 1H), 2.91 (sext, J = 6.8 Hz,
1H), 3.33 (sext, 6.8 Hz, 1H), 3.65 (s, 3H), 3.76 (sext, J = 6.8 Hz, 1H), 3.81 (s, 3H),
3.89 (s, 3H), 6.31 (d, J = 2.4 Hz, 1H), 6.40 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz,
1H), 7.46 (d, J = 2.4 Hz, 1H), 10.04 (s, 1H); 13C NMR (CDCl3, 100 MHz), major one:
δ 11.7, 13.7, 20.8, 37.9, 42.0, 54.9, 55.2, 55.5, 95.3, 105.8, 110.0, 119.2, 124.1, 133.8,
134.2, 137.9, 140.5, 157.4, 159.2, 160.1, 167.1, 190.7; HRMS (ESI) m/z: [M + H]+
calcd. for C22H28NO5 386.1962, found: 386.1962.
2',4'ꢀBis(benzyloxy)ꢀN,Nꢀdiethylꢀ3ꢀformylꢀ5ꢀmethoxyꢀ6'ꢀmethylꢀ[1,1'ꢀbiphenyl]ꢀ2
ꢀcarboxamide (23b). According to the synthetic procedures similar to compound 23a,
atropisomeric mixture aldehyde 23b (5.1 g, 93% yield over 2 steps) was prepared
from lactone 10b (4.7 g, 10.1 mmol) as a colorless oil: IR (CH2Cl2 cast, cmꢀ1) νmax
3064, 3032, 2970, 2933, 2870, 2753, 1696, 1627, 1603, 1498, 1455, 1430, 1394, 1380,
1317, 1278, 1153; 1H NMR (CDCl3, 400 MHz), major one: δ 0.69ꢀ0.75 (m, 6H), 2.14
(s, 3H), 2.64 (sext, J = 7.2 Hz, 1H), 2.89 (sext, J = 6.4 Hz, 1H), 3.20 (sext, J = 7.2 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 42
1
2
3
4
5
6
7
8
9
1H), 3.70 (sext, J = 6.4 Hz, 1H), 3.89 (s, 3H), 4.86 (d, J = 12.4 Hz, 1H), 4.98 (d, J =
12.4, 1H), 5.05 (s, 2H), 6.47 (d, J = 2.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 7.05 (d, J =
2.4 Hz, 1H), 7.10ꢀ7.12 (m, 2H), 7.25ꢀ7.45 (m, 8H), 7.48 (d, J = 2.4 Hz, 1H), 10.02 (s,
1H); 13C NMR (CDCl3, 100 MHz), major one: δ 11.8, 13.5, 20.9, 37.9, 42.3, 55.5,
69.6, 70.0, 97.5, 107.4, 110.3, 119.9, 124.0, 126.4, 127.4, 127.6, 127.9, 128.4, 128.5,
133.8, 134.3, 136.5, 136.8, 137.7, 140.7, 156.4, 159.2, 159.3, 167.0, 190.8; HRMS
(ESI) m/z: [M + H]+ calcd. for C34H36NO5 538.2588, found: 538.2591.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
4ꢀ(Benzyloxy)ꢀN,Nꢀdiethylꢀ2ꢀformylꢀ6ꢀmethylbenzamide (23d). According to the
synthetic procedures similar to compound 23a, aldehyde 23d (2.3 g, 72% yield over 2
steps) was prepared from lactone 10d (2.5 g, 9.8 mmol) as a colorless oil: IR (CH2Cl2
cast, cmꢀ1) νmax 3034, 2976, 2935, 2873, 2750, 1698, 1629, 1603, 1455, 1317, 1286,
1150; 1H NMR (CDCl3, 400 MHz): δ 1.00 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H),
2.30 (s, 3H), 3.06ꢀ3.13 (m, 2H), 3.53ꢀ3.60 (m, 1H), 3.68ꢀ3.75 (m, 1H), 5.11 (s, 2H),
7.09 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.35ꢀ7.45 (m, 5H), 9.96 (s, 1H); 13C
NMR (CDCl3, 100 MHz): δ 12.5, 13.7, 18.5, 38.9, 42.6, 70.1, 110.9, 123.4, 127.4,
128.1, 128.6, 132.7, 133.6, 136.0, 136.8, 158.6, 168.0, 190.4; HRMS (ESI) m/z: [M +
H]+ calcd. for C20H24NO3 326.1756, found: 326.1748.
4ꢀ(2,4ꢀDimethoxyꢀ6ꢀmethylphenyl)ꢀ6ꢀmethoxyꢀ3ꢀoxoꢀ1,3ꢀdihydroisobenzofuranꢀ1
ꢀcarbonitrile (24a). To a stirred solution of aldehyde 23a (1.9 g, 4.9 mmol) in dry
DCM (10 mL) was added cat. 18ꢀcrownꢀ6 (132 mg, 0.50 mmol), cat. KCN (33 mg,
0.50 mmol) and TMSCN (744 mg, 7.50 mmol) at 0 . The resulting solution was
stirred at room temperature under N2 for 2 h and then DCM was evaporated to give
the crude residue, which was dissolved in HOAc (15 mL) and reacted at 60 under
N2 for 15 h. After reaction was complete, HOAc was evaporated under reduced
pressure to give the crude residue, which was recrystallized from diethyl ether and
nꢀhexane to afford diasteromeric mixture cyanophthalide 24a (1.5 g, 87% yield) as a
white solid: mp = 179–183 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3060, 3003, 2941, 2841,
1786, 1608, 1586, 1480, 1466, 1439, 1346, 1320, 1268, 1211, 1154; 1H NMR (CDCl3,
400 MHz): δ 2.02 (s, 1.8H), 2.08 (s, 1.2H), 3.65 (s, 1.2H), 3.69 (s, 1.8 H), 3.84 (s, 3H),
3.95 (s, 3H), 5.97 (s, 1H), 6.40 (d, J = 2.0 Hz, 0.4H), 6.41 (d, J = 2.4 Hz, 0.6H), 6.44
(d, J = 2.4 Hz, 0.6H), 6.46 (d, J = 2.0 Hz, 0.4H), 6.95 (d, J = 2.0 Hz, 1H), 7.05 (d, J =
13
2.0 Hz, 1H); C NMR (CDCl3, 100 MHz): δ 20.2, 20.3, 55.1, 55.5, 56.0, 64.2, 95.8,
95.9, 105.3, 106.4, 106.4, 114.5, 114.8, 114.8, 116.7, 116.7, 121.1, 137.6, 137.7,
140.3, 140.4, 144.9, 145.0, 157.7, 157.7, 160.5, 165.0, 165.9, 166.0; HRMS (ESI) m/z:
[M + Na]+ calcd. for C19H17NO5Na 362.0999, found: 362.1003.
4ꢀ(2,4ꢀBis(benzyloxy)ꢀ6ꢀmethylphenyl)ꢀ6ꢀmethoxyꢀ3ꢀoxoꢀ1,3ꢀdihydroisobenzofur
anꢀ1ꢀcarbonitrile (24b). According to the synthetic procedures similar to compound
24a, diasteromeric mixture cyanophthalide 24b (1.8 g, 75% yield) was prepared from
ACS Paragon Plus Environment

Page 21 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
aldehyde 23b (2.7 g, 5.0 mmol) as a white solid: mp = 66–70 ; IR (CH2Cl2 cast,
cmꢀ1) νmax 3064, 3033, 2929, 2870, 1787, 1607, 1588, 1480, 1455, 1346, 1320, 1213,
1155; 1H NMR (CDCl3, 400 MHz): δ 2.07 (1.8H), 2.10 (s, 1.2H), 3.91 (s, 1.8H), 3.92
(s, 1.2H), 4.89 (d, J = 12.4 Hz, 0.6H), 4.93 (d, J = 12.4 Hz, 0.6H), 4.94 (s, 0.8H), 5.05
(s, 0.8H), 5.06 (s, 1.2H), 5.84 (s, 0.4H), 5.94 (s, 0.6H), 6.53ꢀ6.57 (m, 2H), 6.95ꢀ7.46
(m, 12H); 13C NMR (CDCl3, 100 MHz): δ 20.5, 56.0, 56.1, 64.2, 64.2, 70.0, 70.3,
98.1, 98.3, 105.3, 105.3, 107.9, 107.9, 114.4, 114.5, 115.1, 117.6, 121.1, 121.1, 126.7,
126.9, 127.6, 127.6, 127.7, 128.0, 128.2, 128.4, 128.6, 136.5, 136.7, 136.8, 137.6,
137.9, 140.4, 140.5, 144.8, 144.8, 156.9, 157.0, 159.7, 159.8, 165.0, 165.0, 166.0,
166.1; HRMS (ESI) m/z: [M + Na]+ calcd. for C31H25NO5Na 514.1625, found:
514.1625.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
1,3ꢀdihydroꢀ6ꢀmethoxyꢀ4ꢀmethylꢀ3ꢀoxoisobenzofuranꢀ1ꢀcarbonitrile
(24c).
According to the synthetic procedures similar to compound 24a, cyanophthalide 24c
(1.7 g, 83% yield over 3 steps) was prepared from lactone 10c (1.8 g, 10.1 mmol) as a
white solid: mp = 164.0–165.5 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3050, 2945, 1760, 1619,
1
1589, 1489, 1319, 1148, 1011; H NMR (CDCl3, 400 MHz) δ 2.65 (s, 3H), 3.93 (s,
3H), 5.94 (s, 1H), 6.92 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 17.5, 56.1, 64.6, 104.3,
114.2, 114.3, 119.6, 142.5, 145.0, 165.3, 167.3; HRMS (EI) m/z: [M] calcd. for
C11H9NO3: 203.0582, found: 203.0581.
6ꢀ(Benzyloxy)ꢀ4ꢀmethylꢀ3ꢀoxoꢀ1,3ꢀdihydroisobenzofuranꢀ1ꢀcarbonitrile
(24d).
According to the synthetic procedures similar to compound 24a, cyanophthalide 24d
(1.3 g, 95% yield) was prepared from aldehyde 23d (1.6 g, 4.9 mmol) as a white solid:
mp = 168–169 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3092, 3065, 3035, 2930, 1776, 1613,
1
1596, 1347, 1314, 1150; H NMR (CDCl3, 400 MHz): δ 2.64 (s, 3H), 5.15 (d, J =
11.6 Hz, 1H), 5.20 (d, J = 11.6 Hz, 1H), 5.92 (s, 1H), 6.99 (s, 1H), 7.01 (s, 1H),
7.38ꢀ7.43 (m, 5H); 13C NMR (CDCl3, 100 MHz): δ 17.4, 64.5, 70.7, 105.1, 114.2,
114.4, 120.3, 127.5, 128.5, 128.8, 135.2, 142.5, 144.9, 164.3, 167.3; HRMS (ESI) m/z:
[M + H]+ calcd. for C17H14NO3 280.0968, found: 280.0968.
Tetarimycin A (1). To a stirred solution of enone 9a (192 mg, 0.50 mmol) and
benzylꢀprotecting cyanophthalide 24d (140 mg, 0.50 mmol) in dry THF (2.4 mL) at
0
was added LiHMDS solution (1 M in THF, 0.6 mL) via syringe under argon. The
resulting orange solution was stired at room temperature for 2 h (The orange solution
became dark orange). Saturated NH4Cl solution (5 mL) was added to quench the
reaction at 0
under argon. The aqueous layer was separated and extracted with
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 42
1
2
3
4
5
6
7
8
9
EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried
over MgSO4, filtered and concentrated to 10 mL, in which methanol (1 mL) and 10%
wt Pd/C (100 mg) were added, and then stirred at room temperature under H2 (1 atm)
for 15 h. The reaction mixture was diluted with EtOAc (20 mL), filtrated with celite
and concentrated to give the crude residue, which without purification was dissolved
in EtOAc (10 mL) and treated with DDQ (114 mg, 0.50 mmol) and stirred at room
temperature for 1 h. Saturated NaHCO3(aq) (5 mL) was added to quench the reaction
and extracted with EtOAc (20 mL). The organic extract was washed with saturated
NaHCO3(aq) and brine, dried over MgSO4, filtered and concentrated to give the crude
residue, which was purified by chromatography on silical gel with DCM followed by
EtOAc/DCM (2:1) to afford tetarimycin A (1) (115 mg, 67% yield over 3 steps) as an
orange solid:4e mp > 300 , decomp.; IR (KBr, cmꢀ1) νmax 3441, 3368 (br), 3032,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
1
2984, 2928, 1671, 1630, 1612, 1583, 1560, 1463, 1326, 1276, 1215, 1150; H NMR
(d6ꢀAcetone, 400 MHz): δ 1.82 (s, 6H), 2.61 (s, 3H), 6.31 (d, J =2.0 Hz, 1H), 6.73 (d,
J = 2.0 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 2.8 Hz, 1H), 9.65 (br s, 2H),
13.03 (s, 1H); 13C NMR (d6ꢀAcetone, 100 MHz): δ 21.6, 30.0, 39.9, 101.8, 106.3,
110.7, 111.9, 124.7, 124.9, 136.8, 137.6, 143.2, 155.6, 156.1, 161.8, 165.9, 166.0,
183.8, 186.5, 186.5; HRMS (EI) m/z: [M] calcd. for C21H16O6 364.0947, found:
364.0950.
(±)ꢀNaphthacemycin A9 (6). According to the synthetic procedures similar to
compound 1, compound 6 (293 mg, 57% yield over 3 steps) was prepared from enone
9a (384 mg, 1.00 mmol) and cyanophthalide 24a (339 mg, 1.00 mmol) as a dark
orange solid:4f, 6b mp = 126–127 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3364 (br), 3060, 2939,
1
2840, 1674, 1633, 1608, 1582, 1497, 1464, 1456, 1313, 1200, 1152; H NMR
(d4ꢀMeOH, 400 MHz): δ 1.79 (s, 3H), 1.85 (s, 3H), 2.05 (s, 3H), 3.61 (s, 3H), 3.84 (s,
3H), 3.95 (s, 3H), 6.22 (d, J = 2.0 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.50 (d, J = 2.4
Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H);
13C NMR (d4ꢀMeOH, 100 MHz): δ 21.0, 30.2, 30.7, 40.5, 55.9, 56.2, 56.6, 97.3, 102.1,
106.8, 108.1, 110.5, 110.6, 122.7, 125.5, 127.5, 136.9, 137.4, 138.3, 141.5, 156.5,
157.3, 158.4, 161.7, 164.3, 166.5, 167.2, 184.3, 186.5, 187.0; HRMS (ESI) m/z: [M +
Na]+ calcd. for C30H26O8Na 537.1520, found: 537.1520.
2,4,9ꢀTrimethoxyꢀ7,12,12ꢀtrimethyltetraceneꢀ5,6,11(12H)ꢀtrione (26). According
to the synthetic procedures similar to compound 1, but without hydrogenolysis,
compound 26 (146 mg, 72% yield over 2 steps) was prepared from enone S5 (116 mg,
0.50 mmol) and cyanophthalide 24c (102 mg, 0.50 mmol) as an orange solid: mp =
216–218 oC; IR (KBr, cmꢀ1) νmax 3314 (br), 3084, 2982, 2949, 2848, 1677, 1632, 1608,
1
1586, 1459, 1305, 1159; H NMR (CDCl3, 400 MHz): δ 1.80 (s, 6H), 2.73 (s, 3H),
3.90 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H), 6.42 (d, J = 2.0 Hz, 1H), 6.66 (d, J = 2.0 Hz,
ACS Paragon Plus Environment

Page 23 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1H) 7.01 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
δ 22.3, 29.1, 38.9, 55.4, 55.7, 56.0, 96.9, 102.3, 108.9, 116.2, 123.6, 123.9, 136.4,
138.7, 143.5, 150.4, 154.9, 161.4, 162.5, 164.3, 181.5, 183.4, 185.9; HRMS (EI) m/z:
[M] calcd. for C24H22O6 406.1416, found: 406.1421.
2,4ꢀdihydroxyꢀ9ꢀmethoxyꢀ7,12,12ꢀtrimethyltetraceneꢀ5,6,11(12H)ꢀtrione
(28).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
According to the synthetic procedures similar to compound 1, compound 28 (123 mg,
65% yield over 3 steps) was prepared from enone 9a (192 mg, 0.50 mmol) and
cyanophthalide 24c (102 mg, 0.50 mmol) as an orange solid: mp > 300 , decomp.;
IR (KBr, cmꢀ1) νmax 3314 (br), 3084, 3011, 2982, 2949, 2848, 1677, 1632, 1608, 1586,
1346, 1305, 1235, 1158; 1H NMR (d6ꢀDMSO, 400 MHz): δ 1.73 (s, 6H), 2.60 (s, 3H),
3.92 (s, 3H), 6.24 (d, J = 2.0 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 2.4 Hz,
1H), 7.35 (d, J = 2.4 Hz, 1H), 12.96 (s, 1H); 13C NMR (d6ꢀDMSO, 100 MHz): δ 21.0,
29.4, 38.6, 55.8, 100.7, 105.6, 108.8, 109.0, 123.0, 124.3, 135.2, 135.9, 141.5, 154.4,
154.7, 162.0, 164.1, 165.3, 182.9, 184.8, 185.1; HRMS (EI) m/z: [M] calcd. for
C22H18O6 378.1103, found: 378.1090.
9ꢀHydroxyꢀ2,4ꢀdimethoxyꢀ7,12,12ꢀtrimethyltetraceneꢀ5,6,11(12H)ꢀtrione
(29).
According to the synthetic procedures similar to compound 1, compound 29 (137 mg,
70% yield over 3 steps) was prepared from enone S5 (116 mg, 0.50 mmol) and
cyanophthalide 24d (140 mg, 0.50 mmol) as an orange solid: mp > 300 , decomp.;
IR (KBr, cmꢀ1) νmax 3272 (br), 3004, 2971, 2941, 2841, 1674, 1612, 1596, 1570, 1464,
1
1325, 1207; H NMR (d6ꢀDMSO): δ 1.74 (s, 6H), 2.57 (s, 3H), 3.84 (s, 3H), 3.90 (s,
3H), 6.60 (d, J = 2.2 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 7.26
(d, J = 2.4 Hz, 1H), 10.90 (br s, 1H); 13C NMR (d6ꢀDMSO, 100 MHz): δ 21.5, 28.7,
38.5, 55.7, 55.9, 97.4, 102.9, 111.3, 115.2, 122.1, 123.8, 136.2, 138.4, 142.4, 149.7,
154.7, 160.4, 161.3, 164.0, 180.2, 183.0, 185.4; HRMS (EI) m/z: [M] calcd. for
C23H20O6 392.1260, found: 392.1244.
2,9ꢀDihydroxyꢀ4ꢀmethoxyꢀ7,12,12ꢀtrimethyltetraceneꢀ5,6,11(12H)ꢀtrione
(30).
According to the synthetic procedures similar to compound 1, compound 30 (142 mg,
75% yield over 3 steps) was prepared from enone S7 (154 mg, 0.50 mmol) and
cyanophthalide 24d (140 mg, 0.50 mmol) as an orange solid: mp > 300 ; IR (KBr,
1
cmꢀ1) νmax 3297 (br), 2980, 2932, 2851, 1681, 1592, 1460, 1323, 1260; H NMR
(d6ꢀDMSO, 400 MHz): δ 1.69 (s, 6H), 2.56 (s, 3H), 3.78 (s, 3H), 6.44 (d, J = 2.0 Hz,
1H), 6.66 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 10.52
(br s, 1H), 10.82 (br s, 1H); 13C NMR (d6ꢀDMSO, 100 MHz): δ 21.6, 28.9, 38.2, 55.7,
98.2, 104.5, 111.3, 114.1, 122.2, 123.8, 136.2, 138.7, 142.4, 149.4, 154.8, 160.8,
161.2, 162.9, 180.0, 183.2, 185.5; HRMS (ESI) m/z: [M + Na]+ calcd. for
C22H18O6Na 401.0996, found: 401.0996.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 42
1
2
3
4
5
6
7
8
9
2,9ꢀDihydroxyꢀ7,12,12ꢀtrimethyltetraceneꢀ5,6,11(12H)ꢀtrione (31). According to
the synthetic procedures similar to compound 1, compound 31 (103 mg, 59% yield
over 3 steps) was prepared from enone S8 (139 mg, 0.50 mmol) and cyanophthalide
24d (140 mg, 0.50 mmol) as an orange solid: mp > 300 ; IR (KBr, cmꢀ1) νmax 3321
(br), 2982, 2933, 2729, 1669, 1609, 1594, 1568, 1464, 1324, 1304, 1264, 1244, 1118;
1H NMR (d6ꢀDMSO, 400 MHz): δ 1.73 (s, 6H), 2.56 (s, 3H), 6.89 (dd, J = 8.8, 2.4 Hz,
1H), 6.99 (d, 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.71 (d, J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
13
= 8.8 Hz, 1H), 10.71 (br s, 2H); C NMR (d6ꢀDMSO, 100 MHz): δ 21.2, 28.8, 38.0,
111.0, 112.0, 115.7, 122.8, 123.0, 123.8, 128.6, 135.8, 136.2, 141.9, 152.9, 153.4,
161.1, 162.7, 180.6, 183.4, 186.0; HRMS (ESI) m/z: [M + Na]+ calcd. for
C21H16O5Na 371.0890, found: 371.0890.
2ꢀHydroxyꢀ9ꢀmethoxyꢀ7,12,12ꢀtrimethyltetraceneꢀ5,6,11(12H)ꢀtrione
(32).
According to the synthetic procedures similar to compound 1, compound 32 (127 mg,
70% yield over 3 steps) was prepared from enone S8 (139 mg, 0.50 mmol) and
cyanophthalide 24c (102 mg, 0.50 mmol) as an orange solid: mp = 258–259 ; IR
(KBr, cmꢀ1) νmax 3248 (br), 3079, 2976, 2939, 2838, 1677, 1604, 1581, 1563, 1477,
1
1306, 1230, 1120, 1078, 1052; H NMR (d6ꢀDMSO, 400 MHz): δ 1.74 (s, 6H), 2.60
(s, 3H), 3.91 (s, 3H), 6.90 (dd, J = 8.8, 2.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.22 (d,
J = 2.4 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 10.58 (br s, 1H);
13C NMR (d6ꢀDMSO, 100 MHz): δ 21.1, 28.8, 38.0, 55.8, 108.9, 112.0, 115.8, 122.9,
123.0, 124.1, 128.6, 135.7, 136.0, 141.7, 153.1, 153.4, 162.0, 162.7, 180.4, 183.6,
185.7; HRMS (ESI) m/z: [M + Na]+ calcd. for C22H18O5Na 385.1046, found:
385.1045.
1ꢀChloroꢀ2,4,9ꢀtrihydroxyꢀ7,12,12ꢀtrimethyltetraceneꢀ5,6,11(12H)ꢀtrione
(34).
According to the synthetic procedures similar to compound 1 with hydrogenolysis
carried out for 2 h instead, compound 34 (115 mg, 58% yield over 3 steps) was
prepared from enone 9b (209 mg, 0.50 mmol) and cyanophthalide 24d (140 mg, 0.50
mmol) as an orange solid: mp > 300 ; IR (KBr, cmꢀ1) νmax 3441 (br), 2926, 1669,
1
1633, 1614, 1575, 1564, 1423, 1398, 1361, 1314, 1263, 1212, 1137, 1122; H NMR
(d6ꢀDMSO, 400 MHz): δ 1.96 (s, 6H), 2.55 (s, 3H), 6.53 (s, 1H), 7.01 (d, J = 2.8 Hz,
1H), 7.24 (d, J = 2.8 Hz, 1H), 10.81 (br s, 1H), 13.48 (s, 1H); 13C NMR (d6ꢀDMSO,
100 MHz): δ 21.2, 24.6, 38.9, 102.1, 109.8, 110.6, 111.2, 123.0, 123.9, 132.6, 136.3,
141.9, 149.4, 155.9, 161.2, 161.8, 163.0, 182.5, 184.9, 186.0; HRMS (ESI) m/z: [M +
Na]+ calcd. for C21H15ClO6Na 421.0449, found: 421.0451.
Compound 35 (a mixture of hemiketal and pꢀquinone, HK/Q)23 According to the
synthetic procedures similar to compound 1, compound 35 (186 mg, 55% yield over 3
steps) was prepared from enone 9a ( 269 mg, 0.70 mmol) and cyanophthalide 24b
(344 mg, 0.70 mmol) as a yellow solid: mp > 300 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3336
ACS Paragon Plus Environment

Page 25 of 42
The Journal of Organic Chemistry
1
2
3
4
5
(br), 3019, 2976, 2939, 2838, 1673, 1644, 1619, 1587, 1486, 1465, 1408, 1352, 1313,
1
1236, 1163, 1145; H NMR (d6ꢀAcetone, 400 MHz), HK:Q = 6.5/1, hemiketal (HK):
δ 1.81 (s, 3H), 1.84 (s, 3H), 2.72 (s, 3H), 3.97 (s, 3H), 5.77 (br s, 1H), 6.39 (d, J = 1.6
Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.80 (d, J = 1.6 Hz, 1H),
7.45 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 12.67 (s, 1H); quinone (Q): δ 1.82
(s, 3H), 1.85 (s, 3H), 1.96 (s, 3H), 3.99 (s, 3H), 6.30 (d, J = 1.6 Hz, 1H), 6.33 (s, 2H).
6.73 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 12.95 (s,
1H); 13C NMR (d6ꢀAcetone, 100 MHz), hemiketal (HK): δ 23.0, 26.8, 32.3, 40.4, 56.1,
91.3, 101.9, 104.6, 106.6, 107.6, 110.3, 114.5, 115.2, 118.6, 126.0, 130.9, 132.7,
137.6, 140.5, 151.1, 153.7, 157.2, 159.3, 161.3, 166.0, 166.7, 185.2, 188.5; HRMS
(ESI) m/z: [M + Na]+ calcd. for C28H22O8Na 509.1207, found: 509.1208.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
4ꢀHydroxyꢀ2,9ꢀdimethoxyꢀ7,12,12ꢀtrimethyltetraceneꢀ5,6,11(12H)ꢀtrione (27). To
a stirred solution of tetracene 26 (106 mg, 0.26 mmol) in dry MeCN (2.5 mL) was
added TMSI (520 mg, 2.6 mmol) dropwise at 0 under argon. The reaction mixture
was stirred at room temperature under argon for 15 h. After reaction was complete,
water was added to quench reaction at 0 . After MeCN was vaporated, EtOAc (20
mL) was added to extract the aqueous layer. The organic layer was washed with water
and brine, dried over MgSO4, filtered and concentrated to give the crude residue,
which was purified by chromatography on silical gel with DCM/nꢀhexane (2:1)
followed by DCM to afford compound 27 (45 mg, 44% yield) as an orange solid: mp
= 204–206 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3419 (br), 2975, 2937, 1673, 1633, 1609,
1
1573, 1301; H NMR (CDCl3, 400 MHz): δ 1.81 (s, 6H), 2.72 (s, 3H), 3.89 (s, 3H),
3.94 (s, 3H), 6.41 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 2.8 Hz,
1H), 7.42 (d, J = 2.8 Hz, 1H), 13.07 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 21.8,
29.9, 39.1, 55.6, 55.7, 98.7, 105.2, 108.7, 110.3, 123.7, 124.6, 135.1, 136.2, 142.9,
153.9, 155.3, 162.5, 165.4, 166.3, 183.5, 185.6, 185.6; HRMS (EI) m/z: [M] calcd. for
C23H20O6 392.1260, found: 392.1243.
5,5,10ꢀTrimethylꢀ6,11,12ꢀtrioxoꢀ5,6,11,12ꢀtetrahydrotetraceneꢀ1,3,8ꢀtriyl
triacetate (33). To a stirred solution of tetarimycin A (1) (146 mg, 0.40 mmol) in dry
pyridine (3 mL) at 0 was added Ac2O (412 mg, 381 ꢀL, 4.00 mmol) under N2. The
reaction mixture was stirred at 50 under N2 for 3 h. After reaction was complete,
water was added to quench reaction at 0 . Then the reaction mixture was extracted
with EtOAc (10 mL x 2). The combined organic layer was washed with 5% HCl(aq)
,
water and brine, dried over MgSO4, filtered and concentrated to afford compound 33
(190 mg, 97% yield) as a yellow solid: mp = 201–203 ; IR (CH2Cl2 cast, cmꢀ1) νmax
2959, 2935, 2867, 1587, 1458, 1430, 1362, 1314, 1209, 1154, 1054; 1H NMR (CDCl3,
400 MHz): δ 1.85 (s, 6H), 2.34 (s, 3H), 2.36 (s, 3H), 2.47 (s, 3H), 2.76 (s, 3H), 6.93 (d,
J = 1.6 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 2.4 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 42
1
2
3
4
5
6
7
8
1H); 13C NMR (CDCl3, 100 MHz): δ 21.0, 21.1, 22.0, 29.1, 38.8, 116.3, 117.3, 118.3,
121.3, 127.8, 130.6, 135.7, 136.3, 143.1, 150.6, 152.4, 153.5, 153.6, 154.4, 168.0,
168.6, 169.5, 180.1, 183.1, 184.8; HRMS (ESI) m/z: [M + Na]+ calcd. for
C27H22O9Na 513.1156, found: 513.1172.
Ethyl 2ꢀ(2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ4,6ꢀdimethoxybenzoate (36). To a stirred solution of
16b (8.4 g, 48.8 mmol) and sodium hydride (60%, 5.0 g, 125.0 mmol) in dry THF
(100 mL) at 0 was slowly added diethyl malonate (16.0 g, 100.0 mmol) under N2.
After the mixture was stired at 0 for 30 min, LDA (2.0 M, 25 mL,50 mmol) was
added over 2 h, keeping the temperature below 5 . The reaction mixture was slowly
added to a stirred solution of 5% aqueous HCl (200 mL) at 0 . EtOAc (50 mL x 2)
was added to extract the aqueous layer. The organic portions were combined, washed
with water and brine, dried over MgSO4, filtered and concentrated to give the crude
residue, which was purified by chromatography on silical gel to afford diethyl
homophthalate 36 (6.6 g, 46% yield) as a colorless oil:20 1H NMR (CDCl3, 400 MHz):
δ 1.25 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 3.66 (s, 2H), 3.81 (s, 3H), 3.82 (s,
3H), 4.14 (q, J = 7.2 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 6.41 (s, 2H); 13C NMR (CDCl3,
100 MHz): δ 13.7, 17.4, 19.0, 30.8, 64.5, 68.7, 104.7, 113.8, 114.3, 119.9, 142.3,
145.0, 164.9, 167.4.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
Ethyl 2ꢀ(2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ6ꢀhydroxyꢀ4ꢀmethoxybenzoate (37). To a stirred
solution of 36 (6.4 g, 21.5 mmol) in dry DCM (100 mL) at 0 was added BCl3 (1M
in DCM, 23 mL, 23 mmol ) under N2. After stirring at room temperature for 5 h,
reaction was quenched with ice water at 0 . The organic portion was washed with
sat. NaHCO3(aq) and water, dried over MgSO4, filtered and concentrated to give the
crude residue, which was recrystallized from diethyl ether and nꢀhexane to afford
1
phenol 37 (5.4 g, 89% yield) as white solid:24 mp = 63–65 ; H NMR (CDCl3, 400
MHz): δ 1.25 (t, J = 7.2 Hz, 3H), 1.37 (t, J = 7.2 Hz, 3H), 3.81 (s, 3H), 3.86 (s, 2H),
4.15 (q, J = 7.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 6.28 (d, J = 2.2 Hz, 1H), 6.42 (d, J
= 2.2, 1H), 11.79 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 13.9, 14.1, 42.8, 55.3, 60.6,
61.4, 100.0, 105.2, 112.5, 138.0, 163.8, 165.6, 170.8, 171.3.
2,4ꢀBis(benzyloxy)ꢀ7ꢀ(2,4ꢀbis(benzyloxy)ꢀ6ꢀmethylphenyl)ꢀ1ꢀchloroꢀ6ꢀhydroxyꢀ9ꢀ
methoxyꢀ12,12ꢀdimethyltetracenꢀ5(12H)ꢀone (40). To a stirred solution of 9b (209
mg, 0.50 mmol) and 39b (284 mg, 0.50 mmol) in dry THF (2.4 mL) at 0 was added
LiHMDS (1 M in THF, 0.6 mL) under N2. The mixture was then allowed to react at
room temperature under N2 for 3 h. After reaction was complete, KOH(aq) (2 N, 1 mL)
and MeOH (3 mL) were added sequentially to facilitate basic hydrolysis. The
resulting mixture was stirred at room temperature under N2 for 24 h. After reaction
was complete, solvent was evaporated and resulting aqueous solution was neutralized
to pH~4 with 5% HCl(aq) and then extracted with EtOAc (20 mL x 2). The combined
ACS Paragon Plus Environment

Page 27 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
organic layer was washed with water and brine, dried over MgSO4, filtered and
concentrated to give the corresponding acid intermediate. To a stirred solution of the
acid intermediate in dry toluene (5 mL) was added DBU (381 mg, 2.50 mmol) under
N2. The resulting mixture was heated to reflux for 4 h. After reaction was complete,
5% HCl(aq) (5 mL) was added to quench the reaction. The separated organic layer was
diluted with EtOAc (10 mL), washed with water, dried over MgSO4 and filtered to
give the solution, which in turn was added DDQ (114 mg, 0.50 mmol) in one portion.
The mixture was then allowed to react at room temperature under N2 for 1 h. After
reaction was complete, sat. NaHCO3(aq) was added to quench the reaction. The
separated organic layer was washed with water and brine, dried over MgSO4 and
filtered to give the crude residue, which was purified by chromatography on silical gel
to afford compound 40 (152 mg, 35% over 4 steps) as a yellow solid: mp = 110–
112 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3064, 3031, 2933, 2870, 1608, 1576, 1498, 1454,
1402, 1381, 1306, 1258, 1196, 1173, 1041, 1028; 1H NMR (CDCl3, 400 MHz): δ 2.08
(s, 3H), 2.09 (s, 3H), 2.10 (s, 3H), 3.95 (s, 3H), 4.93 (s, 2H). 5.06 (d, J = 11.4 Hz, 1H),
5.09 (d, J = 11.4 Hz, 1H), 5.14 (s, 2H), 5.17 (s, 2H), 6.51 (d, J = 2.4 Hz, 1H), 6.8 (d, J
= 2.4 Hz, 1H), 6.66 (s, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.93 (s, 1H), 6.94 (d, J = 2.4 Hz,
1H), 7.03ꢀ7.08 (m, 4H), 7.29ꢀ7.53 (m, 16H); 13C NMR (CDCl3, 100 MHz): δ 20.8,
30.0, 30.3, 39.7, 55.2, 70.0, 70.2, 71.0, 71.7, 98.3, 99.7, 105.5, 107.2, 107.7, 114.5,
114.7, 115.7, 117.4, 120.7, 126.5, 127.0, 127.0, 127.0, 127.8, 127.9, 127.9, 128.0,
128.3, 128.5, 128.7, 128.8, 135.6, 136.3, 137.0, 137.2, 137.5, 138.7, 140.7, 148.1,
149.8, 156.7, 158.3, 159.0, 159.9, 160.5, 165.2, 187.3; HRMS (ESI) m/z: [M + H]+
calcd. for C56H48ClO7 867.3083, found: 867.3081.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
2,4ꢀBis(benzyloxy)ꢀ7ꢀ(2,4ꢀbis(benzyloxy)ꢀ6ꢀmethylphenyl)ꢀ6ꢀhydroxyꢀ9ꢀmethoxyꢀ
12,12ꢀdimethyltetracenꢀ5(12H)ꢀone (46). According to the synthetic procedures
similar to compound 40, compound 46 (192 mg, 46% yield over 4 steps) was prepared
from enone 9a (192 mg, 0.50 mmol) and diethyl homophthalide 39b (284 mg, 0.50
mmol) as a yellow solid: mp = 89–90 ; IR (CH2Cl2 cast, cmꢀ1) νmax 3063, 3032,
1
2964, 2928, 2862, 1598, 1498, 1454, 1426, 1398, 1378, 1296, 1263, 1153; H NMR
(CDCl3, 400 MHz): δ 1.72 (s, 3H), 1.75 (s, 3H), 2.08 (s, 3H), 3.94 (s, 3H), 4.93 (s,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 42
1
2
3
4
5
6
7
8
9
2H), 5.06 (d, J = 11.2 Hz, 1H), 5.09 (d, J = 11.2 Hz, 1H), 5.14 (s, 2H), 5.18 (s, 2H),
6.51 (d, J = 2.4 Hz, Hz, 1H), 6.58 (d, J = 2.4 Hz, 2H), 6.82 (d, J = 2.8 Hz, 1H), 6.88
(d, J = 2.4 Hz, 1H), 6.93 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 7.02ꢀ7.04 (m ,4H),
7.30ꢀ7.61 (m, 16H); 13C NMR (CDCl3, 100 MHz): δ 20.7, 33.5, 34.2, 38.9, 55.1, 69.9,
70.0, 70.7, 98.2, 99.0, 104.6, 105.8, 107.1, 109.2, 113.3, 114.0, 117.9, 120.5, 126.4,
126.5, 126.9, 127.5, 127.5, 127.7, 127.8, 127.9, 128.2, 128.4, 128.4, 128.6, 135.8,
136.4, 136.9, 137.1, 137.4, 138.6, 140.0, 144.7, 155.1, 156.5, 158.2, 159.7, 161.9,
163.1, 165.5, 187.6; HRMS (ESI) m/z: [M + H]+ calcd. for C56H49O7 833.3473,
found: 833.3470.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
2,4ꢀBis(benzyloxy)ꢀ7ꢀ(2,4ꢀdimethoxyꢀ6ꢀmethylphenyl)ꢀ6ꢀhydroxyꢀ9ꢀmethoxyꢀ12,1
2ꢀdimethyltetracenꢀ5(12H)ꢀone (47). According to the synthetic procedures similar
to compound 40, compound 47 (92 mg, 27% yield over 4 steps) was prepared from
enone 9a (192 mg, 0.50 mmol) and diethyl homophthalide 39a (208 mg, 0.50 mmol)
as a yellow solid: mp = 98–99 ; IR (CH2Cl2 cast, cmꢀ1) νmax 2924, 2853, 1598, 1498,
1454, 1426, 1398, 1377, 1319, 1296, 1200, 1152; 1H NMR (CDCl3, 400 MHz): δ 1.71
(s, 3H), 1.74 (s, 3H), 1.99 (s, 3H), 3.64 (s, 3H), 3.88 (s, 3H), 3.94 (s, 3H), 5.13 (s, 2H),
5.18 (s, 2H), 6.43 (d, J = 2.4 Hz, 1H), 6.45 (d, J = 2.8 Hz, 1H), 6.58 (d, J = 2.2 Hz,
1H), 6.78 (d, J = 2.8 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 7.04 (d, J = 2.8 Hz, 1H), 7.29
13
(s, 1H), 7.29ꢀ7.46 (m, 8H), 7.59 (d, J = 7.6 Hz, 2H); C NMR (CDCl3, 100 MHz): δ
20.6, 33.6, 34.3, 39.0, 55.1, 55.2, 55.8, 70.1, 70.8, 95.8, 99.1, 104.7, 105.5, 105.7,
109.2, 113.4, 114.1, 117.8, 120.5, 125.6, 126.6, 127.6, 127.6, 128.3, 128.5, 128.7,
135.9, 136.5, 137.1, 138.7, 140.1, 144.8, 155.2, 157.6, 159.0, 159.7, 161.9, 163.2,
165.6, 187.6; HRMS (ESI) m/z: [M + H]+ calcd. for C44H41O7 681.2847, found:
681.2846.
(±)ꢀFasamycin A (2). To a stirred solution of compound 40 (174 mg, 0.20 mmol) in
dry DCM (2 mL) at ꢀ78 was added BBr3 (251 mg, 95 ꢀL, 1.00 mmol) under N2.
The mixture was then allowed to react at room temperature under N2 for 5 h. After
reaction was complete, ice water (5 mL) was added to quench the reaction. DCM was
then evaporated to give the crude residue, which was extracted with EtOAc (20 mL).
The organic portion was was washed with sat. NaHCO3(aq) and brine, dried over
ACS Paragon Plus Environment

Page 29 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
MgSO4, filtered and concentrated to give the crude residue, which was purified by
chromatography on silical gel to afford (±)ꢀfasamycin A (75 mg, 76%) as a yellow
solid:4d mp > 300 ; IR (KBr, cmꢀ1) νmax 3412 (br), 2979, 2937, 1702, 1606, 1594,
1
1560, 1453, 1398, 1384, 1338, 1251, 1183, 1160, 1112; H NMR (d4ꢀMeOH, 400
MHz): δ 1.88 (s, 3H), 2.04 (s, 3H), 2.06 (s, 3H), 6.23 (d, J = 2.4 Hz, 1H), 6.26 (d, J =
2.4 Hz, 1H), 6.44 (s, 1H), 6.71 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 7.34 (s,
1H); 13C NMR (d4ꢀMeOH, 100 MHz): δ 20.8, 30.3, 30.4, 40.8, 101.0, 103.7, 106.4,
108.9, 109.6, 110.1, 113.5, 117.1, 117.9, 122.8, 124.5, 138.4, 141.0, 143.6, 149.3,
150.1, 155.6, 157.6, 160.4, 163.0, 165.6, 166.7, 191.7; HRMS (ESI) m/z: [M + Na]+
calcd. for C27H21ClO7Na 515.0868, found: 515.0865.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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
57
58
59
60
1ꢀChloroꢀ7ꢀ(2,4ꢀdihydroxyꢀ6ꢀmethylphenyl)ꢀ2,4,6ꢀtrihydroxyꢀ9ꢀmethoxyꢀ12,12ꢀdi
methyltetracenꢀ5(12H)ꢀone (41). To a stirred solution of compound 40 (174 mg,
0.20 mmol) in dry DCM (2 mL) at ꢀ78 was added BBr3 (251 mg, 95 ꢀL, 1.00 mmol)
under N2. The mixture was then allowed to react at ꢀ40 under N2 for 10 mins. After
reaction was complete, ice water (5 mL) was added to quench the reaction. DCM was
then evaporated to give the crude residue, which was extracted with EtOAc (20 mL).
The organic layer was washed with sat. NaHCO3(aq) and brine, dried over MgSO4,
filtered and concentrated to give the crude residue, which was purified by
chromatography on silical gel to afford compound 41 (94 mg, 93% yield) as a yellow
solid: mp = 143–145 ; IR (KBr, cmꢀ1) νmax 3307 (br), 2924, 2853, 2734, 1704, 1608,
1
1594, 1558, 1455, 1397, 1372, 1336, 1253, 1201, 1172, 1151; H NMR (d4ꢀMeOH,
400 MHz): δ 1.87 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 3.97 (s, 3H), 6.23 (d, J = 2.4 Hz,
1H), 6.26 (d, J = 2.4 Hz, 1H), 6.46 (s, 1H), 6.75 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 2.4
Hz, 1H), 7.50 (s, 1H); 13C NMR (d4ꢀMeOH, 100 MHz): δ 20.9, 30.3, 30.4, 40.9, 56.0,
100.9, 103.7, 106.9, 106.9, 108.9, 109.7, 113.5, 117.8, 118.5, 122.9, 124.3, 138.4,
140.5, 143.4, 149.6, 150.1, 155.6, 157.7, 162.3, 162.9, 165.6, 166.3, 191.8; HRMS
(ESI) m/z: [M + H]+ calcd. for C28H24ClO7 507.1205, found: 507.1204.
7ꢀ(2,4ꢀDihydroxyꢀ6ꢀmethylphenyl)ꢀ2,4,6ꢀtrihydroxyꢀ9ꢀmethoxyꢀ12,12ꢀdimethyltet
racenꢀ5(12H)ꢀone (42). To a stirred solution of compound 46 (167 mg, 0.20 mmol) in
MeOH/EtOAc (1 mL/5 mL) was added 10% wet Pd/C (50 mg). The mixture was then
allowed to react at room temperature under 1 atm. H2 for 15 h. After the reaction was
complete, it was filtrated with celite and concentrated to afford 42 (94 mg, 99% yield)
as a bright yellow solid: mp = 211–213 ; IR (KBr, cmꢀ1) νmax 3422 (br), 3278 (br),
1
2980, 2927, 2857, 1693, 1614, 1601, 1460, 1375, 1342, 1276, 1200, 1166, 1148; H
NMR (d4ꢀMeOH, 400 MHz): δ 1.72 (s, 3H), 1.74 (s, 3H), 1.87 (s, 3H), 3.97 (s, 3H),
6.21 (d, J = 2.4 Hz, 1H), 6.23 (d, J = 2.0 Hz, 1H), 6.26 (d, J = 2.0 Hz, 1H), 6.67 (d, J
= 2.4 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 7.52 (s, 1H); 13C
NMR (d4ꢀMeOH, 100 MHz): δ 20.9, 34.6, 34.8, 39.8, 56.0, 100.9, 102.2, 107.1, 107.1,
ACS Paragon Plus Environment