Enantioselective Synthesis of des-Epoxy-Amphidinolide N

Article abstract of DOI:10.1021/jacs.8b11827

The synthesis of des-epoxy-amphidinolide N was achieved in 22 longest linear and 33 total steps. Three generations of synthetic endeavors are reported herein. During the first generation, our key stitching strategy that highlighted an intramolecular Ru-catalyzed alkene-alkyne (Ru AA) coupling and a late-stage epoxidation proved successful, but the installation of the α,α′-dihydroxyl ketone motif employing a dihydroxylation method was problematic. Our second generation of synthetic efforts addressed the scalability problem of the southern fragment synthesis and significantly improved the efficiency of the atom-economical Ru AA coupling, but suffered from several protecting group-based issues that proved insurmountable. Finally, relying on a judicious protecting group strategy together with concise fragment preparation, des-epoxy-amphidinolide N was achieved in a convergent fashion. Calculations disclose a hydrogen-bonding bridge within amphidinolide N. Comparisons of ¹³C NMR chemical shift differences using our synthetic des-epoxy-amphidinolide N suggest that amphidinolide N and carbenolide I are probably identical.

Full text of DOI:10.1021/jacs.8b11827

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Article
Enantioselective Synthesis of des-epoxy-Amphidinolide N
Barry M. Trost, Wen-Ju Bai, Craig E. Stivala, Christoph Hohn,
Caroline Poock, Marc Heinrich, Shiyan Xu, and Jullien Rey
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b11827 • Publication Date (Web): 20 Nov 2018
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Enantioselective Synthesis of des-epoxy-Amphidinolide N
Barry M. Trost,* Wen-Ju Bai, Craig E. Stivala, Christoph Hohn, Caroline Poock, Marc Heinrich, Shiyan Xu, Jul-
lien Rey
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Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
ABSTRACT: The synthesis of des-epoxy-amphidinolide N was achieved in 22 longest linear and 33 total steps. Three generations of syn-
thetic endeavors are reported herein. During the first generation, our key stitching strategy that highlighted an intramolecular Ru-catalyzed
alkene-alkyne (Ru AA) coupling and a late-stage epoxidation proved successful, but the installation of the α,α’-dihydroxyl ketone motif em-
ploying a dihydroxylation method was problematic. Our second generation of synthetic efforts addressed the scalability problem of the
southern fragment synthesis and significantly improved the efficiency of the atom-economical Ru AA coupling, but suffered from several pro-
tecting group-based issues that proved insurmountable. Finally, relying on a judicious protecting group strategy together with concise frag-
ment preparation, des-epoxy-amphidinolide N was achieved in a convergent fashion. Calculations disclose a hydrogen-bonding bridge within
amphidinolide N. Comparisons of 13C NMR chemical shift differences using our synthetic des-epoxy-amphidinolide N suggest that am-
phidinolide N and carbenolide I are probably identical.
INTRODUCTION
been impeded by a lack of material; the natural isolation yield
(0.0009%) is meager, and biological efforts to improve product
titers by modifying the culturing process have proven futile.4a The
chemical structure of amphidinolide N was initially proposed to
include two hydroxyl groups at C21 and C24 positions,5a which was
revised two decades later as a THF ring along with stereochemical
assignment relying on NMR studies.5b Within the amphidinolide
family, similar tetrahydrofuran (THF) rings are common, such as
in amphidinolide F.6 However, a tetrahydropyran (THP) moiety is
much scarcer, and a combination of THF and THP motifs has only
been discovered in amphidinolide N (1), making it the most com-
plicated family member with a total of 13 stereocenters. Conse-
quently, amphidinolide N (1) has been an elusive target in spite of
two decades of extensive synthetic studies.7 Furthermore, synthesis
of amphidinolide N (1) could also provide insight into the struc-
ture of caribenolide I (2), which was isolated from a free-swimming
dinoflagellate of the genus Amphidinium in Caribbean Sea.8 Har-
vested from different organisms on opposite hemispheres, am-
phidinolide N (1) and caribenolide I (2) possess comparable levels
of cytotoxicity and identical connectivity, although the stereochem-
istry of the latter was never assigned. Previously, exploration of the
structural relationship between amphidinolide N (1) and cari-
benolide I (2) was unrealistic, as their isolation spectra were rec-
orded in C6D6 and CD2Cl2, respectively. Herein we report an enan-
tioselective synthesis of des-epoxy-amphidinolide N (41) along-
side our findings about the relationship between amphidinolide N
(1) and caribenolide I (2).
Macrolides provide a remarkable source for drug development due
to their marvelous structural diversity and biological activity. For
example, everolimus, an anti-rejection drug that is listed as one of
the Top 100 Brand Name Drugs by Retail Sales in 2016, is essen-
tially a rapamycin derivative. Therefore, syntheses and biological
assessments1 of macrolides2 and their analogues3 have been enthu-
siastically pursued.
HO
HO
HO
Me
Me
HO
H
15
HO
O
O
21
20
H
29
33
Me
OH
OH
H
24
O
H
OH
Me
25
Me
nBu
OH
OH
32
O
OH
OH
O
10
5
1
O
O
O
O
O
O
Me
30
Me
31
amphidinolide N (initial)
Kobayashi, 1994
amphidinolide N (revised, 1)
Kobayashi, 2013
HO
Biological Activity:
HO
O
OH
H
O
amphidinolide N (1)
L1210 (IC50= 80 pM)
KB (IC50= 90 pM)
Me
nBu
Me
OH
OH
O
O
O
caribenolide I (2)
HCT 116 & HCT 116/VM 46 (IC50= 1.6 nM)
in vivo P388 (T/C: 150 at a dose of 0.03 mg/kg)
O
Me
caribenolide I (2)
Shimizu, 1995
Figure 1. Structure and biological activity of amphidinolide N (1)
and caribenolide I (2).
The amphidinolide family of natural products, isolated from
the symbiotic dinoflagellates of the genus Amphidinium in Okina-
wa, is a unique class of cytotoxic macrolides.4 Over 40 members
have been disclosed by Kobayashi, among which amphidinolide N
(1) exhibits the most potent cytotoxicity against murine lymphoma
L1210 and human epidermoid carcinoma KB cell lines, with IC50
values of 80 and 90 pM, respectively (Figure 1).5 Further evalua-
tion of amphidinolide N as a potential chemotherapeutic agent has
RESULTS AND DISCUSSION
Retrosynthetically, amphidinolide N (1) was disconnected in-
to two subunits 5 and 6 of similar size and structural complexity
(Scheme 1). We expected to perform the C4-C5 epoxidation and
the C15-hemiacetal formation on macrocycle 3 at a late stage. The
intermediate 3 might arise from macrocyclic compound 4 by in-
stalling the desired α,α’-dihydroxy ketone motif alongside a C9-
1
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Page 2 of 12
improved the yield to 33%.18 Tuning the amounts of the CuI /
OH oxidation. As the construction of the α,α’-dihydroxyl ketone
moiety seemed challenging, we initially proposed two approaches,
including a dihydroxylation method9 and a Rubottom oxidation
strategy.10 The compound 4, in turn, could be accessed by atom-
economically11 stitching fragments 5 and 6 together employing our
Ru-catalyzed alkene-alkyne coupling12 and an esterification.
1
2
3
4
5
6
7
8
benzoquinone additives slightly enhanced the yield to 37%, while
further varying reaction concentration, temperature, or the reagent
stoichiometry proved futile. Nevertheless, TBS protection of the
metathesis product 10 followed by chemoselective protodesilyla-
tion of the primary TBS group using CSA in MeOH delivered al-
cohol 11. A succeeding Moffatt-Swern oxidation19 gave an alde-
hyde intermediate that was immediately subjected to Marshall
coupling13 with chiral propargyl mesylate 12.20 The stereochemis-
try of the newly generated C9-OH was confirmed by converting
alcohol 13 to the corresponding mandelic esters,21 while the C10
stereocenter was established by ROESY analysis of an intramolecu-
lar hydrosilylation product of alkyne 13.22 Treatment of the
homopropargyl alcohol 13 with Me3SnOH23 followed by a tri-
ethylsilyl- (TES-) protection of the secondary alcohol provided 800
mg of the southern fragment 5 in 8 steps from known compound 7.
Scheme 1. Initial Retrosynthetic Analysis
HO
O
OPMB
19
H
14
HO
15
O
O
Me
Me
9
OH
H
installation of
α,α'-di-OH ketone
H
O
H
O
Me
Me
Me
epoxidation
O
Me
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
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
nBu
H
9
OH
OH
O
THP
formation
C9-OH
oxidation
5
nBu
O
5 TBSO
O
O
O
4
O
PMBO
O
Me
4
Me
3
amphidinolide N (1)
northern fragment (6)
R = H or OH
R
R = H or OH
OPMB
R
OPMB
13
13
Scheme 3. Northern Fragment Synthesis (1st-Gen.)
Me
OP
Ru AA
coupling
OP
Me
12
14
H
12
H
O
O
Me
Et3SiO
PMBO
Keck allylation
Me
H
esterification
H
9
Krische allylation
nBu
19
TBSO
O
OH
HO
nBu
OPMB
Et3SiO
TBSO
OH
OPMB
H
HO
O
PMBO
southern fragment (5)
installation of α,α'-di-OH ketone
O
a. NaH, PMBBr
OTroc
Me
H
H
4
Me
O
O
b. 2-methylbut-2-ene
THF, BH3•Me2S;
then NaOH, H2O2
O
H
H
H
TBDPSO
nBu
TBDPSO
nBu
Pd-AAA
HO
nBu
15
16, 93%, 2 steps
14
a. dihydroxylation approach (R = H)
O
OH
15
14
16
16
14
15
14
16
OPMB
OPMB
16
15
c. [Ir(COD)Cl]2
(S)-BINAP, THF
4-Cl-3-NO2BzOH
O
O
OP
(P = H)
d. TrocCl, Pyr.
DCM, 0 °C
OH OH
OH
OTroc
Me
Me
H
H
O
O
Cs2CO3, 100 °C
e. HF•Pyr.
Pyr., THF
b. Rubottom oxidation approach (R = OH)
H
H
OAc
O
OTMS
16
O
15
[O]
TBDPSO
17, 87%
nBu
HO
nBu
16
14
14
16
15
14, 85%, 2 steps
800 mg prepared
15
14
OP
OP
OH OP
I. The First Generation of Synthetic Endeavors
The northern fragment synthesis exploited a late-stage Krische
allylation24 to construct the homoallylic alcohol motif (Scheme 3).
The starting alcohol 15 was prepared in 8 steps from commercially
available materials,7c highlighting a Pd-asymmetric allylic alkylation
(Pd-AAA) to build the trans-THF ring25 and a Keck allylation26 to
extend the carbon chain. The C19-stereochemistry of alcohol 15
was confirmed by converting it to the corresponding mandelic
esters.21 Masking the known alcohol 15 as its PMB ether, followed
by hydroboration/oxidation generated the primary alcohol 16.
The subsequent Ir-catalyzed allylation produced homoallylic alco-
hol 17 in excellent yield and diastereoselectivity.24 The C16-OH
stereochemistry of 17 was verified by converting the alcohol to the
corresponding mandelic esters.21 Troc-protection of alcohol 17
followed by removal of the TBDPS protecting group afforded 800
mg of the northern fragment 14.
The first generation of the southern fragment synthesis fea-
tured a Marshall coupling to install the propargyl group,13 an enyne
metathesis to create the diene,14 and an Evans aldol15 to generate
the syn aldol-adduct (Scheme 2). The synthesis commenced with
PMB protection of the known propargyl alcohol 7, prepared in 4
steps from commercial materials via an enzymatic resolution.16
Meanwhile, the known allylic alcohol 9 was accessed in 2 steps
utilizing an Evans aldol reaction.7a The subsequent enyne metathe-
sis was carefully investigated. While the typical conditions (10
mol% Grubbs-II, 10 mol% benzoquinone, DCE, 60°C)17 provided
diene 10 in meager yields ranging from 15-25%, addition of CuI
Scheme 2. Southern Fragment Synthesis (1st-Gen.)
Me
Evans aldol
Marshall
b. Grubbs II (10 mol%)
CuI (30 mol%), Et2O, 40 °C
2,6-Cl2-1,4-benzoquinone
With both the southern and northern fragments in hand, we
advanced the synthesis by testing our key stitching strategy: the Ru
AA coupling and the esterification (Scheme 4). Ru AA coupling is
known to generate both linear and branched products.12 For exam-
ple, linear selectivity was seen in an intermolecular Ru AA coupling
during our synthesis of lasonolide A.27 Unlike the prevalent inter-
molecular couplings, the intramolecular variant of this reaction is
incredibly rare. To date, only three examples have been reported in
the syntheses of amphidinolide A,28 pinnatoxin A,29 and lau-
limalide,30 and branched selectivity was observed in all cases.
Therefore, it seemed wise to first join the southern and northern
fragments together using an intermolecular Ru AA coupling to
obtain the linear selectivity, then perform an esterification to close
the macrocyclic ring. However, preliminary results indicated that
enyne
metathesis
TBSO
RO
Me
OH OMe
Et3SiO
TBSO
OH
a. NaH
PMBBr
85%
R = H (7)
R = PMB (8)
O
PMBO
O
Me
9
Me
5
c. TBSOTf, DCM
2,6-lutidine, -78 °C
HO
TBSO
OMe
O
TBSO
PMBO
OH OMe
PMBO
O
d. CSA, 0 °C
MeOH/DCM
Me
Me
11, 58%, 2 steps
10, 37%
Me
e.
(COCl)2, DMSO
Me
g. Me3SnOH
DCE, 75 °C
Et3N, DCM, -78 °C to rt
10
9
5
800 mg
DMAP, DCM, rt prepared
70%, 2 steps
f.
HO
PMBO
TBSO
OMe
O
Pd(dppf)Cl2•CH2Cl2
THF/HMPA 3:1
InI, 0 °C,
h. Et3SiCl, Im.
Me
Me
12
OMs
Me
13, 3.2:1 dr
88%, 2 steps
2
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Scheme 4. Assembly of the 1st-Generation of Southern and Northern Fragments
1
2
3
4
5
6
7
8
OPMB
I.
13
II. Ru AA coupling for macrocyclization
OPMB
OPMB
OTroc
13
12
Me
12
OPMB
OTroc
OTroc
H
Me
Me
Et3SiO
PMBO
c. CpRu(MeCN)3PF6
(25 mol%)
DME, rt, conc.
Me
H
H
O
TrocO
a. Et3N, DMAP
2,4,6-Cl3-BzCl
Me
O
O
H
Me
Me
HO
PMBO
9
H
H
H
25
+
9
nBu
RO
PMBO
TBSO
O
R'
d. Et3SiCl, Im.
DMAP, DMF, rt
Me
benzene, 75 °C
92%
O
TrocO
HO
nBu
nBu
TBSO
O
HO
Me
9
9
14
H
O
R
9
Et3SiO
TBSO
OH
O
Me
TBSO
O
nBu
S
Me
Me
Ru
PMBO
O
b. CSA
MeOH/DCM
97%
R = Et3Si (18)
R = H (19)
20, 39%, 2 steps
(69% brsm)
O
Me
5
Me
exocyclic ruthenocycle
e. CSA
MeOH/DCM
branched product
f. DMP, Pyr., DCM
77%, 2 steps
9
OPMB
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
OPMB
15
16
OPMB
O
R'
OTroc
OPMB
Me
Me
HO
PMBO
linear product
16
OTroc
TrocO
Me
14
H
H
9
OTroc
OH
Me
Me
14 15
H
O
O
H
R
O
Ru
O
Me
Me
O
Me
H
h. Ti(OiPr)4
TBHP
O
H
O
9
Me
H
Me
O
H
Me
nBu
TBSO
nBu
O
OR
O
H
Me
endocyclic ruthenocycle
5
nBu
O
O
4Å MS, DCM
5
O
nBu
O
TBSO
O
PMBO
O
PMBO
O
4
Me
4
O
Me
PMBO
O
Me
R = TBS (21)
R = H (22)
23, 76%
1:1 dr
g. HF•Pyr.
THF, 89%
Me
3
the C9-OTES needed to be unmasked to run the Ru AA coupling
and unfortunately, the C9-OH instead of the C25-OH reacted in
the following macrolactonization. As a result, we decided to reor-
der the sequence. Analysis of the ruthenacyclopentene intermedi-
ates for both the branched and linear products suggested that the
branched product would likely be formed due to the preference for
placing the Cp ligand in an exocyclic position with respect to the
newly formed macrocycle (Scheme 4, II). In contrast, a linear
product would force the Cp ligand endocyclic and might be disfa-
vored due to transannular interactions with the bridging macrocy-
cle. However, we were also cognizant that the C9-OH could po-
tentially occupy the open coordination site on the ruthenium cata-
lyst, stabilizing the endocyclic ruthenacyclopentene intermediate
and consequently favoring the linear product. Indeed, directing
groups proximal to a ruthenacyclopentene are known to have pro-
found effects on linear/branched selectivity as well as reactivity.31
With this in mind, we started to study this crucial Ru-catalyzed
macrocylization.
the obtained allylic alcohol 22 as an advanced model to investigate
the challenging late-stage C4-C5 epoxidation.
Hydroxyl-directed epoxidation has been extensively studied,33
but this transformation has been problematic in previous synthetic
endeavors.7b Considering the challenges of this reaction, we first
screened a series of epoxidation conditions on a relevant substrate
10, and promising results were listed in Table 1 (for more details,
see SI, Table S2). DMDO34 gave the undesired chemoselectivity
(entry 1), whereas the remaining reagents all preferentially formed
epoxide 24. mCPBA provided poor 1.6:1 diastereoselectivity (en-
try 2).35 While Sharpless conditions36 gave no conversion, the mod-
ified conditions (without use of chiral ligand)37 improved the dia-
38
stereoselectivity to 3:1 (entry 3). Gladly, both VO(acac)2 and an
optimized Payne epoxidation39 also delivered good diastereoselec-
tivity (entries 4-5). Next, these conditions (entries 3-5) were ap-
plied to macrocycle 22. Unfortunately, the Payne epoxidation and
VO(acac)2 gave no conversion. Ultimately, we found that the mod-
ified Sharpless conditions (entry 3) effectively delivered the desired
epoxide 23, albeit as a 1:1 mixture of diastereomers (Scheme 4).
The isolated epoxide 23 was unstable, suggesting to us that this
allylic epoxidation should be carried out as late as possible.40
To examine our key Ru AA coupling, Yamaguchi
esterification32 was first deployed to cleanly join fragments 5 and
14 together, offering ester 18 in 92% yield (Scheme 4, I). Removal
of the C9-OTES delivered macrocyclic precursor 19. To our de-
light, employing the typical Ru-AA coupling conditions (10 mol%
Table 1. Epoxidation of Diene 10.a
12
TBSO
OH OMe
[RuCp(MeCN)3]PF6, 0.001M acetone, 23°C) provided ~30%
PMBO
O
conversion with exclusive formation of the linear product. It is
worth noting that no reaction was observed if the C9-OH was pro-
tected as its TES ether (18), highlighting the dramatic selectivity
effect of a proximal coordinating group. Optimizing the reaction
conditions by varying the solvent, temperature, concentration, and
catalyst loading further improved the coupling efficiency (see SI,
Table S1). To alleviate decomposition issues with the coupling
product, the reaction mixture was immediately treated with TESCl
before chromatography purification to deliver macrocycle 20 in
39% yield. The subsequent C9-OTES cleavage followed by Dess-
Martin oxidation smoothly afforded ketone 21. Converting ketone
21 into diketone 3 proved unsuccessful: our preliminary results
showed that deprotection of the C16-OTroc followed by C14-C15
dihydroxylation worked, but subsequent differentiation of the triols
at the C14-16 positions was extremely problematic. Although we
were unable to install the α,α’-dihydroxyl ketone moiety, we decid-
O
TBSO
PMBO
OH OMe
Me
epoxidaton
24
25
O
TBSO
PMBO
OH OMe
Me
10
O
O
Me
entry
conditions
DMDO
mCPBA
convb
100%
100%
24:25b
0:100
91:9
dr (24)b
N/A
1.6:1
1
2
Ti(OiPr)4, TBHP
4Å MS
VO(acac)2, TBHP
5Å MS
3
4
5
100%
100%
72
100:0
100:0
88:12
3:1
>1:20
6:1
3,5-di(CF3)-benzonitrile
H2O2, KHCO3
aAll reactions were carried out on a 10 mg scale. bConversions, product
ratios and diastereoselectivities of 24 were determined by H NMR of
1
the crude reaction mixture.
ed to cleave the C3-OTBS of ketone 21 with HF•pyridine and use
3
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Overall, during the first generation of our synthetic efforts, we
H. With this aldehyde in hand, an asymmetric Mukaiyama aldol42
1
2
3
4
5
6
7
8
were able to 1) address the preparation of both southern and
northern fragments; 2) demonstrate the viability of Ru AA cou-
pling and esterification as the key stitching strategy; 3) achieve a
highly chemoselective epoxidation on a complicated late-state mac-
rocyclic compound. In addition, among all the Ru-catalyzed intra-
molecular alkene-alkyne macrocyclizations, our transformation
represents the first example in which a linear product was generat-
ed. More importantly, key challenges were identified, including 1)
the current synthetic route of the southern fragment relied on an
inefficient enyne metathesis that limited the scalability of the frag-
ment preparation; 2) the intramolecular Ru AA coupling gave low
yield, and improving the coupling efficiency by performing an in-
termolecular Ru AA coupling that could preclude the competing
macrolactionization problem between the C9-OH and C25-OH
with silyl enol ether 32 was implemented to afford 2.5 grams of
syn-adduct 33 in excellent yield. Ensuing TBS-protection of the
secondary alcohol, chemoselective removal of the primary TBS
ether, and Dess-Martin oxidation43 delivered aldehyde 34, which
participated in a Marshall coupling13 with propargyl mesylate 1220
to diastereoselectively form homopropargyl alcohol 35. Overall,
1.5 grams of fragment 35 could be conveniently accessed in 11
steps from commercial materials using our newly designed synthet-
ic approach. Hydrolysis of the thioester using LiOH and H2O2
released the free carboxylic acid 5. The optical rotation and NMR
data of this newly prepared acid matched that of compound 5 that
was previously synthesized during our first generation of synthetic
efforts, therefore confirming the stereoselectivity of our newly de-
veloped southern fragment synthesis.
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
would be greatly appreciated; 3) the installation of the α,α’-
dihydroxyl ketone moiety through a dihydroxylation method was
not achievable, suggesting that we explore a Rubottom oxidation
approach.
Scheme 6. Northern Fragment Synthesis (2nd-Gen.)
a. (COCl)2, DMSO
Et3N, DCM, -78 °C to rt
HO
OPMB
OPMB
HO
Ph2
P
O
O
OH
b.
K3PO4, iPrOH
THF, 60 °C
H
H
Ir
O
O
O
P
Ph2
O
II. The Second Generation of Synthetic Endeavors
O
OBz
36
O
H
H
NC
TBDPSO
16
nBu
TBDPSO
nBu
OBz
NO2
Building upon the foundation laid by our first generation of
synthetic endeavors, we first redevised the southern fragment syn-
thesis (Scheme 5). Whereas Marshall coupling13 was retained to
install the propargyl group in the 2nd generation fragment prepara-
tion, the enyne metathesis was replaced with a Heck reaction41 to
construct the required diene. Additionally, an asymmetric Mukai-
yama aldol reaction42 was employed to access the syn aldol-adduct
instead of the Evans aldol reaction.
37, 64%, 2 steps
400 mg prepared
then K2CO3, MeOH
To allow for the installation of the C14-OH via Rubottom oxi-
dation, the northern fragment was modified to a vicinal diol during
our 2nd generation of synthetic endeavors (Scheme 6). The starting
primary alcohol 16 underwent a Moffatt-Swern oxidation19 to give
an aldehyde intermediate that was further elaborated via a Krische
allylation24 using gem-dibenzoate 36 to afford 400 mg of the new
northern fragment 37.
Scheme 5. Southern Fragment Synthesis (2nd-Gen.)
Scheme 7. Assembly of the 2nd-Generation of Southern
and Northern Fragments
Me
Heck
TBSO
asymmetric aldol
Marshall
NH
CCl3
a.
Me
b. MeLi, THF
-78 °C
O
HO
O
PMBO
PMBO
O
HO
SEt
O
CSA (5 mol%)
DCM
c. TBSCl
Im, DCM, rt
O
27
commercially
available
OPMB
HO
OPMB
a. CpRu(MeCN)3PF6
(20 mol%)
acetone, rt
70%, > 5:1 l/b,
(95% brsm)
28, 85%
PMBO
O
OSiEt3
14
OH
Me
Me
Me
26
H
H
Me
O
H
O
25
e. Pd(OAc)2 (7.5 mol%)
P(oTol)3 (12 mol%), TBAI
DMF/H2O/Et3N,
nBu
+
H
9
25
OTBDPS
Me
HO
PMBO
b. TESOTf, DCM
2,6-lutidine
-78 °C, 95%
TBSO
PMBO
29, 95%
d. LDA, THF
PhNTf2
TBSO
PMBO
O
H
TBSO
Et3SiO
TBSO
SEt
TBDPSO
SEt
nBu
9
Me
t-butyl acrylate
37
OTf
TBSO
PMBO
30, 70%
PMBO
O
-78 °C to rt
f. DIBAL-H
DCM, -78 °C
O
Me
300 mg prepared
31, 50%, 2 steps
O
38
35 Me
H
OTMS
32
SEt
g. nBu2Sn(OAc)2,
Sn(OTf)2,
h. TBSOTf, DCM
TBSO
OH SEt
2,6-lutidine, -78 °C
O
TBSO
SEt
c. LDA, -78 °C
TMSCl, Et3N
HMPA
THF
Me
PMBO
O
PMBO
O
i. CSA, 0 °C
DCM/MeOH
j. DMP, Pyr. DCM
-55 °C
HN
Me
Me
O
TMSO
DCM,
N
OPMB
OPMB
33, 89%
2.5 g prepared
34, 77%, 3 steps
14
Me
OSiEt3
OSiEt3
Me
Me
Et3SiO
PMBO
Me
Me
14
OH
Me
Me
H
H
O
H
O
nBu
OTBDPS
nBu
H
OMs
Me
Me
HO
PMBO
Me
HO
PMBO
OTBDPS
k.
Me
Et3SiO
TBSO
SEt
TBSO
SEt
l. LiOH, H2O2
12
TBSO
SEt
TBSO
OH
O
PMBO
O
Pd(dppf)Cl2•CH2Cl2
InI, 0 °C
THF/HMPA 3:1
THF/H2O
Me
Me
O
O
40
39
Me
Me
5, 95%
35, 4:1 dr, 80%
1.5 g prepared
With both fragments 35 and 37 in hand, we started to evaluate
the Ru AA coupling (Scheme 7). We wanted to perform this trans-
formation in an intermolecular- rather than intramolecular- fashion
to improve the coupling efficiency. To avoid subsequent compet-
ing macrolactionization between the C9-OH and C25-OH, we
envisioned that the C25-OH could be masked as its TBDPS ether,
allowing the C9-OTES to be selectively cleaved and oxidized to the
corresponding ketone after Ru AA coupling and C14-OH installa-
tion. To our delight, the intermolecular Ru AA coupling signifi-
cantly improved the yield of this transformation to 70% (for opti-
mization of conditions, see SI, Table S3). The preferentially
The synthesis of the southern fragment started with masking
the commercial alcohol 27 using PMB acetimidate (Scheme 5).
The obtained lactone 28 was treated with MeLi followed by TBS-
protection to produce methyl ketone 29, which subsequently un-
derwent kinetic deprotonation and PhNTf2-trapping to give vinyl
triflate 30. Using Pd(OAc)2 and P(oTol)3 under basic aqueous
conditions, this vinyl triflate was coupled with t-butyl acrylate in a
Heck reaction,41 and the resulting α,β-unsaturated ester was
smoothly reduced to aldehyde 31 by slow introduction of DIBAL-
4
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Journal of the American Chemical Society
Scheme 8. Finalized Synthetic Route Highlighting a Judicious Protecting Group Strategy
1
2
3
4
5
6
7
8
15
OP4
19
O
HO
HO
Me
Me
HO
H
H
19
15
OP5
HO
Me
Me
Me
Me
O
O
OP7
H
OH
H
OH
H
O
H
O
H
THP
formation
O
epoxidation
H
O
nBu
nBu
9
OH
OH
OH
OH
O
O
OP1
nBu
5
O
5
O
O
O
O
P2
O
O
4
4
O
Me
Me
Me
Protecting Group Strategy
42
amphidinolide N (1)
des-epoxy-amphidinolide N (41)
P1, P5, P6, P7 = TES (triethylsilyl)
P2, P4 = TBS (tert-butyldimethylsilyl)
P3 = TFA (trifluoroacetyl)
C9-OH
oxidation
macrolide
formation
northern fragment (46)
9
OP4
HO
OP4
OP4
O
O
13
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
14
Me
OH
13
12
OP5
OP5
H
14
Me
Me
Me
P3
OP7
H
O
H
H
12
Rubottom
oxidation
Ru AA
coupling
O
O
nBu
OP6
Me
P3
nBu
OP6
Me
P3
H
H
nBu
HO
9
O
OP1 OMe
OP1
OP1
O
O
OMe
OMe
P2
O
O
P2
O
P2
O
O
O
Me
southern fragment (45)
Me
Me
43
44
generated linear ketone product was further masked as its TES
ether 38, which was ready for the C14-OH installation. Before
exploring the Rubottom oxidation appraoch, a direct conversion of
ketone 38 to compound 40 was investigated. Using MoOPH44 or
and believed that the C15-OH stereochemistry of des-epoxy-
amphidinolide N (41) would be insignificant due to the equilibrat-
able nature of the hemiacetal. The corresponding THP ring might
simultaneously emerge upon deprotection of macrocycle 42. Dur-
ing the second generation, we learned that the Ru AA coupling
efficiency could be drastically enhanced by performing the reaction
intermolecularly. Accordingly, to obtain intermediate 42, frag-
ments 45-46 would be stitched together via an intermolecular Ru
AA coupling12 followed by a macrolactonization,53 alongside a Ru-
bottom oxidation to install the C14-OH.10 More importantly, a
logically designed protecting group strategy was critical. Our syn-
thesis would require: 1) P3 to be orthogonal to all other protecting
groups for the C9-OH oxidation; 2) P1-P2, P4-P5, P7 of macrocycle
4 to be globally cleavable for step-economy;54 3) P1 to be remova-
ble in the presence of P2 to direct the C4-C5 epoxidation in case the
allylic epoxidation of des-epoxy-amphidinolide N (41) was non-
regioselective.7b To satisfy these parameters, TFA was selected for
P3, and the remaining six hydroxyl groups were masked as two sets
of silyl ethers.
Davis’ reagent45 with various bases proved fruitless. An α-
acyloxylation
of
ketone
38
using
O-benzoyl-N-
methylhydroxylamine hydrochloride46 also failed to provide any
product 40, and instead only cleaved the TES protecting groups.
As a result, ketone 38 was converted to its TMS enol ether 39 for
the subsequent Rubottom oxidation. A variety of oxidants were
screened, including mCPBA,10 MeReO3,47 OsO4/NMO,48
DMDO34 and Davis’ reagent.49 All failed to give promising results
and in most cases, the starting enol ether 39 quickly decomposed.
We eventually deduced that the thioester did not tolerate these
oxidative conditions and was responsible for the decomposition
issues, suggesting that we should exchange it for a methyl ester in
order to perform the Rubottom oxidation. Meanwhile, another
problem arose when attempting cleavage of the TBDPS and the
two PMB protecting groups of ketone 38. Conditions to remove
the TBDPS group led to massive decomposition of the starting
material 38. In addition, although unmasking a PMB motif in the
presence of a diene moiety is known,50 cleaving them on ketone 38
under various oxidative50, 51 or Lewis acidic conditions52 gave disap-
pointing results. These outcomes prompted us to reconsider our
whole protecting group strategy.
Scheme 9. Southern Fragment Synthesis (Final-Gen.)
d. Pd2(dba)3•CHCl3
Et3SiO
c. LDA, THF
PhNTf2
(2.5 mol%)
P(oTol)3 (5 mol%)
OTf t-butyl acrylate
a. MeLi, THF
-78 °C
O
Et3SiO
TBSO
Me
TBSO
O
TBSO
49, 81%
b. TESCl, Im
DCM, rt
-78 °C to rt
47
commercially
available
O
e. DIBAL-H
DCM, -78 °C
48, 95%
> 85 g prepared
OTMS
32
SEt
f. nBu2Sn(OAc)2,
Sn(OTf)2,
Overall, during the second generation of our synthetic efforts,
we were able to 1) redesign the synthetic route of the southern
fragment, solving the scalability issue; 2) significantly improve the
Ru AA coupling efficiency by performing the reaction in an inter-
molecular fashion. Meanwhile, some valuable lessons were learnt,
including 1) the thioester should be transformed to a methyl ester
in order to carry out the desired Rubottom oxidation; 2) the PMB
and TBDPS protecting groups should be discarded, and the entire
protecting group strategy should be carefully and logically devised
for easy removal as well as better synthetic efficiency.
HO
OH SEt
g. NaOMe
MeOH, 0 °C
Et3SiO
TBSO
O
Me
TBSO
O
H
h. TESOTf, DCM
2,6-lutidine, -78 °C
-55 °C
HN
Me
DCM,
N
51, 80%
22 g prepared
50, 71%, 2 steps
Me
H
OMs
Et3SiO
TBSO
Et3SiO
OMe
j.
Me
i. (COCl)2, DMSO
Et3N, DCM
O
Et3SiO
OMe
O
Me
12
O
TBSO
Me
-78 °C to rt
Pd(dppf)Cl2•CH2Cl2
InI, 0 °C
THF/HMPA 3:1
Me
52, 85%
53, 71%
Me
Me
Me
HO
TBSO
Me
k. TFAA, Pyr.
Et3SiO
OMe
TFAO
TBSO
Et3SiO
OMe
III. The Final Generation of Synthetic Endeavors
DCM, 0 °C
91%
O
O
Taking into account all the successes and shortcomings of the
previous two generations, we finalized our synthetic route (Scheme
8). During the first generation, we determined that it would be
prudent to perform the feasible allylic epoxidation as late as possi-
ble due to the instability of the vinyl epoxide functionality. Based
on this, we envisioned a biomimetic epoxidation in the final step,
Me
Me
45, 5 g prepared
54, 4.5:1 dr
72% (85% brsm)
Similar to the second generation southern fragment synthesis,
the preparation of fragment 45 began with addition of MeLi to
commercial lactone 45, followed by TES-protection to give methyl
5
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Journal of the American Chemical Society
Page 6 of 12
ketone 48 (Scheme 9). Kinetic deprotonation and PhNTf2-
AAA diastereoselectively generated the trans-THF ring.25 Treat-
1
2
3
4
5
6
7
8
trapping delivered vinyl triflate 49, which subsequently underwent
ment of vinyl acetate 59 with Et3N liberated an aldehyde that par-
ticipated in Keck allylation26 and TBS protection to give olefin 60,
the stereochemistry of which was confirmed by converting 60 to its
analog 15 via simple protecting-group manipulations. Successive
hydroboration/oxidation and Dess-Martin oxidation43 afforded
aldehyde 61. A Krische allylation using gem-dibenzoate 3624 was
employed to access the desired 1,2-diol 62, and the stereochemis-
try of the newly generated C16-OH was verified by converting this
alcohol to the corresponding mandelic esters.21 The C15-OH ste-
reocenter was assigned as trans to C16-OH due to the fact that
Krische allylation always provides trans-diols,24 but it is worth not-
ing that this C15 stereochemistry is insignificant as it was destroyed
in the Ru AA coupling. Selective desilylation of 1,2-diol 62 with
PPh3•HBr56 ultimately provided 5 grams of northern fragment 46
in 11 steps with 10.5% overall yield.
a Heck reaction41 with t-butyl acrylate and a DIBAL-H reduction to
afford aldehyde 50. It is worth noting that using Pd2(dba)3•CHCl3
rather than Pd(OAc)2 considerably improved the yield of the Heck
reaction. Asymmetric Mukaiyama aldol with silyl enol ether 32
produced a total of 22 grams of syn-adduct 51,42 and the newly
introduced thioester was immediately converted to a methyl ester
with NaOMe. Use of TESOTf to mask the methyl ester intermedi-
ate delivered di-TES ether 52 that was directly transformed into
aldehyde 53 by a selective Moffatt-Swern oxidation.55 Subjecting
aldehyde 16 to propargyl mesylate 1220 under Marshall conditions
diastereoselectively provided homopropargyl alcohol 54,13 which
upon TFA protection gave southern fragment 45. Using this ro-
bust route, 5 grams of fragment 45 was conveniently prepared in
11 steps with 17% overall yield.
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
With both fragments 45 and 46 in hand, the intermolecular
Ru AA was carried out (Scheme 11). The immediate product of
Scheme 10. Northern Fragment Synthesis (Final-Gen.)
AcO
b. CuI, THF, -78 °C
this coupling, an enol, spontaneously tautomerized to α–hydroxy
ketone 63. Installation of the C14-OH proved extremely challeng-
ing. When a direct approach employing MoOPH44 or Davis’ rea-
gent45 with various bases failed, the Rubottom oxidation was im-
plemented.10 Subjecting freshly prepared silyl enol ether 64 to
mCPBA in ethyl acetate or DCM at 0 °C returned to the ketone
starting material, whereas MeReO3,47 OsO4/NMO,48 DMDO34 and
Davis’ reagent49 gave either no conversion or complex mixtures.
Eventually, we found that a biphasic toluene/pH 7 buffer solvent
system and portionwise addition of freshly purified mCPBA were
crucial to successfully epoxidize silyl enol ether 64. To suppress
decomposition of the siloxy oxirane intermediate during the rear-
rangement/hydrolysis process, buffered acidic conditions were
exploited to afford 1 gram of product 65 as a single diastereomer,
the C14-stereochemistry of which was established later (see Figure
2). Subsequent TES protection and TFA cleavage with NaHCO3
liberated the C9-OH, which was oxidized to afford di-ketone 66.
We were gratified to find that the C25-OTES of 66 could be pref-
erentially cleaved in the presence of the C3, C14, and C16 TES
ethers by careful introduction of PPh3•HBr. Exposure of the re-
sultant alcohol 67 to amano or porcine pancreas lipase in hopes of
O
O
MgBr
AcO
a. TESCl, Im
HO
DCM, rt
HO
nBu
Et3SiO
nBu c. Grubbs II, DCM, 40 °C
OAc
57
55
Et3SiO
nBu
56, 90%
known compound
30 g prepared
85%, 3 steps
58, 67%, 2 steps
OAc
OTBS
AcO
e. Et3N, MeOH
h. 2-methylbut-2-ene
BH3•Me2S, THF
then NaBO3 (aq.)
f. MgBr2, Et2
0 °C to rt
O
d. Pd2(dba)3•CHCl3
Et3N, THF, 50 °C
H
H
O
Bu3Sn
O
H
(R,R)-DACH-
Trost lig.
i. DMP, DCM
Pyr., rt
H
g. TBSOTf, DCM
2,6-lutidine, -78 °C
nBu
Et3SiO
nBu
Et3SiO
60, 53%, 2 steps
15 g prepared
59, 80%
Ph2
P
O
O
j.
K3PO4, iPrOH
THF, 60 °C
OTBS
HO
15
OTBS
H
16
Ir
O
H
P
Ph2
O
O
H
O
OBz
O
OH
36
O
NC
OBz
O
NO2
H
H
then K2CO3, MeOH, 58%
Et3SiO
nBu
RO
nBu
61, 75%, 2 steps
R = Et3Si (62)
k. PPh3•HBr
0 °C, 95%
R = H (46)
5 g prepared
Likewise, the northern fragment 46 commenced with TES-
protection of known epoxide 55, followed by ring opening with
allylmagnesium bromide and cross-metastasis with gem-diacetate
57 to produce trans-olefin 58 (Scheme 10).7c The succeeding Pd-
Scheme 11. Completion of des-epoxy-Amphidinolide N (41)
O
O
OTBS
OTBS
TMSO
OTBS
HO
OTBS
14
OSiEt3
OH
14
Me
Me
Me
Me
TFAO
TBSO
b. TESOTf,
2,6-lutidine,
DCM, -78 °C
OSiEt3
Me
Me
OH
OH
d. mCPBA, Tol.
pH 7 buffer, -5 °C
H
H
H
O
O
H
Me
O
H
a. CpRu(MeCN)3PF6
O
nBu
nBu
H
H
nBu
+
OSiEt3
H
acetone, rt
OH
then THF/H2O
4-NO2-BzOH
c. LDA, -78 °C
TMSCl, Et3N
HMPA, THF
OSiEt3
Me
Et3SiO
OMe
TFAO
Et3SiO
OMe
TFAO
TBSO
Et3SiO
OMe
HO
nBu
pH 6 buffer, 0 °C
46
TBSO
O
O
TFAO
Et3SiO
OMe
O
Me
Me
Me
64
TBSO
O
65, 40%, 3 steps
63 50% (90% brsm)
3.2 g prepared
O
OTBS
1 g prepared
45 Me
OH
Me
Me
OH
H
e. TESOTf, 2,6-lutidine
DCM, -78 °C
O
g. DMP, Pyr.
DCM, rt
H
O
f. NaHCO3, MeOH, rt
TASF, rt
or aq HF, 0 °C
nBu
OH
O
TASF, 0 °C
80-82%
92%
TBSO
O
3
O
16
O
O
OTBS
OTBS
HO
HO
Me
Me
OTBS
Me
68
H
14
OSiEt3
OSiEt3
OSiEt3
OSiEt3
Me
Me
Me
O
OH
Me
Me
OSiEt3
H
H
i. Me3SnOH
DCE, 78 °C
OSiEt3
Et3SiO
67, 80%
h. PPh3•HBr
(1% x 4 times)
O
H
k. TASF, rt
THF/DMF/H2O
H
H
O
O
O
25 nBu
25
Me
nBu
H
H
H
O
nBu
OSiEt3
or aq HF, 0 °C
MeCN/DCM
71-74%
OH
OH
OH
O
MeOH, 0 °C
j. Et3N, Tol.
2,4,6-Cl3-BzCl,
then DMAP
nBu
O
Et3SiO
3
OMe
Et3SiO
O
O
OMe
O
O
TBSO
O
TBSO
O
TBSO
O
Me
des-epoxy-amphidinolide N (41)
Me
42, 51%, 2 steps
Me
66, 75%, 3 steps
Me
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Journal of the American Chemical Society
amphidinolide N (41) and des-epoxy-caribenolide I stereoisomer
(69). [Δδ = ⏐δ41 – δ69⏐ in ppm]
straightforwardly forming macrolactone 42 through intramolecu-
lar transesterification was fruitless.57 Consequently, hydrolysis of
1
2
ester 67 with Me3SnOH23 followed by Yamaguchi esterification31
Nevertheless, the stereochemistry of the THP ring (C14-C19)
of des-epoxy-amphidinolide N (41) was thoroughly investigated
using COSY, HSQC, HMBC and ROESY experiments (Figure 2).
Clear ROESY cross peaks between the C15-OH and multiple pro-
tons at C13, C14, C16, C17 and C19 (Figure 2b, shown in red)
suggested that the C15-OH has the orientation indicated in Figure
2a-b. Taking into account the strong ROESY cross peaks between
the C17 and C19 protons as well as between the C13 and C16 pro-
tons (Figure 2b, shown in green), the conformation of the THP
unit (C14-C19) was established, enabling us to further verify the
C14 stereochemisty. Interestingly, the observed conformation of
the THP ring allows for a stabilizing hydrogen-bonding interaction
between C14 and C16 hydroxyl groups (Figure 2b), which is also
supported by calculations (see SI). In addition, Nicolaou’s des-
epoxy-caribenolide I stereoisomer (69) has identical stereochemis-
try with our des-epoxy-amphidinolide N (41) in the THP part
(C14-C19) (Figure 2c). Comparing absolute values of the 13C
NMR chemical shift differences between these two compounds in
the C14-19 region revealed trivial variances, all within the range of
0.07-0.41 ppm (Figure 2d). This further supports our structural
assignment of des-epoxy-amphidinolide N (41).
was used to yield macrocycle 42.
Subjecting 42 to
3
4
5
6
7
8
9
tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF)58
at 0 °C selectively removed three TES groups, leaving both TBS
groups untouched. The obtained compound 68 could be used for
a C3-OH directed epoxidation. Further deprotection of 68 with
extra TASF at ambient temperature or HF at 0 °C occurred con-
currently with intramolecular hemiacetal formation at C15-
position to generate des-epoxy-amphidinolide N (41). Alterna-
tively, this compound could be obtained directly from macrocycle
42 upon global deprotection. In both cases, the THP ring for-
mation preferentially produced the same macrolide 41.
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
Building upon our previous chemoselective allylic epoxidation
results, modified Sharpless epoxidation conditions37 (Table 1, entry
3) were first applied to des-epoxy-amphidinolide N (41), but un-
fortunately the starting material decomposed.
Employing
VO(acac)2,38 VO(OEt)3,59 or Payne conditions39 gave no conver-
sion. Next, we turned our attention to macrocycle 68 and hoped
that use of this macrocycle would alleviate potential chemoselectiv-
ity issue. Unluckily, exploiting VO(acac)2,38 VO(OEt)3,59 Payne
conditions,39 or Sharpless conditions36 only returned the starting
60
material, whereas modified Sharpless conditions37 and Mo(CO)6
Me
led to decomposition of the starting material 68. In addition, use
of mCPBA35 afforded complicated results (for details of these ef-
forts, see SI, Table S4). Considering the highly chemoselective
allylic epoxidation of macrocycle 22 that was realized in our first
generation of synthetic efforts, the current gloomy epoxidation
outcomes implied that the allylic epoxidation was highly sensitive
to the chemical structure of the macrocycle. We suspected that the
conformations of macrocylces 41 and 68, possibly enforced by
intramolecular hydrogen-bonding interactions, might inhibit the
desired epoxidation process, leading to the unexpected difficulties
in performing the allylic epoxidation at this very late stage.
O
1
Me
O
25
4
H
HO
O
O
5
H
H
7
O
HO
OH
9
16
15
14
O
OH OH Me Me
2.069Å
Me
H
O
Me
9
7
O
5
Me
a.
25
1O
17
b.
HO
O
4
3
O
16
2.182 Å
H
O
H
15
19
O
2.121Å H
H
2.121 Å
HO
O
14
O
H
19
O
14
Me
20
OH
H
H
O
H
15
Me
Me
H
20
13
H
2.017 Å
O
H
O
H
15
O
H
13
H
16
16
nBu
14
17
O
OH
OH
O
OH
H
O
O
O
cross-peak
ROESY of
des-epoxy-amphidinolide N (41)
Me
Figure 3. Intramolecular H-bonds of amphidinolide N (1) re-
vealed by calculations at the B3LYP/6-31G* level.
des-epoxy-amphidinolide N (41)
Our data shows that C15-OH of des-epoxy-amphidinolide N
(41) has the orientation indicated in Figure 2a-b and that the C14
and C20 side-chains reside in equatorial positions (Figure 2b). In
contrast, the C15-OH of amphidinolide N (1) bears the opposite
stereochemistry, placing the C14 side-chain in an axial position
(Figure 3). It is puzzling that the natural product preferentially
adopts this apparently less favorable conformation for its THP ring.
This phenomenon may be rationalized by intramolecular hydro-
gen-bonding interactions within amphidinolide N (1) that com-
pensate for the energetic penalty for placing the C14 side-chain in
an axial position. To further support this idea, conformational
optimization of amphidinolide N (1) was carried out at the
B3LYP/6-31G* level. The results reveal that the C14-hydroxyl
proton is 2.121 Å from the THP ring oxygen and the C7-hydroxyl
proton is only 2.069 Å away from the neighboring C9-carbonyl,
which is consistent with two isolated moderate H-bonds (Figure 3,
c.
17
16
HO
H
19
15
HO
14
O
22
20
OH
H
O
H
Me
Me
24
25
nBu
OH
OH
O
O
O
7
Me
(Nicolaou) stereoisomer of
des-epoxy-caribenolide I (69)
C7, C22, C24, C25 different sterochem.
Figure 2. C14-19 structural elucidation of des-epoxy-
amphidinolide N (41). dComparison of absolute value of the 13C
NMR chemical shift difference at C14-19 between des-epoxy-
7
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Journal of the American Chemical Society
Page 8 of 12
left, cyan & green).61 Similarly, three more modest H-bonds are
*bmtrost@stanford.edu
1
2
3
4
5
6
7
8
observed among C16-OH and C15-OH, C15-OH and C3-OH, as
well as C3-OH and C4/C5 epoxide (Figure 3, dark-red).62 Unlike
the two isolated H-bonds, these three H-bonds may collaboratively
build a hydrogen-bonding bridge across the entire macrocycle to
considerably stabilize the adopted conformation.
ACKNOWLEDGMENT
We thank Prof. J. Du Bois for providing a Shigemi tube, Dr. T. Ka-
keshpour for computational discussion, Dr. S. Lynch for assistance
with NMR spectroscopy, and C. A. Kalnmals for critical reading of
the manuscript. C.E.S. is the recipient of an NIH Ruth L. Kirschstein
National Research Service Award (GM101747). C.P. and M.H. are
the recipients of DAAD fellowships (ISAP and DE1243257 respective-
ly).
Additionally, to shed some light on the relationship between
amphidinolide N (1) and caribenolide I (2), we performed NMR
experiments using our synthetic des-epoxy-amphidinolide (41) in
13
both C6D6 and CD2Cl2, so as to compare our C NMR data with
9
that of 1 and 2. Interestingly, the dissimilarity-pattern of des-
epoxy-amphidinolide N (41) to amphidinolide N (1) was in good
accordance with that of des-epoxy-amphidinolide N (41) to cari-
benolide I (2), implying that 1 and 2 could be identical (For fur-
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
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48
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REFERENCES
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13
ther detailed C NMR comparisons, see SI, Figure S8). Consider-
ing our NMR observations alongside the biogenetic relationship of
these two molecules, we conservatively propose that amphidinolide
N (1) and caribenolide I (2) are likely the same molecule.
CONCLUSION
In conclusion, des-epoxy-amphidinolide N (3) was accom-
plished in 22 longest linear and 33 total steps. The synthesis took
advantage of a convergent design that efficiently joined two frag-
ments with similar levels of structural complexity using a Ru-
catalyzed alkene-alkyne coupling and a macrolactonization. Three
generations of synthetic endeavors were reported. The first genera-
tion validated the key Ru AA coupling stitching strategy and real-
ized a challenging chemoselective allylic epoxidation of a complex
macrocycle, but left installation of the α,α’-dihydroxy ketone moie-
ty and scalable preparation of the southern fragment as unanswered
questions. The second generation addressed the scalability of the
southern fragment synthesis and significantly improved the Ru AA
coupling efficiency, but revealed that the thioether was incompati-
ble with the Rubottom oxidation alongside the deprotection trou-
bles. Evolving from these two generations of synthetic efforts, the
final generation not only logically designed the whole protecting
group strategy, but also successfully installed the C14-OH via a
carefully tuned Rubottom oxidation, allowing us to realize the syn-
thesis of des-epoxy-amphidinolide N. Several remarkable asym-
metric transition-metal-catalyzed reactions were deployed, includ-
ing Mukaiyama aldol (Sn), Marshall coupling (Pd-In), Pd-AAA
(Pd), and Krische allylation (Ir). Structural elucidation of the THP
ring of des-epoxy-amphidinolide N (41) not only verified our as-
signments but also led us to disclose the hydrogen-bonding net-
13
work in amphidinolide N (1). Comparisons of C NMR chemical
shift differences using our synthetic des-epoxy-amphidinolide N
(41) suggest that amphidinolide N (1) and carbenolide I (2) are
possibly the same chemical entity.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental and computational details, compound characteriza-
tion data, and spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
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Journal of the American Chemical Society
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54. Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Function-
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58. Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey, D. S.;
Roush,
W.
R.
Tris(dimethylamino)sulfonium
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Gubiani, J. R.; Deflon, V. M.; Nagashima, N.; Rode, A.; Blackford, K.;
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Table of Contents
1
2
3
4
[Ir]
5
6
7
8
HO
HO
HO
Me
Me
OTBS
H
Ru-AA
H
OH
O
13
OH
H
O
H
Me
13
Me
O
12
12
H
[Pd/In]
Me
TFAO
TBSO
[Pd]
Me
OH
OH
O
9
HO
O
O
Et3SiO
OMe
O
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
Me
des-epoxy-amphidinolide N
macrolactonization
Me
[Sn]
12
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