Total Synthesis of (-)-Marinisporolide C

Article abstract of DOI:10.1021/acs.joc.7b00023

The first total synthesis of (-)-marinisporolide C is described, which establishes unequivocally the relative and absolute configuration of this oxopolyene macrolide. Key features of this synthesis include a series of highly stereoselective aldol reactions followed by directed reductions to build the polyol domain, a Stille cross-coupling reaction to assemble the polyene, and an intramolecular Horner-Wadsworth-Emmons olefination to forge the macrocyclic ring. Despite the initial approach to marinisporolide A using a Yamaguchi macrolactonization reaction that was unsuccessful due to steric hindrance of the oxygen at the C33 position, we were able to prepare a known derivative of marinisporolide A and consequently confirm its stereochemical assignment.

Full text of DOI:10.1021/acs.joc.7b00023

Subscriber access provided by University of Newcastle, Australia
Article
Total Synthesis of (-)-Marinisporolide C
Luiz Carlos Dias, and Emilio Carlos de Lucca Jr.
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 20 Feb 2017
Downloaded from http://pubs.acs.org on February 20, 2017
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 78
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Total Synthesis of (−)-Marinisporolide C
Luiz C. Dias* and Emilio C. de Lucca Jr.
Institute of Chemistry, University of Campinas, 13083-970, C.P. 6154, Campinas, SP, Brasil
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TABLE OF CONTENTS
ABSTRACT
The first total synthesis of (−)-marinisporolide C is described, which establishes
unequivocally the relative and absolute configuration of this oxopolyene macrolide. Key features
of this synthesis include of a series of highly stereoselective aldol reactions followed by directed
reductions to build the polyol domain, a Stille cross-coupling reaction to assemble the polyene,
and an intramolecular Horner−Wadsworth−Emmons olefination to forge the macrocyclic ring.
Despite the initial approach to marinisporolide A using a Yamaguchi macrolactonization reaction
that was unsuccessful due to steric hindrance of the oxygen at the C33 position, we were able
to prepare a known derivative of marinisporolide A and consequently confirm its stereochemical
assignment.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
INTRODUCTION
The polyene macrolides are a class of natural products characterized by having a
1
macrolactone containing a conjugated polyene system and a polyol moiety. In general, polyene
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
unit has four to seven conjugated double bonds. The polyol portion contains 1,2-, 1,3- and/or
1
,4-diol sequences, with 1,3-diol as the most common unit.
Although many of these compounds are known for their remarkable antifungal activity,
only three of them, amphotericin B, nystatin A1 and natamycin (pimaricin) are used by the
pharmaceutical industry.
Due to its complex molecular architecture, combined with low natural occurrence, and
biological potential, polyene macrolides have been selected as a synthetic target by numerous
2
3
4
5
6
research groups. In addition to amphotericin B, mycoticin A, roxaticin, roflamycoin, filipin III,
7
8
dermostatin A, and RK-397 had their total synthesis completed.
In 2009, Fenical and co-workers isolated the polyene macrolides marinisporolide A (1, 16
mg from 40 cultures of 1 L) and B (2, 42 mg from 40 cultures of 1 L) (Figure 1) from the saline
culture of the marine actinomycete Marinispora, strain CNQ-140.9
Figure 1: Marinisporolides A and B.
The marinisporolide A (1) is a 34-membered macrolactone, containing 11 stereogenic
centers, an internal spiroketal with one anomeric effect, and a conjugate pentaene, while
marinisporolide B (2) is the corresponding hemiketal.
A configuration analysis of marinisporolide A suggests that the spiroketal exists in its
thermodynamically favored configuration on the basis of anomeric stabilization and steric
effects.10 Although marinisporolide A spiroketal presents only one anomeric effect, the
substituents in C13, C15, C19, and C21 are in equatorial positions (Figure 2).
2
ACS Paragon Plus Environment

Page 3 of 78
The Journal of Organic Chemistry
1
2
3
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
Figure 2: Conformation of marinisporolide A [6,6]spiroketal.
Since marinisporolides A and B are photosensitive, the authors also isolated three olefin
geometric isomers: marinisporolides C−E (3−5) (Figure 3).
Figure 3: Olefin geometric isomers: marinisporolides C−E.
Recently, we concluded the first total synthesis of marinisporolide C (3).11 Herein, we
provide full details of our efforts that culminated in the total synthesis of marinisporolide C and
the preparation of a known derivative of marinisporolide A. We also established unambiguously
the relative and absolute configuration of marinisporolide C.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
RETROSYNTHETIC ANALYSIS
Our retrosynthetic analysis12 is outlined in schemes 1−4. Marinisporolide A could be
obtained from the phosphonate 6 and the aldehyde 7 through a Horner−Wadsworth−Emmons
reaction and a Yamaguchi macrolactonization (Scheme 1). The controlled ketalization event
would be incorporated into the synthesis plan under the assumption that the desired
configuration would be achieved under equilibration conditions. An olefin cross-metathesis
between crotonaldehyde (8) and olefin 9 would be envisioned to build up the fragment 7. The
compound 9 could be prepared from a Julia−Kocieński olefination between sulfone 10 and
aldehyde 11.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
ACS Paragon Plus Environment

Page 5 of 78
The Journal of Organic Chemistry
1
2
3
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
Scheme 1: Retrosynthetic analysis of marinisporolide A (1).
The phosphonate 6, which corresponds to C1−C8 fragment of marinisporolide A, could
be generated by a Horner−Wadsworth−Emmons olefination between phosphonate 12 and
aldehyde 13 (Scheme 2).
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2: Retrosynthetic analysis of phosphonate 6.
The aldehyde 11, which corresponds to C10−C22 fragment of marinisporolide A, would
be prepared by a Mukaiyama aldol reaction between aldehyde 14 and enolsilane of
methylketone 15 (Scheme 3). The aldehyde 14 could be obtained from (R)-malic acid (16).
Compound 15 would be generated by an aldol reaction between aldehyde 17 and the boron
enolate of methylketone 18.
Scheme 3: Retrosynthetic analysis of aldehyde 11.
The sulfone 10, which corresponds to the C23−C35 fragment of marinisporolide A, was
thought to be synthesized by an aldol reaction between aldehyde 19 and the boron enolate of
6
ACS Paragon Plus Environment

Page 7 of 78
The Journal of Organic Chemistry
1
2
3
methylketone 20 (Scheme 4). The aldehyde 19 could be prepared by an aldol reaction between
isobutyraldehyde (21) and the boron enolate of oxazolidinone 22. Finally, the methylketone 20
would be originated from an aldol reaction between boron enolate of methylketone 18 and
aldehyde 23.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4: Retrosynthetic analysis of sulfone 10.
RESULTS AND DISCUSSION
Synthesis of C23−C30 Fragment of Marinisporolides
The synthesis of the C23−C30 fragment of marinisporolides began with the preparation
of the methylketone 18 and the aldehyde 23 (Scheme 5). The acid-catalyzed protection of the
commercially available homoallylic alcohol 24 using p-methoxybenzyl-2,2,2-trichloroacetimidate
13
(PMBTCA) was followed by a Wacker oxidation to provide the methylketone 18 in 59% yield
over 2 steps.14
Monoprotection of commercially available 1,3-propanediol (26) (TBSCl, imidazole, DMF,
8
6%)15 afforded silicon ether 27 which underwent a Swern oxidation to furnish the desired
aldehyde 23 in 98% yield.16
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5: Preparation of methylketone 18 and aldehyde 23.
The aldol reaction between boron enolate of methylketone 18 and aldehyde 23 gave the
17
1,5-anti aldol adduct 28 (dr = 95:05) (Scheme 6). The Narasaka stereoselective reduction of
18
compound 28 provided the 1,3-syn diol 29 (70% yield, dr > 95:05). Protection of the diol 29
using 2,2-dimethoxypropane (2,2-DMP) and PPTS delivered the acetonide 30 in 81% yield. The
spectral fingerprints of the acetonide 30 confirmed the 1,3-syn configuration between C25 and
C27.19
Scheme 6: Preparation of acetonide 30.
After conversion of the diol 29 into benzilidene acetal 31 (DDQ, 4Å MS, CH
2
Cl
2
, 67%), the
1
1
,3-anti relationship between hydroxyls at C27 and C29 was determined on the basis of H NMR
spectrum and 1D selective NOE analyses (Scheme 7).20
8
ACS Paragon Plus Environment

Page 9 of 78
The Journal of Organic Chemistry
1
2
3
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
Scheme 7: Stereochemistry proof of compound 29.
Removal of PMB ether of compound 30 (DDQ, pH = 7 buffer solution, CH
2
Cl
, 91%)21
2
provided alcohol 32 which underwent a Swern oxidation to give the methylketone 20, which
corresponds to the C23−C30 fragment of marinisporolides, in 97% yield (Scheme 8).16
Scheme 8: Preparation of methylketone 20.
Synthesis of C31−C35 Fragment of Marinisporolides
The aldol reaction between Z boron enolate of oxazolidinone 22 and isobutyraldehyde
(
21) lead to the formation of the known Evans-1,2-syn aldol adduct 33 (89% yield, dr > 95:05)
22
(
Scheme 9). Reductive removal of chiral auxiliary (LiBH , MeOH, THF) delivered the diol 34
4
which, after an acid-catalyzed reaction with p-anisaldehyde diethylacetal, gave the compound
5 in 88% yield over 2 steps. The regioselective cleavage of the PMP acetal 35 (DIBAL-H,
CH Cl , 99%) yielded the primary alcohol 36. Oxidation of compound 36 using the Swern
3
2
2
conditions provided aldehyde 19, which corresponds to the C31−C35 fragment of
marinisporolides, in 99% yield.16
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 9: Preparation of aldehyde 19.
Synthesis of C23−C35 Fragment of Marinisporolides
The aldol reaction between boron enolate of methylketone 20 and aldehyde 19 gave the
1,5-anti/anti-Felkin/1,3-anti aldol adduct 37 (90% yield, dr > 95:05) (Scheme 10).17,23 The anti-
Felkin relative configuration between C31 and C32 was determined on the basis of Roush’s
method.24
Scheme 10: Preparation of aldol adduct 37.
After conversion of the aldol adduct 37 into the PMP acetal 38 (DDQ, 4Å MS, CH
2
Cl ,
2
6
6%), the 1,3-anti relationship between hydroxyls at C31 and C33 was determined on the basis
1
20
of H NMR spectrum and 1D selective NOE analyses (Scheme 11).
1
0
ACS Paragon Plus Environment

Page 11 of 78
The Journal of Organic Chemistry
1
2
3
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
Scheme 11: Stereochemistry proof of compound 37.
Reduction of aldol adduct 37 under Narasaka conditions provided 1,3-syn diol 39 (99%,
18
dr > 95:05) (Scheme 12). Protection of compound 39 using 2,2-DMP and PPTS delivered the
13
acetonide 40 in 87% yield. The C NMR spectrum of the compound 40 shows chemical shifts
in agreement with a cis configuration between C29 and C31, according to the Rychnovsky’s
method.19
Scheme 12: Preparation of acetonide 40.
Incorporation of the phenyltetrazole sulfone moiety at C23 terminus of the compound 40
was executed by a three-step procedure (Scheme 13). Removal of TBS ether of compound 40
(
TBAF, THF, 99%)25 provided the primary alcohol 41 which was subjected to a Mitsunobu
1
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reaction to deliver sulfide 43 in 87% yield.26 Finally, oxidation of compound 43 (H
O ,
2
2
(NH )
4 6
Mo
7
O
24.4H O, EtOH, 92%) gave the sulfone 10, which corresponds to the C23−C35
2
fragment of marinisporolides.26
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 13: Preparation of sulfone 10.
The synthesis of the C23−C35 fragment of marinisporolides required a longest linear
sequence of 13 steps (from alcohol 24) and proceeded with an overall yield of 18%, which
corresponds to an average yield of 88% per step. Due to the convergence, generally excellent
yields and high stereocontrol of our synthetic strategy, we were able to prepare 1.5 grams of
sulfone 10.
Synthesis of C10−C18 Fragment of Marinisporolides
The synthesis of the C10−C18 fragment of marinisporolides began with the preparation
of aldehyde 17 (Scheme 14). The tin-mediated Barbier reaction between glyoxal (44) and allyl
bromide (45) gave the diol 46 in 89% yield which underwent a NaIO -mediated oxidative
4
27
cleavage to yield the β,γ-unsaturated aldehyde 17. Compound 17 is too labile and must be
used immediately in the aldol reaction with methylketone 18.
1
2
ACS Paragon Plus Environment

Page 13 of 78
The Journal of Organic Chemistry
1
2
3
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
Scheme 14: Preparation of β,γ-unsaturated aldehyde 17.
The aldol reaction between boron enolate of methylketone 18 and aldehyde 17 gave the
17
1
,5-anti aldol adduct 47 (88% yield, dr = 92:08) (Scheme 15). Reduction of compound 47 under
Saksena−Evans conditions provided 1,3-anti diol 48 in 99% yield (dr > 95:05).28
Scheme 15: Preparation of diol 48.
At this point, we decided to determine the relative configuration between C13, C15, and
C17 in compound 48 (Scheme 16). Protection of diol 48 delivered the acetonide 49 (2,2-DMP,
13
CSA 74%). The C NMR spectrum of compound 49 shows chemical shifts in agreement with a
trans configuration between C13 and C15, according to the method of Rychnovsky.19
After conversion of diol 48 into the PMP acetal 50 (DDQ, 4Å MS, CH
2
Cl
2
, 60%), the 1,3-
1
syn relationship between hydroxyls at C15 and C17 was determined on the basis of H NMR
spectrum and 1D selective NOE analyses.20
1
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 16: Stereochemistry proof of compound 48.
Protection of diol 48 (TBSOTf, 2,6-lutidine, CH
2
Cl
2
, 91%) delivered compound 51
Cl
7%) gave alcohol 52 which underwent a Swern oxidation to provide the methylketone 15 in
29
(
Scheme 17). Removal of PMB ether of compound 51 (DDQ, pH = 7 buffer solution, CH
2
2
,
9
9
16
5% yield. Finally, treatment of compound 15 with TMSOTf and Et N delivered enolsilane 53,
3
which corresponds to the C23−C30 fragment of marinisporolides, in 99% yield.30
Scheme 17: Preparation of enolsilane 53.
1
4
ACS Paragon Plus Environment

Page 15 of 78
The Journal of Organic Chemistry
1
2
3
Synthesis of C19−C22 Fragment of Marinisporolides
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
With the enolsilane 53 in hands, the next step would be the synthesis of the prospective
aldehyde partners for the Mukaiyama aldol reaction. The Evans research group has showed
good levels of 1,3-anti asymmetric induction in Mukaiyama aldol reactions using benzylic (i.e.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
31
PMB or Bn) protecting groups at the β-position of the aldehyde. However, the incorporation of
a PMB protecting group at C21, would be problematic considering the forthcoming removal of
PMB ether at C33. Similarly, the using of a benzyl as protecting group would also be problematic
for the deprotection step. Considering that, we decided to prepare the aldehydes 14a and 14b
(Figure 4).
Figure 4: Aldehydes 14a and 14b.
The esterification32 of the (R)-malic acid (16) (AcCl, MeOH, CH(OMe)
) followed by a
3
33
chemoselective reduction (BH
3
.Me
2
S, NaBH
4
, THF) gave the diol 54 (Scheme 18). Protection
34
35
of primary alcohol (TBSCl, Et N, DMAP, CH
3
2
Cl
2
, 77% or TrCl, pyridine, CH
2
Cl , 93% ) yielded
2
compounds 55a and 55b. Conversion of the remaining hydroxyl into a TBS ether afforded
compounds 56a and 56b in good yields.36 Reduction of esters 56a and 56b (DIBAL-H,
hexanes)37 delivered alcohols 57a and 57b which underwent a Swern oxidation to give the
aldehydes 14a and 14b.16
1
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 18: Preparation of aldehydes 14a and 14b.
Synthesis of C10−C22 Fragment of Marinisporolides
The BF
3
.Et O-catalyzed Mukaiyama aldol reaction between enolsilane 53 and aldehydes
2
1
4a and 14b gave 1,3-anti aldol adducts 58a and 58b in good yields and diastereoselectivities
(
Scheme 19).38
Scheme 19: Mukaiyama aldol reaction between enolsilane 53 and aldehydes 14a and 14b.
After conversion of aldol adduct 58a into hexaol 61 (i. Et
2
BOMe, LiBH , THF, MeOH, 62%,
4
dr > 95:05; ii. HF.py, THF, 99%), the 1,3-anti relationship between hydroxyls at C19 and C21
was determined on the basis of Kishi’s method (Scheme 20).39 Furthermore, the spectral
fingerprints of the acetonide 60 confirmed the 1,3-syn configuration between C17 and C19.19
1
6
ACS Paragon Plus Environment

Page 17 of 78
The Journal of Organic Chemistry
1
2
3
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
Scheme 20: Stereochemistry proof of compound 58a.
Protection of aldol adducts 58a and 58b (TBSOTf, 2,6-lutidine, CH
2
Cl ) provided
2
29
compounds 62a and 62b in excellent yields (Scheme 21). Removal of primary silyl ether of
compound 62a (HF.py, pyridine, THF) delivered alcohol 63 in only 22% yield.40 On the other
hand, removal of trityl ether of compound 62b gave alcohol 63 (DDQ, pH = 7 buffer solution,
41
16
CH
2
Cl ) in 52%, which underwent to a Swern oxidation to provide aldehyde 11 in 99% yield.
2
1
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 21: Preparation of aldehyde 11.
The synthesis of the C10−C22 fragment of marinisporolides required a longest linear
sequence of 12 steps (from alcohol 24) and proceeded with an overall yield of 17%, which
corresponds to an average yield of 86% per step. Due to the convergence, generally excellent
yields and high stereocontrol of our synthetic strategy, we were able to prepare more than 1
gram of aldehyde 11.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of C9−C35 Fragment of Marinisporolides
The Julia−Kocieński reaction between sulfone 10 and aldehyde 11 gave the E olefin 64
(74% yield, dr > 95:05) (Scheme 22).42 Removal of PMB ether of compound 64 delivered
21
compound 9 (DDQ, pH = 7 buffer solution, CH
2
Cl , 91%), which underwent to an olefin cross-
2
metathesis with crotonaldehyde (8) to provide the C9−C35 fragment 7 (Hoveyda−Grubbs II,
, 89%, dr > 95:05).43
CH Cl
2 2
1
8
ACS Paragon Plus Environment

Page 19 of 78
The Journal of Organic Chemistry
1
2
3
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
Scheme 22: Preparation of aldehyde 7.
1
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Synthesis of C1−C8 Fragment of Marinisporolides
With the aldehyde 7 in hands, the synthesis of the prospective phosphonate partners 6a
and 6b was addressed (Schemes 23−25).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Monoprotection of diol 65 (TBSCl, imidazole, THF, 88%) furnished the compound 66
44
(
Scheme 23). Oxidation of alcohol 66 (PCC, K
2
CO
3
, 4Å MS, CH
2
Cl , 78%) gave the aldehyde
2
67, which underwent to a Horner−Wadsworth−Emmons olefination to deliver the E,E-ester 69 in
83% yield (dr > 95:05). Finally, reduction of compound 69 with DIBAL-H provided the alcohol 70
in 99% yield.
Scheme 23: Preparation of alcohol 70.
16
A Swern oxidation of alcohol 70 provided compound 13 in 99% yield (Scheme 24). A
Horner−Wadsworth−Emmons olefination between aldehyde 13 and phosphonates 12a or 12b
furnished E,E,E-trieneesters 71a and 71b in good yields and excellent levels of
diastereoselectivity.
Scheme 24: Preparation of esters 71a and 71b.
2
0
ACS Paragon Plus Environment

Page 21 of 78
The Journal of Organic Chemistry
1
2
3
4
5
The synthesis of C1−C8 fragment proceeded uneventfully and phosphonates 6a and 6b
25
were obtained in good yields from removal of silicon ether of compounds 71a and 71b, followed
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
by treatment with PBr and pyridine, and finally a Michaelis−Arbuzov reaction (Scheme 25).
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 25: Preparation of phosphonates 6a and 6b.
Synthesis of C1−C35 Fragment of Marinisporolide A and Attempts to Macrolactonization
At this point, we turned our attention to the installation of polyene fragment (Scheme 26).
The Horner−Wadsworth−Emmons olefination between aldehyde 7 and phosphonate 6a (R = Et)
furnished pentaene 73a in 28% yield and excellent levels of diastereoselectivity (dr > 95:05). At
this point, we suspected our system was unstable under basic conditions. For this reason, we
lowered the reaction time of the olefination with phosphonate 6b (R = Me) and pentaene 73b
was obtained in 50% yield (dr > 95:05).
As expected, hydrolysis of ethyl ester 73a under basic conditions completely destroyed
the starting material, while removal of methyl ester of compound 73b using Me
acid 74 in 79% yield.45
3
SnOH gave seco
2
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 26: Synthesis of seco acid 74.
46
The macrolactonization of seco acid 74 posed a problem as the standard Yamaguchi
procedure47 provided only trace yields of macrolactone 75 accompanied by the symmetric
anhydride 76 as the predominant product (Scheme 27). In addition, investigation of various
lactonization conditions reported by Yonemitsu,48 Shiina,49 and Keck50 did not result in any
improvement in the yield of 75.
2
2
ACS Paragon Plus Environment

Page 23 of 78
The Journal of Organic Chemistry
1
2
3
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
Scheme 27: Attempts of macrolactonization of seco acid 74.
51
52
53
As shown by the research groups of Yonemitsu, Roush, and Evans, the presence of
a α substituent in a α,β-unsaturated seco acid creates a bulky environment, which decreases
the efficiency of the macrolactonization step. With the aim to increase this efficiency, we decided
54
to incorporate a preorganization element through the prior formation of the spiroketal before
the macrolactonization step (Scheme 28). So the deprotection of silyl ethers of the compound
3b with HF.py provided the spiroketal 77 in 85% yield as a mixture of C17 epimers.55
7
1
The H NMR of our synthetic spiroketal 77 was identical to the compound prepared by
the Fenical’s research group.9a Thus the unambiguous nature of our synthesis with regard to
setting stereocenters confirms Fenical’s assignment of stereochemistry of marinisporolide A (1).
2
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
At this point we were not concerned about the epimer mixture, because in the final stage
of the synthesis we were expecting to reequilibrate this mixture under acidic conditions to remove
the acetonide groups.
Hydrolysis of the methyl ester 77 (LiOH, THF, MeOH, H O, 99%) gave seco acid 78.
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Unfortunately, the use of the Yamaguchi’s protocol with compound 78 provided a complex
mixture.
Scheme 28: Attempts of macrolactonization of seco acid 78.
2
4
ACS Paragon Plus Environment

Page 25 of 78
The Journal of Organic Chemistry
1
2
3
New Retrosynthetic Analysis of Marinisporolide A
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
At this point, we decided to redesign our synthetic strategy using the C9−C35 aldehyde 7
Scheme 29). Marinisporolide A could be obtained from the phosphonate-aldehyde 79 through
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
an intramolecular Horner−Wadsworth−Emmons reaction. A Stille cross-coupling between
stannane 80 and vinyl iodide 81 would be envisioned to build up the compound 79. The
compound 81 could be prepared from a Takai−Utimoto olefination using aldehyde 7.
Scheme 29: New retrosynthetic analysis of marinisporolide A (1).
Synthesis of C3−C7 Fragment of Marinisporolides
Protection of propargyl alcohol (82) (TBSCl, imidazole, CH
2 2
Cl , 99%) gave compound
56
8
3, which underwent to a hydrostannation reaction (Bu
3
SnH, AIBN), followed by a deprotection
2
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
7
(
TBAF, THF) to provide compound 84 in 52% yield (2 steps) (Scheme 30). The Swern oxidation
of alcohol 84 furnished the aldehyde 85 in 99% yield.16
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 30: Preparation of stannane 80.
A Horner−Wadsworth−Emmons olefination between phosphonate 68 and aldehyde 85
delivered the E,E-ester 86 in 78% yield (dr > 95:05). Finally, reduction of compound 86 with
DIBAL-H provided the alcohol 80 in 90% yield.
Synthesis of C8−C35 Fragment of Marinisporolide A
The Takai−Utimoto olefination between aldehyde 7 and iodoform gave the E vinylic iodide
58
87 (82% yield, dr = 89:11), which underwent to a Yamaguchi esterification to afford compound
8
1 (92%, dr = 50:50) (Scheme 31).47
As an earlier version of this strategy with the free ketone did not furnish the desired
macrolactone during the macrocyclization step, we decided to prepare the spiroketal at this
point. Removal of TBS ethers (HF.py, THF), followed by protection of remaining hydroxyls
(TBSOTf, 2,6-lutidine, CH
2
Cl ) delivered the spiroketal 88 in 87% yield (2 steps) as a mixture of
2
epimers.
2
6
ACS Paragon Plus Environment

Page 27 of 78
The Journal of Organic Chemistry
1
2
3
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
Scheme 31: Preparation of compound 88.
2
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 78
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Total Synthesis of (−)-Marinisporolide C
The Stille cross-coupling between vinyl iodide 88 and stannane 80 (PdCl
2
(MeCN)
) provided aldehyde 89 (Scheme 32).60
Compound 89 was submitted to a Horner−Wadsworth−Emmons macrocyclization under
2
, DMF,
59
9
8%), followed by an oxidation (TEMPO, BAIB, CH
Cl
2 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
61
62
Masamune−Roush conditions to give the desired macrolactone. To our complete surprise,
after full deprotection, first with HF.py and then with HCl, (−)-marinisporolide C (3), which was
1
13
identical in all aspects ( H and C NMR, HRMS, UV/Vis, and circular dichroism) to the natural
sample, was obtained in 15% yield (over 4 steps).
Scheme 32: Endgame: total synthesis of marinisporolide C (3).
2
8
ACS Paragon Plus Environment

Page 29 of 78
The Journal of Organic Chemistry
1
2
3
CONCLUSIONS
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
We concluded the first total synthesis of (−)-marinisporolide C in 25 steps (longest linear
sequence) and an overall yield of 1.15%, which corresponds to an average yield of 83% yield
per step, starting from alcohol 24. Since the configuration of all the stereogenic centers created
in this synthetic endeavor were unambiguously determined, this work ultimately established the
relative and absolute configuration of marinisporolide C.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Key features of this synthesis include of a series of highly stereoselective aldol reactions
followed by directed reductions to build the polyol domain, a Stille cross-coupling reaction to
assemble the polyene, and an intramolecular Horner−Wadsworth−Emmons olefination to forge
the macrocyclic ring.
Despite the initial approach to marinisporolide A using a Yamaguchi macrolactonization
that was unsuccessful due to steric hindrance of the oxygen at the C33 position, we were able
to prepare a known derivative of marinisporolide A and consequently confirm its stereochemical
assignment.
EXPERIMENTAL SECTION
General Information
All reactions were carried out under an atmosphere of argon with dry solvents under
anhydrous conditions unless otherwise stated. Yields refer to chromatographically and
1
spectroscopically ( H NMR) homogeneous material, unless otherwise stated.
Tetrahydrofuran (THF), diethyl ether (Et
sodium/benzophenone prior to use. Triethylamine (Et
dichloromethane (CH Cl ), benzene (PhH), toluene (PhMe), hexane, and 1,2-dichloroethane
DCE) were distilled from CaH prior to use. Oxalyl chloride ((COCl) ), acetonitrile (MeCN),
2
O), and dioxane were distilled from
3
N), pyridine (py), 2,6-lutidine,
2
2
(
2
2
isobutyraldehyde (i-PrCHO), and crotonaldehyde were distilled prior to use. Acetic acid (AcOH)
was fractionally distilled from acetic anhydride and chromium (VI) oxide prior to use. Methanol
(
MeOH) was distilled from Mg(OMe)
2
and stored over molecular sieves. N,N-dimethylformamide
and
(DMF) and dimethyl sulfoxide (DMSO) were distilled under reduced pressure from CaH
2
2
9
ACS Paragon Plus Environment