Total synthesis involving sulfur chemistry

Article abstract of DOI:10.1080/10426507.2019.1602619

Novel findings during the course of the total synthesis of sulfur-containing natural products are described. These natural products include sporidesmin A, dehydrogliotoxin, tantazole B, and leinamycin.

Full text of DOI:10.1080/10426507.2019.1602619

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Total synthesis involving sulfur chemistry
Tohru Fukuyama
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Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2019.1602619
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1602619
Total synthesis involving sulfur chemistry
Tohru Fukuyama
University of Tokyo, Tokyo, Japan
ABSTRACT
ARTICLE HISTORY
Received 27 March 2019
Accepted 29 March 2019
Novel findings during the course of the total synthesis of sulfur-containing natural products are
described. These natural products include sporidesmin A, dehydrogliotoxin, tantazole B,
and leinamycin.
KEYWORDS
Natural products; total
synthesis; epidithiodiketopi-
perazine; thiazoline;
dithiolanone
GRAPHICAL ABSTRACT
I encountered with sulfur chemistry for the first time when hand, 11 did not cyclize under the same conditions, but
Professor Yoshito Kishi, my Ph.D. mentor, asked me to help instead gave the alkylation product 12 after addition of
another graduate student synthesize sporidesmin A (1) at ClCH2OMe. Both 10 and 12 were successfully converted
Harvard University (Figure 1).[1]
to dehydrogliotoxin (8) in several steps.[3]
Tantazole (13) caught my eye at the Gordon
It was already known in our labs that the thioacetal 2
B
undergoes a regiospecific methylation to give 3, which Conference on Natural Products in 1989. The unique struc-
could then be converted to epidithiodiketopiperazine 4 ture includes four consecutive thiazoline rings capped by an
under mild conditions (Scheme 1).[2] My task was to oxazole ring. The proposed structure was later revised as 14
establish a more robust route to 3 for further exploration
(Scheme 2). Initial reaction conditions were extremely
harsh in that a mixture of methylidenethiol 5, p-anisalde-
hyde, and TFA was heated at 100 ꢀC in a steel bomb using
hydrogen sulfide as a solvent. While checking the reaction
mixture by TLC, I realized a subtle increase of the desired
compound 6 where the reaction mixture and the starting
by total synthesis in our labs (Figure 2). It was known that
N-acylaziridines 15 can be transformed to thiazolines 17 via
N-thioacylaziridines 16 (Scheme 4). When 18 was treated
with Lawesson’s reagent, however, the rearrangement pro-
ceeded in the undesired direction, giving exclusively the dia-
stereomeric thiazoline 19.
The attempted conversion of 20 to the desired thiazoline
material 5 were co-spotted. I suspected that trithiane 7, a via thioamide 21 failed presumably due to the facile forma-
by-product of the reaction, might have played an import- tion of thioacylaziridine 22, yielding once again the
ant role. Indeed, when 5 was heated with 7 and BF3ꢁEt2O undesired thiazoline 23 (Scheme 5).
in refluxing CH2Cl2, a diastereomeric mixture 6 was
We next attempted an aza-Wittig reaction of 30 in the
obtained in high yield. We next turned our attention to hope that the reactivity of thioester is comparable to that of
the total synthesis of dehydrogliotoxin (8) in which the ketones (Scheme 6). To our big surprise, upon treatment of
regiospecific deprotonation of the bridgehead proton of azide 30 with Ph3P, oxazoline 32 was obtained instead of
the bicyclic thioacetal such as 2 was clearly demonstrated the desired thiazoline. Apparently, a rapid acyl migration to
(Scheme 3). Upon treatment with n-BuLi at –78 ꢀC, 9 the nitrogen atom followed by migration of the triphenyl-
underwent a facile cyclization to give 10. On the other phosphonium species to the sulfur atom occurred to give
CONTACT Tohru Fukuyama
tohru.fukuyama@post.harvard.edu
ß 2019 Taylor & Francis Group, LLC

2
T. FUKUYAMA
Figure 1. Structure of sporidesmin A.
Figure 2. Proposed and revised structures of tantazole B.
Scheme 1. Regiospecific alkylation.
Scheme 4. Conversion of N-acylaziridines to thiazolines.
Scheme 2. Construction of thioacetal 6.
Scheme 5. Facile formation of N-thioacylaziridine.
Scheme 6. Unsuccessful aza-Wittig reaction.
Scheme 3. Total synthesis of dehydrogliotoxin (8).
giving the intermediate 35. The ensuing dehydration would
lead to the formation of the desired thiazoline 36 (Scheme 7).
Indeed, removal of the Boc group of 37 with TFA followed by
evaporation and heating in refluxing CH2Cl2 furnished the
desired 37 for the first time.
the intermediate 31, which underwent the Mitsunobu-type
reaction to give the oxazoline 32.
It occurred to us that cyclization of 33 under acidic condi-
tions would form 34 from which preferred protonation would
take place on the oxygen atom instead of the sulfur atom,
Having established a procedure for constructing the
requisite thiazoline, we next focused on an efficient

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Scheme 10. Preparation of the oxazole moiety.
Scheme 7. Successful formation of thiazoline.
Scheme 11. Completion of the total synthesis.
Scheme 12. Attempted construction of the dithiolanone structure.
Scheme 8. Preparation of b-lactones.
Figure 3. Structure of leinamycin.
(Scheme 8). As illustrated in Scheme 8, both 41 and 42
could be synthesized from the same intermediate 40 which
in turn could be prepared from the readily available malon-
ate derivative 39 by enzymatic (PLE) hydrolysis.
Scheme 9. Iterative preparation of consecutive thiazoline rings.
preparation of both enantiomers of N-Boc-2-methylcysteine.
For reiterative construction of a “thiazoline chain,” use of a
b-lactone block such as 41 and 42 appeared quite attractive
When (þ)-b-lactone 42 was treated with commercially
available thioisobutyric acid and K2CO3 in THF at room

4
T. FUKUYAMA
Leinamycin (53) is one of the most interesting com-
pounds synthesized in our laboratories (Figure 3). Its unique
spirocyclic structure consisting of 1,2-dithiolan-3-one 1-
oxide is undoubtedly one of a kind among natural products.
In our model studies, a straightforward construction of the-
dithiolanone oxide was first attempted by thermolysis of 54.
Unfortunately, no desired product 56 was obtained. We next
tried an intramolecular Michael addition of acyldithiolate 58 to
form the dithiolanone 59 (Scheme 13). Apparently, elimination
of elemental sulfur was much faster than the Michael addition,
giving only the uncyclized thiocarboxylic acid. Since a variety
of tether-assisted intramolecular Michael addition of sulfur
nuclephiles failed, we were compelled to try the formation of a
five-membered sulfide (Scheme 14). Gratifyingly, facile forma-
tion of a diastereomeric mixture of five-membered sulfide 62
was achieved by treatment of bromoketone, derived from 60,
with Li2S at room temperature. The next task was to remove
one carbon atom from 62 in preparation for construction of
the dithiolanone ring. As illustrated in Scheme 15, we solved
this problem by means of Beckmann fragmentation. Thus, bro-
moketone 63 was converted to a 4:1 diastereomeric mixture of
cyclic sulfide 64 by treatment with H2S and Et3N. The major
product proved to be our desired compound on the basis of
NOE studies. Transformation of ketone 64 to oxime 65 pro-
ceeded uneventfully under conventional conditions. For the
critical Beckmann fragmentation, the oxime 65 was activated
by esterification with 2,6-dimethylbenzoyl chloride. Upon treat-
ment of 66 with excess NaSEt, the fragmentation occurred
smoothly to give the desired thioester 68 by way of thiocyanate
67. Conversion of thioester 68 to thiocarboxylic acid with
NaSH followed by oxidation with iodine afforded the dithiola-
none 69. This protocol was successfully applied to the total
synthesis of leinamycin (53).[6]
Scheme 13. Attempted intramolecular Michael addition.
Scheme 14. Formation of a five-membered sulfide.
Scheme 15. Successful construction of the dithiolanone structure.
Total synthesis of sulfur-containing natural products
imposes a special challenge because of the highly reactive
nature of sulfur. We look forward to seeing further develop-
ment of novel sulfur chemistry in this area.
temperature, facile ring opening proceeded to give thioester
43 in 87% yield (Scheme 9). Deprotection of the Boc group
with TFA, evaporation, and heating in refluxing benzene
afforded the thiazoline 44. Since thiocarboxylic acid is not a
very easy functional group to handle, we opted to convert
44 to thioester 45 using methyl 3-mercapotopropionate and
BOP-Cl. The requisite thiocarboxylate could be readily gen-
erated from 45 by treatment with t-BuOK at 0 ꢀC, to which
(–)-b-lactone 41 was added to give thioester 46. Reiteration
of the protocol twice led to carboxylic acid 48 via 47. Since
there was no high-yielding procedure available for oxazoles
starting from carboxylic acids, oxazole 51 was separately
prepared from 42 as shown in Scheme 10.
Condensation of acid 48 and thiol 51with BOP-Cl gave
amide 52 uneventfully which was converted to tantazole B
(14) in two isolated steps (Scheme 11). As shown in Figure 2,
Moore reported the structure of tantazole B as 13, which, of
course, was the one we synthesized first.[4] However, the
optical rotation of the synthetic tantazole B was –320ꢀ whereas
the reported value was –94ꢀ. Therefore, we systematically
changed the stereochemistry of the methyl groups and found
that 14 was identical to the natural product (Scheme 12).[5]
References
[1] Kishi, Y.; Nakatsuka, S.; Fukuyama, T.; Havel, M. Total
Synthesis of Sporidesmin A. J. Am. Chem. Soc. 1973, 95,
6493–6495. DOI: 10.1021/ja00800a079.
[2] Kishi, Y.; Fukuyama, T.; Nakatsuka, S. New Method for the
Synthesis of Epidithiodiketopiperazines. J. Am. Chem. Soc.
1973, 95, 6490–6491. DOI: 10.1021/ja00800a077.
[3] Kishi, Y.; Fukuyama, T.; Nakatsuka, S. Total Synthesis of
Dehydrogliotoxin. J. Am. Chem. Soc. 1973, 95, 6492. DOI:
10.1021/ja00800a078.
[4] Carmeli, S.; Moore, R. E.; Patterson, G. M. L.; Corbett, T. H.;
Valeriote, F. A. Tantazoles, Unusual Cytotoxic Alkaloids from
the Blue-Green Alga Scytonema Mirabile. J. Am. Chem. Soc.
1990, 112, 8195–8197. DOI: 10.1021/ja00178a070.
[5] Fukuyama, T.; Xu, L. Total Synthesis of (-)-Tantazole B. J. Am.
Chem. Soc. 1993, 115, 8449–8450. DOI: 10.1021/ja00071a065.
[6] Kanda, Y.; Fukuyama, T. Total Synthesis of (þ)-Leinamycin. J.
Am. Chem. Soc. 1993, 115, 8451–8452. DOI: 10.1021/
ja00071a066.