One and Two-Carbon Homologation of Primary and Secondary Alcohols to Corresponding Carboxylic Esters Using β-Carbonyl BT Sulfones as a Common Intermediate

Article abstract of DOI:10.1021/acs.joc.8b00112

Herein we report the efficient one- and two-carbon homologation of 1° and 2° alcohols to their corresponding homologated esters via the Mitsunobu reaction using β-carbonyl benzothiazole (BT) sulfone intermediates. The one-carbon homologation approach uses standard Mitsunobu C-S bond formation, oxidation and subsequent alkylation, while the two-carbon homologation uses a less common C-C bond forming Mitsunobu reaction. In this latter case, the use of β-BT sulfone bearing esters lowers the pK_a sufficiently enough for the substrate to be used as a carbon-based nucleophile and deliver the homologated β-BT sulfone ester, and this superfluous sulfone group can then be cleaved. In this paper we describe several methods for the effective desulfonylation of BT sulfones and have developed methodology for one-pot alkylation-desulfonylation sequences. As such, overall, a one-carbon homologation sequence can be achieved in a two-pot (four step) procedure and the two-carbon homologation in a two-pot (three step) procedure (three-pot; four step when C-acid synthesis is included). This methodology has been applied to a wide variety of functionality (esters, silyl ethers, benzyls, heteroaryls, ketones, olefins and alkynes) and are all tolerated well providing good to very good overall yields. The power of our method was demonstrated in site-selective ingenol C20 allylic alcohol two-carbon homologation.

Full text of DOI:10.1021/acs.joc.8b00112

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One and two-carbon homologation of primary and
secondary alcohols to corresponding carboxylic esters
using #-carbonyl BT sulfones as common intermediate
David J.-Y. D. Bon, Ond#ej Ková#, Vendula Ferugová, František Zálešák, and Jiri Pospisil
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00112 • Publication Date (Web): 18 Apr 2018
Downloaded from http://pubs.acs.org on April 18, 2018
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One and two-carbon homologation of primary and secondary alcohols to
corresponding carboxylic esters using β-carbonyl BT sulfones as common
intermediate
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David J.ꢀY. D. Bon,a Ondřej Kováč,a Vendula Ferugová,a František Zálešák,b and Jiří Pospíšila,c*
a Department of Organic Chemistry, Faculty of Science, Palacky University, tř. 17. listopadu 1192/12, CZꢀ771 46 Olomouc,
Czech republic.
b Institute of Molecular and Translation Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5,
779 00 Olomouc, Czech Republic.
c Laboratory of Growth Regulators, Palacký University & Institute of Experimental Botany AS CR, Šlechtitelů 27, 783 71
Olomouc, Czech Republic
* Corresponding author eꢀmail: j.pospisil@upol.cz
Abstract: Herein we report the efficient oneꢀ and twoꢀcarbon homologation of 1° and 2° alcohols to their
corresponding homologated esters via the Mitsunobu reaction using βꢀcarbonyl benzothiazole (BT) sulfone
intermediates. The oneꢀcarbon homologation approach uses standard Mitsunobu CꢀS bond formation, oxidation
and subsequent alkylation, while the twoꢀcarbon homologation uses a less common CꢀC bond forming Mitsunobu
reaction. In this latter case, the use of βꢀBT sulfone bearing esters lowers the pKa sufficiently enough for the
substrate to be used as a carbonꢀbased nucleophile and deliver the homologated βꢀBT sulfone ester, this
superfluous sulfone group can then be cleaved. In this paper we describe several methods for the effective
desulfonylation of BT sulfones and have developed methodology for oneꢀpot alkylationꢀdesulfonylation
sequences. As such, overall, a oneꢀcarbon homologation sequence can be achieved in a twoꢀpot (four step)
procedure and the twoꢀcarbon homologation in a twoꢀpot (three step) procedure (threeꢀpot; four step when Cꢀacid
synthesis is included). This methodology has been applied to a wide variety of functionality (esters, silyl ethers,
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benzyls, heteroaryls, ketones, olefins and alkynes) and are all tolerated well providing good to very good overall
yields. The power of our method was demonstrated in siteꢀselective ingenol C20 allylic alcohol twoꢀcarbon
homologation.
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Introduction
Elongation of the existing molecular framework by one or two functionalized carbon atoms is one of the most
commonly encountered operations in organic synthesis. Such transformation is in general achieved in two to four
(or more) synthetic transformations with regard of the oxidation state of the starting substrate and the desired
product. Most commonly, carbonyl compounds are employed as starting materials within such transformations.1
Amongst these, ArndtꢀEistert homologation,2 Wittig reaction,3 or Julia olefination methods,4 are being most
commonly employed to achieve successfully such transformations.
However when it comes to primary and secondary alcohols, in comparison only few options are available when
the above mentioned extensions are attempted. 5,6 The standard protocols used to extend an alcohol by one or two
carbons requires in principle 3 distinct synthetic operations: (1) activation of the alcohol (transformation to a
GoodꢀLeaving Group – GLG); (2) displacement of activated alcohol by Cꢀnucleophile (e.g. cyanide for one
carbon extension7 or carbonyl enolate for two carbon extension8); and (3) transformation of the introduced
functional group into the desired functionality (e.g. hydrolysis of nitrile to carboxylic acid; hydrolysis and
monodecarboxylation of dimethylmalonate etc.).
One can immediately recognize that in situ direct activation of alcohols would be beneficial for the overall
transformation. In this context the Mitsunobu reaction is the first transformation that comes to mind.9 Indeed,
mild reaction conditions, wide substrate scope and high stereospecificity make the Mitsunobu reaction the
reaction of the choice when it comes to the transformation of the C–O bond in primary and secondary alcohols to
C−O, C−S, and C−N bond. Unfortunately when it comes to a C−C bond formation, the method is rather limited.
The reason is that the Mitsunobu reaction requires rather acidic nucleophiles to proceed10 (upper pKa limit is ≤
15;11 but in general pKa of 11 to 12 is required to achieve satisfactory results12). From the literature it is known
that although bis(phenylsulfonyl)methane 1 (pKa = 12.2)13 is a suitable Cꢀnucleophile for the Mitsunobu
reaction,1] sulfoesters 2 (pKa ~13 to 13.5) or diesters 3 (pKa ~16)15 are rather poor ones. At this stage we
speculated that the electrophilic properties of benzothiazole in BTꢀsulfonyl ester 416,17 might diminish the pKa
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value of βꢀalkoxycarbonyl BTꢀsulfones 4 to the suitable level allowing their use in the Mitsunobu reaction
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(Figure 1).
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Figure 1. pKa values of relevant Cꢀacids used in the Mitsunobu reaction13,15
.
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Results and Discussion
Sometime ago we developed a short and efficient approach to βꢀcarbonyl BTꢀsulfones18 and recently we have
decided to extend their use as one and two carbon homologationꢀfunctionalization reagents (Scheme 1). In our
design, common intermediate 8 of both homologation approaches plays a key role in our strategy, since we were
expecting to develop the selective desulfonylation reaction of 8 to 9 under nucleophilic, radical or reductiveꢀ
elimination conditions (Figure 2). Such approach should assure wide functional group tolerance of the overall
homologation transformations.
Scheme 1. Planned one and twoꢀcarbon homologation reaction sequences.
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one-carbon homologation
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8
O
BT-SH
Mitsunobu reaction
R1 OH
R1 SO2BT
GLG OR3
ref. 16
R2
R2
6
7
then
oxidation
9
SO2BT
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OR3
R1
R2
N
S
8a
R1
O
= BT
OR3
desulfonylation
R2
9a
O
two-carbon homologation
O
SO2BT
OR3
R1 OH
BTO2S
OR3
R1
desulfonylation
R2
Mitsunobu
reaction
R2
O
6
8b
R1
OR3
R2
O
9b
Figure 2. Three main approaches chosen to desulfonylate intermediate 8.
Since the first two steps of the oneꢀcarbon homologation approach have been already described,18 our initial study
was aimed to validate our homologation approaches focused on the Mitsunobu reaction required for the twoꢀ
carbon homologation. Thus the reaction of tertꢀbutyl BTꢀsulfonyl acetate with primary alcohols was evaluated
(Table 1, entry 1).19 It was found that the use of ADDP (1.5 equiv) and PPh3 (1.5 equiv) delivered the desired
adduct in 87% yield (conditions A). Interestingly, when these conditions were applied to secondary or allylic
alcohols (Table 1, entries 6 to 10), the desired product was obtained in very low yields. In these cases further
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reaction optimization revealed that the Mitsunobu reaction had to be carried out in the presence of DEAD instead
of the ADDPꢀactivating reagent (conditions B).19
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Having secured the first step of the two carbon homologation process, we turned our attention to the
desulfonylation step. First we decided to explore the reactivity of the nucleophilic attack to the C=N carbon atom
in the BT group. Various nucleophilic reagents and conditions were screened20 to accomplish the desired
transformation and the combination of EtSꢀNa+/TFA were identified as the reagents of choice (Table 1, Method
A).21 In this oneꢀpot twoꢀstep process the thiolate anion acts as the nucleophile that cleaves the BTꢀ group. The
resulting sodium sulfinate then, upon protonation with TFA, releases SO2 and yields the desired ester 9 (Scheme
2).
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Scheme 2. EtSꢀNa+/TFA promoted desulfonylation reaction. (EtSꢀNa+ ꢀ sodium ethanthiolate; TFA –
trifluoracetic acid)
Next we turned our attention to stannyl radicalꢀmediated desulfonylation reaction. This approach is based on the
work of Wnuk and Robbins22 that previously reported selective and high yielding desulfonylation reaction of πꢀ
deficient heterocyclic sulfones. The desired transformation proceeded smoothly under “classical” nBu3SnH (1.25
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equiv)/AIBN (0.2 equiv)/benzene/80°C conditions (Table 1, Method B) as well as catalytic Bu3SnCl (0.10
equiv)/AIBN/PMHS/KF/H2O/toluene/110°C conditions23 (Table 1, Method C) in very good to excellent yields.
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Table 1. Twoꢀcarbon homologation twoꢀpot process – Mitsunobu reaction followed by desulfonylation.
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9
Entry
1
Mitsunobu
reactiona,b
Desulfonylation
methodb,c
Product
Entry
9
Mitsunobu
reactiona,b
Desulfonylation
methodb,c
Product
Overall yieldb,d
Overall yieldb,d
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Cond. A
(87%)
Cond. B
(53%)
A (44%)
B (88%)
C (81%)
D (94%)
E (78%)
Cond. A
(18%)
Cond. B
(88%)
A (77%, 90% ee)
B (94%, 95% ee)
C (91%, 96% ee)
D (81%, 96% ee)
E (85%, 96% ee)
82%
81%
83%, 96% ee
Cond. A
(89%)
Cond. B
(46%)
A (49%)
B (87%)
C (91%)
D (85%)
E (76%)
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Cond. A
(26%)
Cond. B
(86%)
A (35%)
B (82%)
C (83%)
D (76%)
E (74%)
2
71%
82%
Cond. A
(91%)
Cond. B
(42%)
A (58%)
B (87%)
C (85%)
D (92%)
E (82%)
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15
Cond. A
(89%)
Cond. B
(46%)
A (83%)
B (92%)
C (90%)
D (89%)
E (89%)
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7
84%
Cond. A
(88%)
Cond. B
(49%)
A (76%)
B (93%)
C (90%)
D (86%)
E (89%)
Cond. A
(91%)
Cond. B
(62%)
A (45%)
B (89%)
C (93%)
D (95%)
E (69%)
82%
87%
72%
Cond. A
(78%)
Cond. B
(32%)
A (54%)
B (81%)
C (80%)
D (71%)
E (72%)
Cond. A
(88%)
Cond. B
(56%)
A (34%)
B (82%)
C (84%)
D (77%)
E (71%)
63%
Cond. A
(11%)
Cond. B
(87%)
A (65%, 24% ee)
B (90%, 55% ee)
C (88%, 56% ee)
D (90%, 55% ee)
E (78%, 56% ee)
Cond. A
(91%)
Cond. B
(62%)
A (72%)
B (88%)
C (89%)
D (93%)
E (78%)
78%, 55% ee
85%
Cond. A
(12%)
Cond. B
(79%)
A (42%, 12% ee)
B (88%, 28% ee)
C (81%, 27% ee)
D (76%, 29% ee)
E (73%, 28% ee)
Cond. A
(78%)
Cond. B
(31%)
A (63%)
B (89%)
C (81%)
D (82%)
E (67%)
78%
70% 28% ee
Cond. A
(15%)
Cond. B
(83%)
A (73%, 71% ee)
B (90%, 75% ee)
C (89%, 75% ee)
D (72%, 75% ee)
E (76%, 75% ee)
16
Cond. A
(12%)
Cond. B
(92%)
A (72%)
B (81%)
C (84%)
D (83%)
E (71%)
8
81%
75%, 75% ee
aConditions A: alcohol 6 (1.0 equiv), C-acid (1.2 equiv), ADDP (1.5 equiv), PPh3 (1.5 equiv), toluene, 0°C to RT, 12h; Conditions B: alcohol 6 (1.0 equiv),
C-acid (1.2 equiv), DEAD (1.5 equiv), PPh3 (1.5 equiv), toluene, 0°C to RT, 6h. bRefers to pure isolated compounds. cMethod A: EtS-Na+ (2.0 equiv,
CH2Cl2, 0°C, 1h, then TFA (20 equiv), 2h; Method B: nBu3SnH (1.25 equiv), AIBN (0.2 equiv), benzene, 80°C, 1h; Method C: nBu3SnCl (0.10 equiv),
AIBN (0.03 equiv), PMHS (0.1 mL/mmol KF), KF (2.0 equiv), toluene/H2O = 4/1 (V/V), 110°C, 3h. Method D: SmI2 (6.5 equiv), MeOH (50 equiv), THF, -
78 °C, 30 min; Method E: Zndust (5.0 equiv), THF/AcOH = 5:1 (V/V), 0°C to RT, 8h. dYield over two steps related to the highest yielding Mitsunobu step
and desulfonylation method.
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Table 2. Oneꢀcarbon homologation via a twoꢀpot process – Mitsunobu reaction followed by desulfonylation.
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Entry
1st one-pot
Carbonylation
stepb,c
(GLG group)
Desulfonylation
methodb,d
Product
Entry
1st one-pot
Carbonylation
stepb,c
(GLG group)
Desulfonylation
methodb,d
Product
protocola,b
/
Overall yieldb,e
protocola,b
/
Overall yieldb,e
2nd one-pot
protocolb,d
2nd one-pot
protocolb,d
91%
(OBoc)
A (65%)
B (85%)
C (75%)
D (94%)
E (67%)
5
90% / 82%
93%
(CN)
A (76%)
B (93%)
C (90%)
D (86%)
E (89%)
1
96% / 62%
60%
72%
74%
93%
(CN)
A (45%)
B (81%)
C (80%)
D (86%)
E (67%)
6
78% / 75%
87%
(OBoc)
A (35%)
B (82%)
C (83%)
D (76%)
E (74%)
2
96% / 75%
59%
67%
93%
(CN)
A (34%)
B (82%)
C (84%)
D (77%)
E (71%)
7
8
89% / 75%
86% / 71%
94%
(CN)
A (83%)
B (92%)
C (90%)
D (89%)
E (89%)
3
4
89% / 69%
89% / 75%
61%
67%
90%
(OBoc)
A (45%)
B (89%)
C (93%)
D (95%)
E (69%)
94%
(CN)
A (72%)
B (88%)
C (89%)
D (93%)
E (78%)
61%
aConditions: alcohol 6 (1.0 equiv), BT-SH (1.2 equiv), DEAD (1.2 equiv), PPh3 (1.2 equiv), THF, 0°C to RT, 12h then Na2WO4.2H2O (0.1 equiv), 30% aq.
H2O2 (30 equiv), EtOH, 0°C to RT, 12h. bRefers to pure isolated compounds. cConditions: sulfone (1.0 equiv), carbonyl reagent (1.05 equiv), LiHMDS (2.2
equiv), THF, -78 °C, 30 min. dMethod A: EtS-Na+ (2.0 equiv, CH2Cl2, 0°C, 1h, then TFA (20 equiv), 2h; Method B: nBu3SnH (1.25 equiv), AIBN (0.2 equiv),
benzene, 80°C, 1h; Method C: nBu3SnCl (0.10 equiv), AIBN (0.03 equiv), PMHS (0.1 mL/mmol KF), KF (2.0 equiv), toluene/H2O = 4/1 (V/V), 110°C, 3h.
Method D: SmI2 (6.5 equiv), MeOH (30 equiv), THF, -78 °C, 30 min; Method E: Zndust (5.0 equiv), THF/AcOH = 5:1 (V/V), 0°C to RT, 8h. eYields obtained
over two one-pot protocols.
Finally, the desulfonylation of the intermediate 8 was attempted using metalꢀmediated reductive conditions. Since
many metals are known to promote desulfonylation of βꢀcarbonyl phenyl sulfones,24 we expected that the
identification of the suitable conditions would be rather easy. Surprisingly this was not the case, and only
SmI2/MeOH and Zndust/AcOH systems were able to yield the desired desulfonylated products in good to excellent
yields (Table 1, Methods D and E).18 The disadvantage of the SmI2/MeOH reduction conditions (Method D) is
the use of large excess of SmI2 (min 6.0 equiv) caused by the follow up reduction of the eliminated BT group to
Nꢀmethylꢀ2ꢀthioaniline 13 (Scheme 3). On the other hand, the transformation proceeds at low temperature and is
rather fast. In the case of Zndust/AcOH, the reaction proceeds at RT in a mixture of THF/AcOH (5:1, V/V), and
does not require anoxic or anhydrous conditions, making it more suitable for practical largeꢀscale synthesis.
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Scheme 3. SmI2/MeOH promoted reductive desulfonylation – proposed reaction mechanism.
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9
O
H
N
O2
S
O
SmI2 (6.5 equiv)
N
OR
+
R
OR
MeOH (30 equiv)
THF, -78 °C
S
N
R
SH
8
9
13
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SmI2
O
O2
S
SmI2
(4.0 equiv)
MeO-SmI2
MeOH
OR
S
R
N
H
SmI2
S
O SmI2
SO2
SmI2
H
S
OR
O
O
O
N
S
R
S
+
N
O
MeOH
MeO-SmI2
S
Having found suitable desulfonylation conditions our attention turned to a oneꢀcarbon homologation sequence.
Since the synthesis of βꢀcarbonyl BTꢀsulfones 8 has already been reported,25 we have focused on the
desulfonylation conditions (Table 2). At this stage we wished to develop a twoꢀpot (four steps) protocol suitable
for the direct transformation of alcohol 6 to ester 9a (Table 2). The first “oneꢀpot”, transformation of alcohol 6 to
BTꢀsulfone 7 via Mitsunobu reaction/oxidation sequence, is well documented in the literature and commonly
used in the context of total syntheses.26 On the other hand the second part, oneꢀpot two step procedure combining
already known baseꢀpromoted coupling of sulfone 7 with carbonylating agent18 with desulfonylation had to be
developed. As a desulfonylating agent we decided to employ the Zn/AcOH system. Gratifyingly, the coupling
adduct intermediate, upon the AcOH quench and subsequent Zndust addition, smoothly desulfonylated to yield the
desired ester in good to very good overall yields (Table 2). Overall, the oneꢀcarbon homologation reaction
sequence can be easily achieved in a twoꢀpot operationally simple protocol and yields the desired homologated
products in good to excellent overall yields.
Finally the two important aspects of the two homologation sequences should be discussed, functional group
tolerance and stereoselectivity. First, it was observed that radicalꢀbased (Methods B and C) and metalꢀmediated
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(Methods D and E) reductive desulfonylation conditions yields, in general, the desired esters in higher overall
yields when compared to EtSꢀNa+/TFA (Method A) system (Table 1, Table 2). From the functional group pointꢀ
ofꢀview, esters (Table 1, entries 1, 2, 3, 6 and 7), TBDPS ether (Table 1, entry 4; Table 2, entry 5), benzyl ether
(Table 1, entry 15), ketone (Table 1, entry 5), olefins (Table 1, entries 10 and 11; Table 2, entries 6 and 7),
(hetero)aryls (Table 1, entry 16; Table 2, entries 1 and 2), and alkynes (Table 1, entry 14; Table 2, entry 8) are
tolerated. From the stereoselectivity view point, it was observed that the Mitsunobu reactions do not proceed with
full inversion of the secondary alcohol and partial erosion of the inverted stereogenic center is observed (Table 1,
entries 8 and 9). If ethyl lactate was used as the starting secondary alcohol, stereodegradation was even more
significant (Table 1, entries 6 and 7). It seems that the degree of the stereo integrity strongly depends on the steric
requirements of the Cꢀacid. Additional epimerization of the alcoholꢀoriginated stereogenic center was also
observed during the EtSꢀNa+/TFA promoted desulfonylation reaction (Table 1, entries 6 to 9).27
Finally, we were interested in evaluating the robustness and siteꢀselectivity of our method. To evaluate the
robustness, 2.52 g of tertꢀbutyl tetracosonoate was prepared in 3 steps and 67% overall yield from the
corresponding alcohol (Scheme 4).
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Scheme 4. Multigram scale synthesis of tertꢀbutyl tetracosonoate.
To address the second challenge, twoꢀcarbon homologation of natural product ingenol (14) was attempted
(Scheme 5). Recently, we have disclosed that C20 hydroxy group in 14 can be selectively (only one out of four
hydroxy groups) transformed into its acetate.36 Thus we were interested if our Cꢀacids could also be used in this
reaction as nucleophiles. Gratifyingly, using our method the C20 hydroxy group was selectively in two steps and
45% overall yield transformed into the corresponding ingenol derivative 16.
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Scheme 5. Selective C20 hydroxy group twoꢀcarbon homologation of ingenol (14).
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Conclusions
In conclusion, we have developed a new synthetic strategy allowing one and twoꢀcarbon homologation of
primary and secondary alcohols in good to very good overall yields. The strong point of the overall processes is
the desulfonylation reaction that could be carried out using several chemically different reaction conditions. In
both cases, ester (oneꢀcarbon homologation) or alkyl acetate (twoꢀcarbon homologation) groups could be
successfully introduced. Thus, developed methods are an alternative to already existing oneꢀ and twoꢀcarbon
homologation/functionalization methods, and we believe that due to their versatile character they will soon find
use in total synthesis of complex natural products.
EXPERIMENTAL SECTION
General Information. All reactions were performed in roundꢀbottom flasks fitted with rubber septa using the
standard laboratory techniques. Reactions sensitive to air and/or moisture were performed under a positive
pressure of argon. Analytical thinꢀlayer chromatography (TLC) was performed using aluminum plates preꢀcoated
with silica gel (silica gel 60 F254). TLC plates were visualized by exposure to ultraviolet light and then were
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stained by submersion in basic potassium permanganate solution or in ethanolic phosphomolybdic acid solution
followed by brief heating. Flashꢀcolumn chromatography was carried out on silica gel (60 Å, 230–400 mesh)
using Petroleum ether/EtOAc solvent mixtures (for appropriate ratios see experimental part). All reagents were
obtained from commercial suppliers and were used without further purification. Diethyl azodicarboxylate (DEAD,
97%) was purchased from Alpha Aesar. Dry solvents were obtained using standard drying protocols: THF was
distilled under argon from sodium benzophenone ketyl; CH2Cl2 was distilled from CaH2; and CH3CN from P2O5.
Sulfones 7 and 8a (Table 2), and C-acids used in twoꢀcarbon homologation protocol (Table 1) were prepared
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1
using the previously published protocols.18 1H and 13C spectra were recorded at 500, 400, or 300 MHz (for H
1
NMR), and 125, 100, or 75 MHz (for 13C NMR), respectively, at 25°C in CDCl3. Chemical shifts (δ ppm) H
NMR are reported in a standard fashion with relative to the remaining CHCl3 present in CDCl3 (δH = 7.27 ppm).
13C NMR chemical shifts (δ ppm) are reported relative to CHCl3 (δC = 77.23 ppm, central line of triplet). Proton
coupling patterns are represented as singlet (s), doublet (d), doublet of doublet (dd), triplet (t), quintet (quint),
quintet of doublet (quintd), and multiplet (m), and coupling constants (J) are reported in Hz. Analysis and
assignments were made by comparison with literature spectroscopic data or using 2DꢀCOSY, HSQC, HMBC,
2DꢀNOESY and NOEdiff experiments. HRMS data were obtained using quadrupole/ion trap mass analyzer.
Melting points (mp) were tested on a capillary melting point apparatus. The ee of products was determined by
chiral GC using Chiraldex® γꢀTA capillary column, and Chiraldex® βꢀPM column, respectively. The major
enantiomer was determined with help of optical rotation measurement.
One-carbon homologation protocol
General Procedure for Alcohol 6 to sulfone 7 Transformation: A solution of benzo[d]thiazol (BTꢀSH) (1.2
mmol, 1.2 equiv), PPh3 (1.2 mmol, 1.2 equiv) and alcohol 6 (1.0 mmol, 1.0 equiv) in THF (10 mL, 0.1M) was
cooled to 0°C and DEAD (1.2 mmol, 1.2 equiv) was added. The resulting solution was allowed to warm to rt and
stirred for 5ꢀ8 h. The resulting solution was diluted with EtOH (25 mL), cooled to 0°C and Na2WO4.2H2O (0.1
mmol, 0.1 equiv) in one portion. After 5 min at 0°C, an aqueous 35% solution of H2O2 (30.0 mmol, 30 equiv)
was added dropwise with a use of pipette Pasteur. The resulting yellowish solution was allowed to warm to rt and
stirred at rt for 10h. Water (50 mL) was added and the whole mixture was extracted with EtOAc (3x100 mL). The
combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the solvents were
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evaporated under reduced pressure. The residue was purified by flash chromatography on SiO2 using the
appropriate eluting system.
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2ꢀ(benzylsulfonyl)benzo[d]thiazole (7, Table 2, entries 1 and 2).19 The residue was purified by flash column
chromatography (petroleum ether:EtOAc = 10:1ꢀ>2:1) yielding the desired sulfone (0.278 g, 96%). Mp = 112ꢀ
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113°C; 1H NMR (300 MHz, CDCl3):
Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3):
δ 4.78 (s, 1H, Hꢀ2), 7.23ꢀ7.38 (m, 5H), 7.56ꢀ 7.75 (m, 2H), 7.96 (d, J = 8.0
δ
61.2, 122.5, 125.7, 126.5, 127.9, 128.2, 129.1,
129.4, 131.3, 137.3, 152.8, 165.4; MS (CI), m/z (%): 290 (43) [M]+; Anal. Calcd for C14H11NO2S2: C, 58.11; H,
3.83; N, 4.84. Found: C, 58.14; H, 3.80; N 4.86.
2ꢀ(tricosanylsulfonyl)benzo[d]thiazole (7, Table 2, entries 3 and 4).19 Purification by flash chromatography
1
(petroleum ether:EtOAc = 50:1 ꢀ> 10:1) yielding the desired sulfone (0.459 g, 89%). Mp = 35ꢀ36°C; HꢀNMR
(300 MHz, CDCl3):
δ 0.85 (t, J = 6.8 Hz, 3H, Hꢀ3), 1.05 – 1.79 (m, 40H), 1.88 (dt, J = 12.1, 7.6 Hz, 2H, Hꢀ2),
3.51 (dd, J = 9.1, 7.0 Hz, 2H, Hꢀ1), 7.62 (quintd, J = 7.2, 1.4 Hz, 2H), 8.03 (dd, J = 7.2, 1.7 Hz, 1H), 8.23 (dd, J
= 7.3, 1.5 Hz, 1H); 13CꢀNMR (75 MHz, CDCl3):
δ
14.3 (Cꢀ6), 22.9, 26.4, 27.1, 29.2, 29.3, 29.6, 29.8, 29.9, 31.5,
54.8 (Cꢀ1), 122.4, 125.6, 127.8, 128.2, 136.9, 152.9, 166.1 (Cꢀ4); MS (APCI), m/z (%): 522 (100) [M]+; Anal.
Calcd for C30H51NO2S2: C, 69.05; H, 9.85; N, 2.68. Found: C, 69.07; H, 9.84; N, 2.69.
2ꢀ(hexꢀ5ꢀenꢀ1ꢀylsulfonyl)benzo[d]thiazole (7, Table 2, entry 7).19 Purification by flash chromatography
(petroleum ether:EtOAc = 10:1 ꢀ> 4:1) yielded the desired sulfone (0.250 g, 89%). Mp = 42ꢀ43°C; 1HꢀNMR (300
MHz, CDCl3):
δ 1.18 – 1.36 (m, 2H), 1.67 (dt, J = 14.6, 6.7 Hz, 2H), 2.34 (dt, J = 12.1, 7.6 Hz, 2H, Hꢀ5), 3.48
(dd, J = 9.3, 7.0 Hz, 2H, Hꢀ2), 4.92 – 5.08 (m, 2H, Hꢀ7), 5.65 (ddt, J = 16.1, 11.2, 6.4 Hz, 1H, Hꢀ6), 7.63 (quintd,
J = 7.2, 1.3 Hz, 2H), 8.01 (dd, J = 7.2, 1.7 Hz, 1H), 8.22 (dd, J = 7.3, 1.5 Hz, 1H); 13CꢀNMR (75 MHz, CDCl3):
δ
23.2, 28.7, 31.5, 55.6, 115.8, 122.54, 125.63, 127.83, 128.18, 133.8, 136.95, 152.93, 166.1; MS (APCI), m/z (%):
282 (100) [M]+; Anal. Calcd for C13H15NO2S2: C, 55.49; H, 5.37; N, 4.98. Found: C, 55.51; H, 5.38; N, 4.97.
2ꢀ(hexꢀ3ꢀynꢀ1ꢀylsulfonyl)benzo[d]thiazole (7, Table 2, entry 8).19 Purification by flash chromatography
(petroleum ether:EtOAc = 10:1 ꢀ> 4:1) yielded the desired sulfone (0.216 g, 86%). Mp = 40ꢀ41°C; 1H NMR (300
MHz, CDCl3): δ 1.80 (t, J = 2.3 Hz, 3H, Hꢀ6), 2.03 – 2.23 (m, 2H, Hꢀ2), 2.38 – 2.52 (m, 2H, Hꢀ3), 3.25 (t, J = 8.2
Hz, 2H, Hꢀ2), 7.64 (quintd, J = 7.2, 1.5 Hz, 2H), 8.03 (dd, J = 7.2, 2.1 Hz, 1H), 8.26 (dd, J = 7.4, 2.0 Hz, 1H); 13C
NMR (75 MHz, CDCl3): δ 14.4, 21.2, 25.8, 60.6, 75.9, 78.2, 122.5, 125.9, 128.0, 128.5, 137.4, 152.8, 164.2 (Cꢀ
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1); MS (APCI), m/z (%): 280 (100) [M]+; Anal. Calcd for C13H13NO2S2: C, 55.89; H, 4.69; N, 5.01. Found: C,
55.90; H, 4.69; N, 5.00.
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General Procedure for sulfone 7 to ester 9a Transformation: To a solution of sulfone 7 (1.0 mmol, 1.0 equiv)
in THF (10 mL, 0.1 M) cooled to ꢀ78 °C was added LiHMDS (2.2 mL, 2.2 mmol, 2.2 equiv; 1.0 M sol. in THF).
After 30 seconds acylating reagent (1.1 mmol, 1.1 equiv) in THF (1.1 mL, 1.0 M to acylating reagent) was added.
The resulting mixture was stirred at ꢀ78 °C for an additional 30 min before it was allowed to warm to 0 °C
(exchange of cooling baths). After 10 min at 0 °C, AcOH (5 mL, 0.2M to BTꢀsulfone) was added and the
resulting mixture was allowed to stir at RT for an additional hour. Zinc dust (0.327 g, 5.0 mmol, 5.0 equiv) was
added and the resulting mixture was stirred at RT for 8 h. The mixture was diluted with EtOAc (50 mL), filtered
through a pad of Celite® and the filter cake was washed with an additional EtOAc (3x 25 mL). The combined
organic filtrates were washed with water (25 mL), brine (25 mL), dried over Na2SO4 and evaporated under
reduced pressure to provide the crude product.
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General Procedure for two step sulfone 7 to ester 9a Transformation
Reaction of the BTꢀsulfone 7 with carbonylating reagent. A solution of BTꢀsulfone 7 (1.0 mmol, 1.0 equiv) in
THF (5 mL, 0.20M) was cooled to ꢀ78°C and LiHMDS (1.0M sol. in THF) (2.2 mL, 2.2 mmol, 2.2 equiv) was
added dropwise. Immediately after the addition, a solution of alkoxy carbonylating agent (Boc2O or methyl
cyanoformate (Mander’s reagent) or allyl cyanoformate) (1.1 mmol, 1.1 equiv) in THF (0.5 mL) was added. The
resulting mixture was stirred at ꢀ78°C for 30 min, allowed to warm to 0°C within 1h and stirred at 0°C for a
further 30 min before sat. aq. sol. of NH4Cl (15 mL) was added. The whole mixture was extracted with EtOAc
(3x75 mL) and the combined organic layers were washed with brine (50 mL), dried over NaSO4, and the solvents
were removed under reduced pressure. The residue was purified by flash column chromatography on SiO2 with
appropriate solvent system to yield desired βꢀcarbonyl sulfone 8a.
General Protocols for Desulfonylation Reaction.
Method A:21 A solution of BTꢀsulfone ester 8 (0.5 mmol, 1.0 equiv) in CH2Cl2 (5.0 mL, 0.1M) was cooled to 0 °C
and EtSꢀNa+ (0.084 g, 1.0 mmol, 2.0 equiv) was added. The resulting mixture was stirred at 0 °C for 1 h and
trifluoroacetic acid (0.766 mL, 10.0 mmol, 20 equiv) was added. Stirring was continued for the next 2 h prior to
toluene (10 mL) addition. The resulting mixture was evaporated under reduced pressure to provide the crude
product.
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Method B:22 To a solution of BTꢀsulfone ester 8 (0.1 mmol, 1.0 equiv) in benzene (0.5 mL, 0.2M) was added
nBu3SnH (0.336 mL, 0.125 mmol, 1.25 equiv) and the resulting mixture was stirred at rt for 5 min. AIBN (0.003
g, 0.02 mmol, 0.2 equiv) was added and the mixture was placed on a preheated oil bath (90 °C). The mixture was
kept at 90 °C (external) for 60 min before it was allowed to cool to RT (heating bath removed). CH3CN (10 mL)
was added and the reaction mixture was extracted with nꢀpentane (3x 15 mL). The acetonitrile layer was dried
over MgSO4, filtered and evaporated to dryness to provide the crude product.
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Method C:23 Argon was bubbled (5 min) through a solution of BTꢀsulfone ester 8 (0.25 mmol, 1.0 equiv),
Bu3SnCl (0.007 mL, 0.025 mmol, 0.1 equiv), and AIBN (0.002 g, 0.008 mmol, 0.03 equiv) in toluene (2 mL) for
15 min. The solution was heated at reflux and PMHS (0.05 mL) and KF (0.03 g, 0.5 mmol, 2.0 equiv; in H2O (0.5
mL)) were sequentially added in three portions (t = 0 min, 1h and 2 h). After 3 h, the reaction mixture was cooled
to RT and volatiles were removed under reduced pressure. The residue was partitioned between EtOAc (10mL)
and sat. aq. NaHCO3 (10mL). Resulting layers were separated and the aqueous layer was extracted with EtOAc
(2x10 mL). The organic layers were washed with brine (10mL), dried over Na2SO4, and evaporated to dryness to
provide the crude product.
Method D: A solution of SmI2 (6.25 mL, 0.625 mmol, 6.25 equiv; 0.1 M solution in THF) was placed under inert
atmosphere and MeOH (0.202 mL, 5.0 mmol, 50 equiv) was added. The resulting mixture was cooled to ꢀ78 °C
(dry ice/acetone) and BTꢀsulfone ester 8 (0.1 mmol, 1.0 equiv) in dry THF (1 mL) was added. If the typical deep
blue color of SmI2 faded upon the sulfone solution addition, additional SmI2 was added until the deep blue color
persisted. The resulting mixture was stirred at ꢀ78 °C for an additional 15 min before the sat. aq. NH4Cl (10 mL)
was added. The resulting phases were separated and the water layer was extracted with EtOAc (3x 15 mL). The
combined organic layers were washed with sat. aq. Na2S2O3 (10 mL), brine (10 mL), dried over MgSO4 and
evaporated under reduced pressure to provide the crude product.
Method E: To a solution of BTꢀsulfone ester 8 (0.5 mmol, 1.0 equiv) in THF (5 mL, 1.0 M) was added zinc dust
(0.163 g, 2.5 mmol, 5.0 equiv), the mixture was cooled to 0 °C and AcOH (1.0 mL) was added. The reaction was
allowed to warm and stirred at RT for 8 h. The mixture was diluted with EtOAc (25 mL), filtered through a pad
of Celite® and the filter cake was washed with EtOAc (3x 20 mL). The combined filtrates were washed with
brine (10 mL), dried over Na2SO4 and evaporated under reduced pressure to provide the crude product.
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tertꢀbutyl 2ꢀphenylacetate (9, Table 2, entry 1).28 The residue was purified by column chromatography on silica
gel (P.E.:EtOAc = 100:1 → 50:1 → 20:1) and yielded the targeted compound as colorless oil (Rf = 0.94,
P.E.:EtOAc = 10:1). 1H NMR (300 MHz, CDCl3): δ 1.47 (s, 9H), 3.56 (s, 2H), 7.11 – 7.41 (m, 5H); 13C NMR (75
MHz, CDCl3): δ 28.2, 42.8, 80.9, 122.0, 123.7, 125.7, 126.3, 126.9, 128.6, 129.3, 134.8, 154.0, 171.0; MS (CI+),
m/z (%): 193 (38) [M+H]+; HRMS (ESI) calcd for C12H16NaO2 [M+Na]+: 215.1043, found: 215.1044.
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Methyl 2ꢀphenylacetate (9, Table 2, entry 2).29 The residue was purified by column chromatography on silica gel
(P.E.:EtOAc = 100:1 → 50:1 → 20:1) and yielded the targeted compound as colorless oil (Rf = 0.88, P.E.:EtOAc
1
= 10:1). H NMR (400 MHz, CDCl3): δ 3.63 (s, 2H), 3.69 (s, 3H), 7.14ꢀ7.29 (m, 5H); 13C NMR (100 MHz,
CDCl3): δ 41.2, 52.1, 127.1, 128.6, 129.3, 134.0, 172.1; HRMS (ESI) calcd for C9H10NaO2 [M+Na]+: 173.0568,
found: 173.0573; Anal. Calcd for C9H10O2: C, 71.98; H, 6.71. Found: C, 72.01; H, 6.70.
tertꢀbutyl tetracosanoate (9, Table 2, entry 4; Table 1, entry 12). The residue was purified by column
chromatography on silica gel (P.E.:EtOAc = 100:1 → 50:1) and yielded the targeted compound as white solid (Rf
1
=0.91, P.E.:EtOAc = 20:1). M.p. = 67ꢀ69 °C; H NMR (300 MHz, CDCl3): δ 0.89 (d, J = 6.7 Hz, 3H), 1.26 (s,
40H), 1.45 (s, 9H), 1.51 – 1.67 (m, 2H), 2.20 (t, J = 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 14.3, 22.9, 25.4,
28.3, 29.3, 29.5, 29.6, 29.7, 29.8, 29.9, 29.9, 32.2, 35.9, 80.1, 173.5; IR (film): νꢀ1 3008 (w), 2982 (w), 2925 (m),
2853 (m), 1724 (m), 1467 (m), 1369 (m), 1155 (s), 908 (s), 729 (s); MS (APCI+), m/z (%): 426 (12) [M+H]+;
Anal. Calcd for C28H56O2: C, 79.28; H, 13.38. Found: C, 78.86; H, 13.38.
Methyl tetracosanoate (9, Table 2, entry 3; Table 1, entry 13). The residue was purified by column
chromatography on silica gel (P.E.:EtOAc = 50:1 → 20:1 → 10:1) and yielded the targeted compound as white
1
solid (Rf = 0.91, P.E.:EtOAc = 4:1). M.p. = 58ꢀ59 °C; H NMR (300 MHz, CDCl3): δ 0.89 (t, J = 6.6 Hz, 3H),
1.26 (s, 40H), 1.62 (q, J = 7.1 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 3.67 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 14.3,
22.9, 25.2, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 29.9, 32.2, 34.3, 51.6, 174.5; IR (film): νꢀ1 2921 (s), 2946 (s), 1749
(m), 1477 (m), 1467 (w), 1169 (m), 904 (s); MS (APCI+), m/z (%) = 383 (100) [M]+; Anal. Calcd for C25H50O2: C,
78.47; H, 13.17. Found: C, 78.53; H, 13.24.
1ꢀ(tertꢀbutyl) 8ꢀmethyl octanedioate (9, Table 1, entry 1). The residue was purified by column chromatography on
silica gel (P.E.:EtOAc = 20:1 → 10:1) and yielded the targeted compound as colorless viscous oil (Rf = 0.71,
P.E.:EtOAc = 10:1). 1H NMR (300 MHz, CDCl3): δ 1.33 (dq, J = 7.3, 3.4 Hz, 4H), 1.44 (s, 9H), 1.51 – 1.70 (m,
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4H), 2.20 (t, J = 7.4 Hz, 2H), 2.30 (t, J = 7.5 Hz, 2H), 3.67 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 25.0, 25.1,
28.3, 28.9, 29.0, 34.2, 35.7, 51.7, 80.2, 173.4, 174.4; IR (film): νꢀ1 2977 (w), 2948 (w), 2932 (m), 1733 (s), 1458
(m), 1434 (w), 1369 (m), 848 (w); MS (APCI+), m/z (%) = 245 (27) [M+H]+; Anal. Calcd for C13H24O4: C, 63.91;
H, 9.90. Found: C, 64.22; H, 9.95.
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Dimethyl octanedioate (9, Table 1, entry 2). The residue was purified by column chromatography on silica gel
(P.E.:EtOAc = 10:1 → 4:1) and yielded the targeted compound as colorless viscous oil (Rf = 0.73, P.E.:EtOAc =
4:1). 1H NMR (300 MHz, CDCl3): δ 1.32 (quint, J = 3.7 Hz, 4H), 1.62 (t, J = 7.3 Hz, 4H), 2.30 (td, J = 7.3, 2.2
Hz, 4H), 3.66 (d, J = 2.8 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 24.9, 28.9, 34.1, 51.7, 174.3; IR (film): νꢀ1 2948
(w), 2929 (w), 1739 (s), 1436 (m); MS (APCI+), m/z (%) 203 (55) [M+H]+; Anal. Calcd for C10H18O4: C, 59.39;
H, 8.97. Found: C, 59.67; H, 9.21.
1ꢀallyl 8ꢀmethyl octanedioate (9, Table 1, entry 3). The residue was purified by column chromatography on silica
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gel (P.E.:EtOAc = 10:1) and yielded the targeted compound as colorless oil (Rf = 0.68, P.E.:EtOAc = 4:1). H
NMR (300 MHz, CDCl3): δ 1.33 (quint, J = 3.6 Hz, 4H), 1.53 – 1.76 (m, 4H), 2.31 (q, J = 7.8 Hz, 4H), 3.65 (d, J
= 2.2 Hz, 3H), 4.53 – 4.62 (m, 2H), 5.22 (dt, J = 10.4, 1.5 Hz, 1H), 5.30 (dd, J = 17.2, 1.7 Hz, 1H), 5.80 – 6.05
(m, 1H); 13C NMR (75 MHz, CDCl3): δ 24.9, 28.9, 34.2, 34.3, 51.6, 65.1, 118.3, 132.5, 173.5, 174.3; IR (film): νꢀ
1 2949 (w), 2926 (w), 1732 (s), 1435 (m); MS (APCI+), m/z (%) 229 (100) [M+H]+; Anal. Calcd for C12H20O4: C,
63.14; H, 8.83. Found: C, 62.96; H, 9.04.
Methyl 5ꢀ((tertꢀbutyldiphenylsilyl)oxy)pentanoate (9, Table 1, entry 4; Table 2, entry 5). The residue was purified
by column chromatography on silica gel (P.E.:EtOAc = 20:1 → 10:1) and yielded the targeted compound as a
1
slightly yellow oil (Rf = 0.83, P.E.:EtOAc = 2:1). H NMR (300 MHz, CDCl3): δ 1.07 (s, 9H), 1.53 – 1.70 (m,
2H), 1.70 – 1.83 (m, 2H), 2.34 (t, J = 7.4 Hz, 2H), 3.68 (s, 3H), 7.32 – 7.48 (m, 7H), 7.60 – 7.77 (m, 4H); 13C
NMR (75 MHz, CDCl3): δ 19.4, 21.6, 27.1, 32.1, 34.0, 51.7, 63.6, 127.8, 129.8, 134.1, 135.8, 174.3; IR (film): νꢀ1
2949 (w), 2950 (w), 2940 (w), 2895 (w), 1739 (s), 1429 (m), 1111 (s); MS (APCI+), m/z (%) = 371 (48) [M+H]+;
Anal. Calcd for C22H30O3Si: C, 71.31; H, 8.16. Found: C, 71.49; H, 8.25.
Methyl 5ꢀoxohexanoate (9, Table 1, entry 5). The residue was purified by column chromatography on silica gel
(P.E.:EtOAc = 10:1 → 4:1 → 2:1) and yielded the targeted compound as a colorless oil (Rf = 0.65, P.E.:EtOAc =
1:1). 1H NMR (300 MHz, CDCl3): δ 1.89 (quint, J = 7.2 Hz, 2H), 2.14 (s, 3H), 2.34 (t, J = 7.2 Hz, 2H), 2.51 (t, J
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= 7.2 Hz, 2H), 3.67 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 19.0, 30.1, 33.2, 42.6, 51.8, 173.8, 208.2; IR (film): νꢀ
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2961 (w), 2952 (w), 1729 (s), 1712 (s), 1438 (m), 1253 (m); MS (APCI+), m/z (%) 145 (73) [M+H]+; Anal.
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Calcd for C7H12O3: C, 58.32; H, 8.39. Found: C, 58.57; H, 8.19.
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1ꢀethyl 4ꢀmethyl (R)ꢀ2ꢀmethylsuccinate (9, Table 1, entry 6). The residue was purified by column
chromatography on silica gel (P.E.:EtOAc = 20:1 → 10:1 → 4:1) and yielded the targeted compound as a
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colorless oil (Rf = 0.70, P.E.:EtOAc = 4:1). ꢀꢁꢂꢃ = +3.02 (c 1.2, ꢄꢅꢄꢆꢃ); 1H NMR (300 MHz, CDCl3): δ 1.20 (t,
J = 7.0 Hz, 3H), 1.24 (d, J = 7.1 Hz, 3H), 2.38 (dd, J = 16.4, 6.0 Hz, 1H), 2.72 (dd, J = 16.4, 8.2 Hz, 1H), 2.89
(dq, J = 13.9, 7.1 Hz, 1H), 3.66 (s, 3H), 4.13 (q, J = 7.1 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 14.3, 17.1, 36.0,
37.5, 51.8, 60.8, 172.4, 175.3; IR (film): νꢀ1 2963 (w), 2949 (w), 1730 (s), 1716 (s), 1434 (m), 1251 (m); MS
(CI+), m/z (%) 175 (41) [M+H]+; HRMS(EI+), m/z calcd. for C8H14O4 [M]+: 174.0892, found 174.0886; ee = 56 %.
The ee of the product was determined by chiral GC using γꢀTA column (80 °C, τ(S)ꢀminor = 30.6 min, τ(R)ꢀmajor
=
34.3 min). The major enantiomer was determined to be (R) with help of optical rotation measurement (the sign of
the measured value was compared with known values).30
4ꢀallyl 1ꢀethyl (R)ꢀ2ꢀmethylsuccinate (9, Table 1, entry 7). The residue was purified by column chromatography
on silica gel (P.E.:EtOAc = 50:1 → 10:1) and yielded the targeted compound as a colorless oil (Rf = 0.55,
P.E.:EtOAc = 10:1). ꢀꢁꢂꢃ = +0.62 (c 1.11, ꢄꢅꢄꢆꢃ); 1H NMR (300 MHz, CDCl3): δ 1.21 (d, J = 7.1 Hz, 3H), 1.24
(t, J = 7.1 Hz, 3H), 2.42 (dd, J = 16.4, 6.0 Hz, 1H), 2.76 (dd, J = 16.4, 8.2 Hz, 1H), 2.89 (dt, J = 14.0, 7.1 Hz, 1H),
4.13 (q, J = 7.1 Hz, 2H), 4.57 (dt, J = 5.7, 1.3 Hz, 2H), 5.21 (dq, J = 10.5, 1.2 Hz, 1H), 5.30 (dq, J = 17.1, 1.5 Hz,
1H), 5.89 (ddt, J = 17.3, 10.4, 5.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 14.3, 17.2, 36.0, 37.7, 60.8, 65.4, 118.4,
132.2, 171.7, 175.3; IR (film): νꢀ1 2990 (w), 2979 (w), 2921 (w), 2875 (w), 1729 (s), 1381 (m); MS (CI+), m/z
(%) 201 (100) [M+H]+; HRMS(EI+), m/z calcd for C10H17O4 [M+H]+: 201.1127, found 201.1125; ee = 28 %. The
ee of the product was determined by chiral GC using γꢀTA column (110 °C (25 min) → 10°C/min till 170 °C →
170 °C (15 min), τ(S)ꢀminor = 32.50 min, τ(R)ꢀmajor = 32.81 min). The major enantiomer was determined to be (R)
with help of optical rotation measurement (the sign of the measured value was compared with known values).31
Allyl (S)ꢀ3ꢀmethylnonanoate (9, Table 1, entry 8). The residue was purified by column chromatography on silica
gel (P.E.:EtOAc = 100:1 → 50:1 → 20:1) and yielded the targeted compound as a colorless oil (Rf = 0.75,
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P.E.:EtOAc = 10:1). ꢀꢁꢂꢃ = −0.14 (c 1.4, ꢄꢅꢄꢆꢃ); H NMR (300 MHz, CDCl3): δ 0.87 (t, J = 6.2 Hz, 7H), 0.93
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(d, J = 6.6 Hz, 3H), 1.13 – 1.38 (m, 10H), 1.96 (quint, J = 6.5 Hz, 1H), 2.13 (dd, J = 14.7, 8.2 Hz, 1H), 2.33 (dd,
J = 14.6, 6.1 Hz, 1H), 4.57 (dd, J = 5.7, 1.5 Hz, 2H), 5.22 (dt, J = 10.4, 1.2 Hz, 1H), 5.31 (dt, J = 17.2, 1.4 Hz,
1H), 5.91 (dddd, J = 17.4, 11.5, 5.7, 1.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 14.3, 19.9, 22.8, 27.1, 29.6, 30.6,
32.0, 36.9, 42.0, 65.0, 118.2, 132.6, 173.1; IR (film): νꢀ1 2959 (w), 2927 (w), 2855 (w), 1739 (s), 1381 (w); MS
(CI+), m/z (%) = 213 (100) [M+H]+; HRMS(ESI+), m/z calcd. for C13H24O2Na [M+Na]+: 235.1669, found
235.1669; Anal. Calcd for C13H24O2: C, 73.54; H, 11.39; Found: C, 73.55; H 11.41; ee = 75 %. The ee of the
product was determined by chiral GC using CHIRALDEX βꢀPM column (100 °C (25 min) → 10°C/min till
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160 °C → 160 °C (4 min), τ(R)ꢀminor = 27.80 min, τ(S)ꢀmajor = 29.05 min). The major enantiomer was determined to
be (S) with help of optical rotation measurement (the sign of the measured value was compared with known
values).32
tertꢀbutyl (R)ꢀ3ꢀmethylnonanoate (9, Table 1, entry 9). The residue was purified by column chromatography on
silica gel (P.E.:EtOAc = 100:1 → 50:1) and yielded the targeted compound as a colorless oil (Rf = 0.81,
P.E.:EtOAc = 50:1). ꢀꢁꢂꢃ = +1.07 (c 1.1, ℎꢇꢈꢉꢊꢇ); 1H NMR (300 MHz, CDCl3): δ 0.96 (t, J = 7.1 Hz, 3H), 1.09
(d, J = 7.6 Hz, 2H), 1.17 – 1.40 (m, 6H), 1.44 (s, 9H), 1.46 – 1.64 (m, 4H), 1.89 (q, J = 5.2 Hz, 1H), 2.00 (dd, J =
14.2, 8.0 Hz, 1H), 2.20 (dd, J = 14.1, 5.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 14.3, 19.9, 22.9, 26.8, 28.3,
30.7, 32.2, 36.9, 43.4, 80.1, 173.0; IR (film): νꢀ1 = 2956 (w), 2930 (w), 2853 (w), 1702 (s), 1465 (w); MS (CI+),
m/z (%): 229 (100) [M+H]+; HRMS(CI+), m/z calcd. for C14H29O2H [M+H]+: 229.2162, found 229.2161; ee =
95 %. The ee of the product was determined by chiral GC using CHIRALDEX βꢀPM column (100 °C (25 min)
→ 10°C/min till 160 °C → 160 °C (4 min), τ(R)ꢀmajor = 27.49 min, τ(S)ꢀminor = 28.38 min). The major enantiomer
was determined to be (R) with help of optical rotation measurement (the sign of the measured value was
compared with known values).32
tertꢀbutyl (Z)ꢀoctꢀ4ꢀenoate (9, Table 1, entry 10; Table 2, entry 6). The residue was purified by column
chromatography on silica gel (P.E.:EtOAc = 50:1 → 20:1) and yielded the targeted compound as a colorless oil
(Rf = 0.98, P.E.:EtOAc = 4:1). (E/Z) = 2:>95. 1H NMR (300 MHz, CDCl3): δ 0.92 (t, J = 7.3 Hz, 3H), 1.38 (dt, J
= 14.9, 7.5 Hz, 2H), 1.45 (s, 9H), 2.03 (dd, J =13.9, 6.7 Hz, 2H), 2.20 – 2.39 (m, 4H), 5.37 (quintd, J = 10.8, 6.9
Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 14.0, 23.0, 23.2, 28.3, 29.5, 35.8, 80.3, 128.0, 131.2, 172.0; IR (film): νꢀ1
2959 (w), 2934 (w), 2921 (w), 1733 (s), 1460 (w); MS (APCI+), m/z (%): 199 (24) [M+H]+; HRMS(EI+), m/z
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calcd. for C12H22O2H [M+H]+: 199.1693, found 199.1695; Anal. Calcd for C12H22O2: C, 72.68; H, 11.18. Found:
C, 72.73; H, 11.10.
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Methyl heptꢀ6ꢀenoate (9, Table 1, entry 11; Table 2, entry 7). The residue was purified by column
chromatography on silica gel (P.E.:EtOAc = 100:1 → 20:1) and yielded the targeted compound as a colorless oil
(Rf = 0.88, P.E.:EtOAc = 4:1). 1H NMR (300 MHz, CDCl3): δ 1.42 (quint, J = 7.5, 7.1 Hz, 2H), 1.58 – 1.72 (m,
2H), 2.07 (q, J = 7.2 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 3.66 (s, 3H), 4.95 (dq, J = 10.1, 1.2 Hz, 1H), 5.01 (q, J =
17.4, 2.0 Hz, 1H), 5.79 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 24.6, 28.5, 33.5, 34.1,
51.7, 114.9, 138.6, 174.3; HRMS(ESI+), m/z calcd. for C8H14O2Na[M+Na]+: 165.0886, found 165.0892.
tertꢀbutyl tetracosanoate (9, Table 1, entry 12; Table 2, entry 4). The residue was purified by column
chromatography on silica gel (P.E.:EtOAc = 50:1 → 20:1 → 10:1) and yielded the targeted compound as a
colorless solid (Rf = 0.92, P.E.:EtOAc = 4:1). M.p. = 62ꢀ63°C; 1H NMR (300 MHz, CDCl3): δ 0.90 (t, J = 6.6 Hz,
3H), 1.28 (s, 40H), 1.48 (s, 9H), 1.63 (quint, J = 7.1 Hz, 2H), 2.30 (t, J = 7.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3): δ 14.4, 22.8, 25.2, 28.0, 29.3, 29.5, 29.6, 29.7, 29.83, 29.89, 29.93, 32.2, 34.3, 80.1, 174.8; MS (CI), m/z
(%): 426 (72) [M+H]+; HRMS(ESI+), m/z: calcd. for C28H56O2Na[M+Na]+: 447.41725, found 447.41733.
Methyl tetracosanoate (9, Table 1, entry 13; Table 2, entry 3). The residue was purified by column
chromatography on silica gel (P.E.:EtOAc = 50:1 → 20:1 → 10:1) and yielded the targeted compound as a
colorless solid (Rf = 0.88, P.E.:EtOAc = 4:1). M.p. = 53ꢀ54°C; 1H NMR (300 MHz, CDCl3): δ 0.89 (t, J = 6.6 Hz,
3H), 1.26 (s, 40H), 1.62 (quint, J = 7.1 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 3.67 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 14.3, 22.9, 25.2, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 29.9, 32.2, 34.3, 51.6, 174.5; MS (APCI), m/z (%):
383 (23) [M+H]+; HRMS(ESI+), m/z: calcd. for C25H50O2Na[M+Na]+: 405.3703, found 405.3705.
Methyl heptꢀ5ꢀynoate (9, Table 1, entry 14; Table 2, entry 8). The residue was purified by column
chromatography on silica gel (P.E.:EtOAc = 20:1 → 10:1) and yielded the targeted compound as a colorless oil
(Rf = 0.82, P.E.:EtOAc = 4:1). 1H NMR (300 MHz, CDCl3): δ 1.77 (t, J = 2.5 Hz, 3H), 1.83 (quint, J = 7.1 Hz,
2H), 2.20 (ddq, J = 7.1, 5.1, 2.5 Hz, 2H), 2.44 (t, J = 7.4 Hz, 2H), 3.68 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 3.6,
22.6, 26.1, 34.4, 51.7, 76.6, 78.1, 174.0; MS (APCI), m/z (%): 141 (15) [M+H]+; HRMS(EI+), m/z: calcd. for
C8H12O2H [M+H]+: 141.0910, found 141.0919.
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Methyl 6ꢀ(benzyloxy)hexanoate (9, Table 1, entry 15).33 The residue was purified by column chromatography on
silica gel (P.E.:EtOAc = 4:1 → 2:1 → 1:1) and yielded the targeted compound as colorless oil (Rf = 0.16,
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P.E.:EtOAc = 1:1). H NMR (400 MHz, CDCl3): δ 1.36–1.52 (m, 2H), 1.62–1.70 (m, 4H), 2.34 (t, J = 7.5 Hz,
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2H), 3.49 (t, J = 6.5 Hz, 2H), 3.69 (s, 3H), 4.52 (s, 2H), 7.33–7.43 (m, 5H); 13C NMR (125 MHz, CDCl3): δ 24.5,
25.6, 29.5, 33.7, 51.5, 70.5, 73.0, 127.8, 128.0, 128.3, 138.1, 174.2; HRMS (ESI) calcd. for C14H20NaO3
[M+Na]+: 259.1305, found: 259.1301; Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.20; H, 8.50.
Methyl 3ꢀ(pyridinꢀ2ꢀyl)propanoate (9, Table 1, entry 16).34 The residue was purified by column chromatography
on silica gel (P.E.:EtOAc = 10:1 → 4:1→ 2:1) and yielded the targeted compound as colorless oil (Rf = 0.26,
P.E.:EtOAc = 1:1). 1H NMR (400 MHz, CDCl3): δ 2.82 (t, J = 7.5 Hz, 2H), 3.12 (t, J = 7.5 Hz, 2H), 3.66 (s, 3H),
7.07 – 7.14 (m, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.58 (td, J = 7.7, 1.8 Hz, 1H), 8.52 (d, J = 3.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 32.9, 33.2, 51.6,121.4,122.9, 136.4,149.3,160.0, 173.5; HRMS (ESI) calcd. for
C9H11NNaO2 [M+Na]+: 188.0682, found: 188.0686; Anal. Calcd for C9H11NO2: C, 65.44; N, 8.48; H, 6.71.
Found: C, 65.45; N, 8.52; H, 6.70.
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General Protocol for Mitsunobu reaction Reactions.
Conditions A: A solution of BTꢀsulfone (C-acid) (1.2 mmol, 1.2 equiv), PPh3 (0.393 g, 1.5 mmol, 1.5 equiv) and
alcohol 6 (1.0 mmol, 1.0 equiv) in toluene (10 mL, 0.1M) was cooled to 0°C and ADDP (1,1'ꢀ
(azodicarbonyl)dipiperidine) (0.378 g, 1.5 mmol, 1.5 equiv) was added. The resulting solution was allowed to
warm to rt and stirred at this temperature for additional 12 h. Silica gel (2g per 1 mmol of alcohol 6) was added
and the whole mixture was concentrated under reduced pressure. The residue was purified by flash column
chromatography on SiO2 with appropriate solvent system.
Conditions B: A solution of BTꢀsulfone (C-acid) (1.2 mmol, 1.2 equiv), PPh3 (0.393 g, 1.5 mmol, 1.5 equiv) and
alcohol 6 (1.0 mmol, 1.0 equiv) in toluene (10 mL, 0.1M) was cooled to 0°C and DEAD (Diethyl
azodicarboxylate) (0.238 mL, 1.5 mmol, 1.5 equiv) was added. The resulting solution was allowed to warm to rt
and stirred at this temperature for additional 6 h. Silica gel (2g per 1 mmol of alcohol 6) was added and the whole
mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on
SiO2 with appropriate solvent system.
Products 8b prepared via Mitsunobu reaction.
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1ꢀ(tertꢀbutyl) 8ꢀmethyl 2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)octanedioate (8b, Table 1, entry 1). Starting from methyl
5ꢀhydroxypentanoate. Purification by flash chromatography (petroleum ether:EtOAc = 10:1 ꢀ> 4:1); Rf = 0.34
(P.E.:EtOAc = 4:1); 1H NMR (300 MHz, CDCl3): δ 1.34 (s, 9H), 1.45ꢀ1.59 (m, 4H), 1.58ꢀ1.75 (m, 2H), 2.05ꢀ2.29
(m, 2H), 2.31 (t, J = 7.4 Hz, 2H), 3.67 (s, 3H), 4.36 (dd, J = 8.9, 6.2 Hz, 1H), 7.61ꢀ7.66 (m, 2H), 8.03 (dd, J = 7.9,
0.3 Hz, 1H), 8.25 (dd, J = 7.8, 0.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 24.5, 25.8, 26.6, 27.6, 28.5, 33.8, 51.5,
70.3, 84.0, 122.3, 125.6, 127.7, 128.2, 137.0, 152.6, 163.6, 164.7, 173.9; MS (CI+), m/z (%): 442 (11) [M+H]+;
HRMS (ESI) calcd. for C20H27NNaO6S2 [M+Na]+: 464.1172, found: 464.1170.
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dimethyl 2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)octanedioate (8b, Table 1, entry 2). Starting from methyl 5ꢀ
hydroxypentanoate. Purification by flash chromatography (petroleum ether:EtOAc = 4:1 ꢀ> 2:1); Rf = 0.71
(P.E.:EtOAc = 2:1); 1H NMR (300 MHz, CDCl3): δ 1.30 – 1.51 (m, 4H), 1.62 (quint, J = 7.3 Hz, 2H), 2.14 – 2.35
(m, 4H), 3.65 (s, 3H), 3.73 (s, 3H), 4.44 (dd, J = 8.6, 6.2 Hz, 1H), 7.55 – 7.72 (m, 2H), 8.02 (ddd, J = 7.4, 1.4, 0.7
Hz, 1H), 8.19 – 8.30 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 24.6, 26.2, 26.8, 28.6, 33.9, 51.7, 53.5, 69.8, 122.5,
125.9, 127.9, 128.5, 137.3, 152.8, 164.4, 165.5, 174.0; MS (CI+), m/z (%): 401 [M+H]+; HRMS (ESI) calcd. for
C17H21NNaO6S2 [M+Na]+: 422.0702, found: 422.0702.
1ꢀallyl 8ꢀmethyl 2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)octanedioate (8b, Table 1, entry 3). Starting from methyl 5ꢀ
hydroxypentanoate. Purification by flash chromatography (petroleum ether:EtOAc = 4:1 ꢀ> 2:1); Rf = 0.22
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(P.E.:EtOAc = 2:1); H NMR (300 MHz, CDCl3): δ 1.03 – 1.57 (m, 4H), 1.54 – 1.81 (m, 2H), 2.15 – 2.37 (m,
4H), 3.65 (s, 3H), 4.46 (dd, J = 8.6, 6.2 Hz, 1H), 4.58 (ddd, J = 6.0, 2.7, 1.2 Hz, 2H), 5.12 (dd, J = 10.4, 1.2 Hz,
1H), 5.19 (dt, J = 17.2, 1.4 Hz, 1H), 5.70 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 7.52 – 7.79 (m, 2H), 7.92 – 8.09 (m,
1H), 8.17 – 8.29 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 24.6, 26.1, 26.7, 28.6, 33.9, 51.7, 67.2, 69.8, 119.7,
119.8, 122.4, 125.8, 127.9, 128.4, 130.7, 137.3, 152.8, 164.4, 164.7, 174.0; MS (CI+), m/z (%): 427 [M+H]+;
HRMS (ESI) calcd. for C19H23NO6S2H [M+H]+: 426.1040, found: 426.1042.
Methyl 2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)ꢀ5ꢀ((tertꢀbutyldiphenylsilyl)oxy)pentanoate (8b, Table 1, entry 4). Starting
from 4ꢀhydroxybutanꢀ2ꢀone. Purification by flash chromatography (petroleum ether:EtOAc = 10:1ꢀ>4:1);
Keto/enol = ~6:1; Peaks belonging to enol form are marked with*; Rf = 0.46 (P.E.:EtOAc = 4:1); 1H NMR (300
MHz, CDCl3): δ 0.99 (s, 9H, Hꢀ9), 1.58 – 1.77 (m, 2H), 2.33 – 2.48 (m, 2H), 3.68 (t, J = 5.9 Hz, 2H), 3.73 (s, 3H),
4.62 (dd, J = 9.6, 5.4 Hz, 1H), 5.30 (s, 1H*), 7.30 – 7.47 (m, 6H), 7.57 – 7.69 (m, 6H), 7.85 – 7.94 (m, 2H*), 8.02
(dd, J = 6.7, 2.1 Hz, 1H), 8.24 (dd, J = 7.2, 2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 19.3, 23.6, 26.9, 29.7,
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53.5 (Cꢀ4), 63.0, 69.7, 122.5, 126.0, 127.9, 128.4, 129.9, 133.6, 135.7, 137.4, 152.9, 164.5, 165.5; MS (APCI),
m/z (%): 568 (100) [M+]; Anal. Calcd for C29H33NO5S2Si: C, 61.35; H, 5.86; N, 2.47. Found: C, 61.34; H, 5.89; N,
2.48.
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Methyl 2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)ꢀ5ꢀoxohexanoate (8b, Table 1, entry 5).18b Starting from 4ꢀhydroxybutanꢀ
2ꢀone. Purification by flash chromatography (petroleum ether:EtOAc = 4:1 ꢀ> 2:1ꢀ>1:1); Rf = 0.36 (P.E.:EtOAc =
1:1); 1H NMR (300 MHz, CDCl3): δ 2.14 (s, 3H), 2.37 – 2.89 (m, 4H), 3.70 (s, 3H), 4.60 (dd, J = 8.3, 5.8 Hz, 1H),
7.51 – 7.73 (m, 2H), 8.02 (d, J = 7.9 Hz, 1H), 8.23 (d, J = 8.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 20.7, 30.0,
39.8, 53.5, 68.4, 122.5, 125.8, 127.9, 128.5, 137.3, 152.7, 164.3, 165.3, 206.4; IR (film): νꢀ1 2957 (w), 2938 (w),
2929 (w), 2855 (w), 1747 (s), 1471 (m), 1429 (m), 1340 (s), 1317 (m), 1151 (s), 1111 (s), 910 (s), 764 (s), 704 (s),
600 (w); MS (CI+), m/z (%): 342 [M+H]+; HRMS (ESI) calcd. for C14H15NNaO5S2 [M+Na]+: 364.0284, found:
364.0284.
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4ꢀethyl 1ꢀmethyl (3S)ꢀ2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)ꢀ3ꢀmethylsuccinate (8b, Table 1, entry 6). Starting from
ethyl (R)ꢀ2ꢀhydroxypropanoate. Purification by flash chromatography (petroleum ether:EtOAc = 10:1 ꢀ> 4:1); As
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a mixure of stereoisomers; Rf = 0.73 (P.E.:EtOAc = 2:1); H NMR (300 MHz, CDCl3): δ 1.17 – 1.35 (m, 3H),
1.41 (d, J = 6.9 Hz, 3H), 1.49 (d, J = 7.2 Hz, 3H), 1.61 (d, J = 7.2 Hz, 3H), 2.87 (d, J = 5.0 Hz, 1H), 3.53 – 3.63
(m, 1H), 3.63 (s, 3H), 3.70 (s, 3H), 3.73 (s, 3H), 4.06 – 4.33 (m, 2H), 4.59 (s, 1H), 4.90 (d, J = 8.6 Hz, 1H), 5.25
(d, J = 6.7 Hz, 1H), 7.53 – 7.72 (m, 2H), 8.02 (dt, J = 6.6, 1.5 Hz, 1H), 8.16 – 8.31 (m, 1H); 13C NMR (75 MHz,
CDCl3): δ 14.2, 14.3, 15.8, 20.6, 37.6, 38.9, 53.4, 53.5, 58.7, 61.8, 61.9, 66.9, 70.0, 71.5, 122.5, 122.6, 125.7,
125.8, 127.9, 127.9, 128.5, 137.3, 152.6, 162.3, 164.1, 165.1, 172.2, 172.7, 175.9; MS (CI+), m/z (%): 372
[M+H]+; HRMS (ESI) calcd. for C15H17NNaO6S2 [M+Na]+: 394.0389, found: 394.0390.
1ꢀAllyl 4ꢀethyl (3S)ꢀ2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)ꢀ3ꢀmethylsuccinate (8b, Table 1, entry 7). Starting from ethyl
(R)ꢀ2ꢀhydroxypropanoate. Purification by flash chromatography (petroleum ether:EtOAc = 4:1 ꢀ> 2:1); as a
mixure of stereoisomers; Rf = 0.54 (P.E.:EtOAc = 2:1); 1H NMR (300 MHz, CDCl3): δ 1.13 – 1.30 (m, 3H), 1.51
(dd, J = 7.2, 1.2 Hz, 3H), 1.63 (dd, J = 7.2, 1.2 Hz, 3H), 1.69 (d, J = 7.3 Hz, 3H), 3.54 – 3.68 (m, 1H), 3.94 – 4.26
(m, 3H), 4.40 – 4.52 (m, 1H), 4.56 (dt, J = 5.9, 1.3 Hz, 2H), 4.93 (dd, J = 8.6, 1.2 Hz, 1H), 5.01 – 5.22 (m, 2H),
5.28 (d, J = 6.6 Hz, 1H), 5.48 – 5.82 (m, 1H), 7.47 – 7.75 (m, 2H), 7.94 – 8.09 (m, 1H), 8.16 – 8.28 (m, 1H); 13C
NMR (75 MHz, CDCl3): δ 12.6, 14.1, 14.2, 14.2, 15.9, 17.0, 37.6, 38.8, 42.0, 61.4, 61.8, 61.9, 67.1, 67.3, 69.8,
71.0, 71.4, 119.5, 119.7, 122.4, 125.8, 125.8, 127.7, 127.9, 127.9, 128.4, 128.5, 130.5, 132.5, 137.2, 137.3, 152.6,
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163.3, 164.3, 164.8, 165.3, 172.1, 172.7; MS (CI+), m/z (%): 399 [M+H]+; HRMS (ESI) calcd. for
C17H19NNaO6S2 [M+Na]+: 420.0546, found: 420.0545.
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Allyl (3S)ꢀ2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)ꢀ3ꢀmethylnonanoate (8b, Table 1, entry 8). Starting from ethyl (R)ꢀ
octanꢀ2ꢀol. Purification by flash chromatography (petroleum ether:EtOAc = 10:1 ꢀ> 4:1); As a mixure of
stereoisomers; Rf = 0.45 (P.E.:EtOAc = 4:1); 1H NMR (300 MHz, CDCl3): δ 0.72 – 0.96 (m, 3H), 1.08 – 1.46 (m,
13H), 1.55 – 1.75 (m, 1H), 2.54 – 2.78 (m, 1H), 2.89 – 3.17 (m, 1H), 4.41 – 4.69 (m, 2H), 4.90 (q, J = 6.3 Hz,
1H), 5.04 – 5.29 (m, 2H), 5.60 – 5.90 (m, 1H), 7.56 – 7.71 (m, 2H), 8.02 (dt, J = 7.3, 2.4 Hz, 1H), 8.23 (ddd, J =
8.5, 7.4, 1.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 14.3, 16.8, 18.0, 19.8, 22.7, 25.3, 26.6, 29.2, 29.3, 30.4, 30.7,
31.8, 32.6, 33.1, 33.8, 35.2, 35.7, 66.8, 66.9, 69.2, 72.8, 74.4, 74.9, 119.7, 119.8, 122.5, 125.7, 125.9, 127.8,
127.9, 128.3, 128.4, 130.9, 131.6, 137.2, 152.7, 164.0, 164.5, 165.9; MS (CI+), m/z (%): 411 [M+H]+; HRMS
(ESI) calcd. for C20H27NNaO4S2 [M+Na]+: 432.1274, found: 432.1273.
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tertꢀbutyl (3R)ꢀ2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)ꢀ3ꢀmethylnonanoate (8b, Table 1, entry 9). Starting from ethyl
(S)ꢀoctanꢀ2ꢀol. Purification by flash chromatography (petroleum ether:EtOAc = 10:1 ꢀ> 4:1); As a mixure of
stereoisomers; Rf = 0.87 (P.E.:EtOAc = 4:1); 1H NMR (300 MHz, CDCl3): δ 0.86 (dt, J = 13.5, 6.9 Hz, 3H), 1.16
– 1.37 (m, 20H), 1.37 – 1.56 (m, 1H), 1.56 – 1.77 (m, 1H), 2.59 (dt, J = 12.7, 6.4 Hz, 1H), 4.41 (d, J = 7.3 Hz,
1H), 4.51 (d, J = 4.9 Hz, 1H), 7.62 (quintd, J = 7.2, 1.5 Hz, 2H), 7.98 – 8.05 (m, 1H), 8.17 – 8.27 (m, 1H); 13
C
NMR (75 MHz, CDCl3): δ 14.2, 16.8, 18.0, 22.7, 26.4, 27.8, 27.9, 31.7, 31.9, 32.5, 33.1, 33.6, 35.2, 73.3, 75.6,
84.0, 122.5, 125.6, 127.8, 128.2, 137.1, 152.7, 163.6, 164.1, 166.4; MS (CI+), m/z (%): 427 [M+H]+; HRMS
(ESI) calcd. for C21H31NNaO4S2 [M+Na]+: 448.1587, found: 448.1586.
tertꢀbutyl (Z)ꢀ2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)octꢀ4ꢀenoate (8b, Table 1, entry 10). (Z)ꢀhexꢀ2ꢀenꢀ1ꢀol. Purification
by flash chromatography (petroleum ether:EtOAc = 4:1 ꢀ> 2:1); As a mixure of stereoisomers; Rf = 0.73
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(P.E.:EtOAc = 2:1); H NMR (300 MHz, CDCl3): δ 0.89 (t, J = 7.4 Hz, 3H), 1.34 (s, 9H), 1.32 – 1.45 (m, 2H),
2.05 (tdd, J = 9.2, 6.4, 1.9 Hz, 2H), 2.87 – 3.19 (m, 2H), 4.38 (dd, J = 10.5, 4.5 Hz, 1H), 5.24 – 5.39 (m, 1H),
5.50 – 5.64 (m, 1H), 7.54 – 7.85 (m, 2H), 7.98 – 8.11 (m, 1H), 8.18 – 8.37 (m, 1H); 13C NMR (75 MHz, CDCl3):
δ 13.9, 22.7, 24.5, 27.8, 29.5, 70.2, 84.1, 122.3, 122.5, 125.8, 127.9, 128.4, 134.9, 137.2, 152.9, 160.5, 164.9; MS
(CI+), m/z (%): 397 [M+H]+; HRMS (ESI) calcd. for C19H25NNaO4S2 [M+Na]+: 418.1117, found: 418.1112.
methyl 2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)heptꢀ6ꢀenoate (8b, Table 1, entry 11).18b Starting from pentꢀ4ꢀenꢀ1ꢀol.
Purification by flash chromatography (petroleum ether:EtOAc = 10:1 ꢀ> 4:1); Keto/enol forms = ~11:1; Rf = 0.51
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(P.E.:EtOAc = 2:1); 1H NMR (300 MHz, CDCl3): δ 1.45 – 1.58 (m, 2H), 2.11 (dt, J = 14.2, 4.7 Hz, 2H), 2.20 –
2.32 (m, 2H), 3.73 (s, 3H), 4.47 (td, J = 7.9, 5.4 Hz, 1H), 4.95 (dd, J = 10.5, 1.3 Hz, 1H), 5.05 (dt, J = 3.0, 1.5 Hz,
1H), 5.73 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 7.64 (quintd, J = 7.2, 1.5 Hz, 2H), 8.03 (dd, J = 7.2, 2.1 Hz, 1H), 8.25
(dd, J = 7.4, 1.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 25.8, 26.3, 33.1, 53.5, 69.8, 115.9, 122.5, 125.9, 127.9,
128.5, 137.2, 137.3, 152.8, 164.4, 165.5; IR (film): νꢀ1 = 2940 (w), 2932 (w), 2923 (w), 2911 (w), 2903 (w), 1739
(s), 1641 (w), 1554 (w), 1471 (m), 1338 (s), 1149 (s), 1024 (m), 854 (m), 764 (s), 731 (s), 619 (m); MS (APCI),
m/z (%): 340 (100) [M+]; Anal. Calcd for C15H17NO4S2: C, 53.08; H, 5.05; N, 4.13. Found: C, 52.95; H, 5.17; N
4.16.
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tertꢀbutyl 2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)tetracosanoate (8b, Table 1, entry 12).18b Starting from docosanꢀ1ꢀol.
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Purification by flash chromatography (petroleum ether:EtOAc = 50:1ꢀ>20:1). M.p. = 101ꢀ103°C; H NMR (300
MHz, CDCl3): δ 0.87 (t, J = 6.7 Hz, 3H), 1.05 – 1.46 (m, 40H), 1.51 (s, 9H), 2.14 – 2.34 (m, 2H), 4.42 (dd, J =
8.8, 6.1 Hz, 1H), 7.59 – 7.72 (m, 2H), 8.02 (dd, J = 7.1, 1.9 Hz, 1H), 8.25 (dd, J = 7.2, 1.8 Hz, 1H); 13C NMR (75
MHz, CDCl3): δ 14.3, 22.9, 26.4, 27.1, 28.9, 29.2, 29.3, 29.6, 29.6, 29.8, 29.8, 29.9, 29.9, 32.1, 70.0, 81.0, 122.5,
125.9, 127.9, 128.4, 137.4, 152.8, 164.5, 165.6.; IR (film): νꢀ1 = 3062 (w), 2997 (s), 2929 (s), 1802 (w), 1748 (s),
1471 (m), 1331 (s), 1142 (s), 1122 (s); MS (APCI), m/z (%): 622 (100) [M+]; Anal. Calcd for C35H59NO4S2: C,
67.59; H, 9.56; N, 2.25. Found: C, 67.62; H, 9.52; N, 2.29.
Methyl 2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)tetracosanoate (8b, Table 1, entry 13).18b Starting from docosanꢀ1ꢀol.
Purification by flash chromatography (petroleum ether:EtOAc = 20:1ꢀ>10:1). Keto/enol forms = ~8:1. Peaks
belonging to enol form are marked with*. M.p. = 111ꢀ112°C; 1H NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.7 Hz,
3H), 1.05 – 1.71 (m, 40H), 2.14 – 2.34 (m, 2H), 3.64 (t, J = 6.7 Hz, 2H*), 3.74 (s, 3H, Hꢀ4), 4.44 (dd, J = 8.8, 6.0
Hz, 1H, Hꢀ2), 5.30 (s, 1H*), 7.58 – 7.71 (m, 2H), 8.03 (dd, J = 7.1, 1.9 Hz, 1H), 8.26 (dd, J = 7.2, 1.8 Hz, 1H);
13C NMR (75 MHz, CDCl3): δ 14.3, 22.9, 26.4, 27.1, 29.2, 29.3, 29.6, 29.8, 29.9, 32.1, 53.5, 70.0, 122.5, 125.9,
127.9, 128.4, 137.4, 152.8, 164.5, 165.6; IR (film): νꢀ1 = 3061 (w), 2996 (s), 2929 (s), 1801 (w), 1744 (s), 1472
(m), 1331 (s), 1143 (s), 1122 (s), 761 (s), 727 (s); MS (APCI), m/z (%): 580 (100) [M+]; Anal. Calcd for
C32H53NO4S2: C, 66.28; H, 9.21; N, 2.42. Found: C, 66.49; H, 9.17; N, 2.57.
Methyl 2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)heptꢀ5ꢀynoate (8b, Table 1, entry 14).18b Starting from pentꢀ3ꢀynꢀ1ꢀol.
Purification by flash chromatography (petroleum ether:EtOAc = 10:1ꢀ>4:1ꢀ>2:1ꢀ>1:1). Keto/enol forms = ~8:1.
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Peaks belonging to enol form are marked with*. 1H NMR (300 MHz, CDCl3): δ 1.73 (t, J = 2.3 Hz, 3H), 2.13 –
2.33 (m, 1H), 2.34 – 2.49 (m, 3H), 2.67 – 2.87 (m, 2H*), 3.74 (s, 3H), 4.70 (dd, J = 7.8, 6.1 Hz, 1H), 5.31 (s,
1H*), 5.39 – 5.55 (m, 1H), 7.49 – 7.37 (m, 1H*), 7.63 (quint, J = 7.2 Hz, 1H), 7.65 (quint, J = 7.2 Hz, 1H), 7.94
– 7.80 (m, 2H*), 8.03 (dd, J = 7.2, 2.1 Hz, 1H), 8.26 (dd, J = 7.4, 2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 3.6,
14.4, 16.7, 21.2, 25.8, 53.6, 60.6, 68.9, 75.8, 78.6, 122.5, 125.9, 128.0, 128.5, 137.4, 152.8, 164.2, 165.2; IR
(film): νꢀ1 = 2954 (w), 2917 (w), 1739 (s), 1471 (m), 1436 (m), 1336 (s), 1149 (s), 1024 (m), 854 (m), 764 (s),
731 (s), 694 (m), 640 (m); MS (APCI), m/z (%): 338 (100) [M+]; Anal. Calcd for C15H15NO4S2: C, 53.40; H,
4.48; N, 4.15. Found: C, 53.71; H, 4.63; N, 4.25.
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Methyl 2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)ꢀ6ꢀ(benzyloxy)hexanoate (8b, Table 1, entry 15). Starting from 4ꢀ
(benzyloxy)butanꢀ1ꢀol. Purification by flash chromatography (petroleum ether:EtOAc = 10:1 ꢀ> 4:1ꢀ>2:1); Rf =
0.34 (P.E.:EtOAc = 2:1); 1H NMR (500 MHz, CDCl3): δ 1.38 – 1.52 (m, 1H), 1.53 – 1.77 (m, 3H), 2.21 (dtd, J =
11.3, 6.5, 5.6 Hz, 1H), 2.29 – 2.41 (m, 1H), 3.32 – 3.48 (m, 2H), 3.73 (s, 3H), 4.36 (d, J = 11.9 Hz, 1H), 4.39 (d,
J = 12.0 Hz, 1H), 4.49 (t, J = 5.9 Hz, 1H), 7.23 – 7.32 (m, 5H), 7.37 – 7.45 (m, 2H), 7.91 (dd, J = 7.5, 1.6 Hz,
1H), 7.95 (dd, J = 7.1, 2.1 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 23.7, 24.7, 29.5, 52.9, 68.9, 70.5, 73.0, 122.5,
124.4, 127.7, 127.9, 127.9, 128.0, 128.4, 135.2, 138.2, 153.1, 164.5, 165.5; MS (CI+), m/z (%): 435 [M+H]+;
HRMS (ESI) calcd. for C21H23NNaO5S2 [M+Na]+: 456.0910, found: 456.0908; Anal. Calcd for C21H23NO5S2: C,
58.18; H, 5.35. Found: C, 58.21; H, 5.33.
methyl 2ꢀ(benzo[d]thiazolꢀ2ꢀylsulfonyl)ꢀ3ꢀ(pyridinꢀ2ꢀyl)propanoate (8b, Table 1, entry 16). Starting from pyridinꢀ
2ꢀylmethanol. Purification by flash chromatography (petroleum ether:EtOAc = 10:1 ꢀ> 4:1); Rf = 0.46
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(P.E.:EtOAc = 4:1); M.p. = 143ꢀ145°C; H NMR (500 MHz, CDCl3): δ 3.69 (d, J = 7.6 Hz, 2H), 3.73 (s, 2H),
4.44 (t, J = 7.6 Hz, 1H), 7.09 – 7.15 (m, 2H), 7.40 – 7.48 (m, 2H), 7.86 (td, J = 7.6, 1.5 Hz, 1H), 7.92 – 7.98 (m,
2H), 8.54 (dd, J = 3.8, 1.7 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 31.8, 52.7, 69.0, 122.1, 122.7, 124.2, 127.7,
128.8, 136.5, 137.0, 149.5, 153.1, 155.2, 166.0, 172.7; MS (ESI+), m/z (%): 363 [M+H]+; HRMS (ESI) calcd. for
C16H14N2NaO4S2 [M+Na]+: 385.0287, found: 385.0291; Anal. Calcd for C16H14N2O4S2: C, 53.03; H, 3.89. Found:
C, 53.05; H, 3.88.
Side products of the SmI2-mediated reductive elimination
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4:1) and yielded the targeted compound as colorless oil (Rf =0.56, P.E.:EtOAc = 2:1). H NMR (400 MHz,
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CDCl3): δ 9.04 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.59 – 7.50 (m, 1H), 7.50 – 7.42 (m,
1H); 13C NMR (101 MHz, CDCl3): δ 122.1, 123.7, 125.8, 126.4, 133.7, 153.0, 154.2.
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2ꢀ(methylamino)benzenethiol (13).35 Purification by column chromatography on silica gel (P.E.:EtOAc = 50:1 →
20:1 → 10:1 → 4:1) and yielded the targeted compound as colorless oil (Rf = 0.42, P.E.:EtOAc = 4:1). Colorless
oil. 1H NMR (300 MHz, CDCl3): δ 2.79 (s, 3H), 4.90 (t, J = 1.3 1H), 6.49ꢀ6.63 (m, 2H), 7.12ꢀ7.30 (m, 2H); 13C
NMR (75 MHz, CDCl3): δ 29.9, 122.1, 123.9, 125.8, 126.4, 154.1; MS (ESI+), m/z (%): 140 [M+H]+; HRMS
(ESI) calcd. for C7H9NNaS [M+Na]+: 162.03479, found: 162.03480; Anal. Calcd for C7H9NS: C, 60.39; H, 6.52;
N, 10.06. Found: C, 60.43; H, 6.57; N, 9.97.
Multigram scale synthesis of tert-butyl tetracosanoate (Scheme 4)
Sulfone (7, Table 2, entry 4). A solution of benzo[d]thiazol (BTꢀSH) (1.77 g, 10.6 mmol, 1.2 equiv), PPh3 (2.77
g, 10.6 mmol, 1.2 equiv) and docosanꢀ1ꢀol (3.0 g, 8.8 mmol, 1.0 equiv) in THF (88 mL, 0.1M) was cooled to 0°C
and DEAD (1.67 mL, 10.6 mmol, 1.2 equiv) was added. The resulting solution was allowed to warm to rt and
stirred for 12 h. The resulting solution was diluted with EtOH (250 mL), cooled to 0°C and Na2WO4.2H2O (413
mg, 1.1 mmol, 0.1 equiv) was added in one portion. After 15 min at 0°C, an aqueous 35% solution of H2O2 (25.6
mL, 264 mmol, 30 equiv) was added dropwise with the use of a dropping funnel over a period of 45 min. The
resulting yellowish solution was allowed to warm to rt and stirred at rt for 18 h. Deionized water (500 mL) was
added and the mixture was extracted with EtOAc (6x 250 mL). The combined organic layers were washed with
brine (500 mL), dried over Na2SO4, filtered and the solvents were evaporated under reduced pressure. The
residue was purified by flash chromatography on SiO2 (petroleum ether:EtOAc = 50:1 ꢀ> 10:1) yielding the
desired sulfone (4.22 g, 91%). β-carbonyl sulfone (8a, Table 2, entry 4). A solution of BTꢀsulfone 7 (4.22 g, 8.1
mmol, 1.0 equiv) and Boc2O (2.12 g, 9.7 mmol, 1.2 equiv) in THF (41 mL, 0.20M) was cooled to ꢀ78°C and
precooled (ꢀ20°C) LiHMDS (1.0M sol. in THF) (17.8 mL, 17.8 mmol, 2.2 equiv) was added within 2 min. The
resulting mixture was stirred at ꢀ78°C for 30 min, allowed to warm to 0°C within 3 h and stirred at 0°C for a
further 60 min before sat. aq. sol. of NH4Cl (150 mL) was added. The mixture was extracted with EtOAc (3x 250
mL) and the combined organic layers were washed with brine (250 mL), dried over NaSO4, and the solvents were
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removed under reduced pressure. The residue was purified by flash column chromatography on SiO2 (petroleum
ether:EtOAc = 50:1ꢀ>20:1) yielding the desired product (3.98 g, 79%) tert-butyl tetracosanoate (9, Table 2,
entry 4). To a solution of BTꢀsulfone ester (3.98 g, 6.4 mmol, 1.0 equiv) in benzene (35 mL, 0.2M) was added
nBu3SnH (2.16 mL, 8.0 mmol, 1.25 equiv) and the resulting mixture was stirred at rt for 5 min. AIBN (0.21 g,
1.28 mmol, 0.2 equiv) was added and the mixture was placed on a preheated oil bath (90 °C). The mixture was
kept at 90 °C (external) for 60 min before it was allowed to cool to rt (heating bath removed). CH3CN (250 mL)
was added and the reaction mixture was extracted with nꢀpentane (3x 100 mL). The acetonitrile layer was dried
over MgSO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica
gel (P.E.:EtOAc = 20:1 → 10:1) and yielded the targeted compound as colorless viscous oil (2.52 g, 93%).
Two-carbon homologation of ingenol (16, Scheme 5)
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Ingenol derivative 15. A solution of ingenol 14 (0.032 g, 0.09 mmol, 1.0 equiv.), methyl ester Cꢀacid (0.028 g,
0.1 mmol, 1.1 equiv.) and PPh3 (0.027 g, 0.1 mmol, 1.1 equiv.) in dry benzene (1.0 mL, 0.1 M) was cooled to
0 °C and the resulting mixture was stirred for 5 min prior to DIAD (19.8 ꢀL, 0.1 mmol, 1.1 equiv.) addition. The
resulting mixture was stirred at 0 °C for an additional 30 min and then at rt for 12 h. The resulting mixture was
evaporated under reduced pressure to dryness and the residue was purified by column chromatography on silica
gel (CHCl3/EtOAc = 4:1ꢀ>2:1ꢀ>1:1ꢀ>0:100) to give 0.028g (51%) of desired adduct 15 (two diastereoisomers in
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~1:1 ratio). Rf = 0.11 (CHCl3/EtOAc = 1:1); H NMR (500 MHz, CDCl3): δ 0.71 (td, J = 8.6, 6.3 Hz, 1H), 0.96
(d, J = 7.0 Hz, 3H), 1.08 (s, 3H), 1.11 (s, 3H), 1.27 (dt, J = 9.9, 7.2 Hz, 1H), 1.76 (ddd, J = 15.7, 6.3, 5.2 Hz, 1H),
1.85 (d, J = 1.4 Hz, 3H), 2.27 (ddd, J = 15.6, 8.9, 3.1 Hz, 1H), 2.30 – 2.38 (m, 1H), 3.35ꢀ3.48 (m, 2H), 3.68 (s,
1H), 3.78 (s, 3H), 4.08 (dd, J = 11.3, 3.6 Hz, 1H), 4.43 (s, 1H), 4.63ꢀ4.79 (m, 1H), 5.94 (d, J = 1.5 Hz, 1H), 6.10
(dd, J = 4.7, 1.3 Hz, 1H), 7.56 – 7.71 (m, 2H), 8.01 (dd, J = 7.1, 1.7 Hz, 1H), 8.27 (dd, J = 7.0, 1.6 Hz, 1H); 13
C
NMR (125 MHz, CDCl3): δ 15.5, 15.6, 17.1, 17.4, 21.2, 22.9, 23.0, 23.1, 23.2, 23.8, 23.9, 30.6, 30.9, 33.1, 33.2,
39.2, 39.8, 44.1, 44.2, 53.0, 53.4, 68.8, 70.9, 72.5, 72.6, 73.7, 79.8, 79.9, 84.3, 84.4, 122.4, 125.8, 125.9, 127.7,
128.5, 132.3, 136.0, 136.3, 137.3, 137.4, 139.5, 139.6, 152.7, 164.1, 164.2, 165.3, 165.5, 207.1, 207.2; HRMS
(ESI): m/z calcd. for C30H35NNaO8S2 [M+Na]+ 624.1696, found 624.1697.
Product of ingenol homologation (16). To a solution of BTꢀsulfone ester 15 (0.027 g, 0.045 mmol, 1.0 equiv) in
benzene (0.5 mL) was added nBu3SnH (0.056 mL, 0.056 mmol, 1.25 equiv) and the resulting mixture was stirred
at rt for 5 min. AIBN (0.002 g, 0.009 mmol, 0.2 equiv) was added and the mixture was placed on a preheated oil
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bath (90 °C). The mixture was kept at 90 °C (external) for 60 min before it was allowed to cool to rt (heating bath
removed). CH3CN (10 mL) was added and the reaction mixture was extracted with nꢀpentane (3x 10 mL). The
acetonitrile layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column
chromatography on silica gel (CHCl3/EtOAc = 4:1ꢀ>2:1ꢀ>1:1ꢀ>0:100) and yielded the targeted compound 16
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(0.016 g, 89%). Rf = 0.15 (CHCl3/EtOAc = 1:1); ꢀꢁꢂꢃ = +39 (c 1.01, ꢄꢅꢃꢋꢅ); H NMR (500 MHz, CDCl3): δ
0.68 (td, J = 8.5, 6.3 Hz, 1H), 0.93 (dd, J = 11.5, 8.5 Hz, 1H), 0.96 (d, J = 7.0 Hz, 3H), 1.05 (s, 3H), 1.11 (s, 3H),
1.20 (t, J = 7.0 Hz, 1H), 1.39 – 1.71 (broad s, 3H), 1.71 – 1.79 (m, 2H), 1.85 (d, J = 1.2 Hz, 3H), 2.09ꢀ2.21 (m,
2H), 2.27 – 2.39 (m, 2H), 2.62ꢀ2.75 (m, 2H), 3.72 (s, 3H), 3.81 (s, 1H), 4.11 (ddd, J = 10.4, 6.4, 2.1 Hz, 1H), 4.40
(s, 1H), 5.94 (quint, J = 1.5 Hz, 1H), 6.04 (d, J = 5.3 Hz, 1H); 13C NMR (126 MHz, CDCl3): δ 14.3, 15.5, 15.6,
17.6, 21.2, 23.0, 23.4, 23.9, 28.6, 31.0, 31.1, 32.4, 39.4, 44.1, 51.8, 72.7, 74.9, 79.9, 84.3, 127.3, 128.9, 139.3,
140.7, 171.4, 208.4; HRMS (ESI): m/z calcd. for C23H32NaO6 [M+Na]+ 427.2091, found 427.2090.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: j.pospisil@upol.cz
Author Contributions
D.J.ꢀY.D.B., O.K., V.F. and F.Z. performed most of the experiments. D.J.ꢀY.D.B. and J.P. led the team for
synthesis and analyzed chemistry and structureꢀrelated results. D.J.ꢀY.D.B. partially designed the experimental
plans. J.P. initiated the project, led the project team, designed experiments, analyzed results and wrote the paper
with input from all authors.
ORCID
Jiří Pospíšil: 0000ꢀ0002ꢀ0198ꢀ8116
David J. ꢀY. D. Bon: 0000ꢀ0001ꢀ7867ꢀ6877
Ondřej Kováč: 0000ꢀ0001ꢀ5721ꢀ5537
František Zálešák: 0000ꢀ0003ꢀ1469ꢀ5248
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