Divergent total synthesis of penaresidin B and its straight side chain analogue

Article abstract of DOI:10.1016/j.tet.2018.07.023

The divergent synthesis of penaresidin B and its straight side chain analogue was accomplished by constructing an azetidine ring via S_N2 type cyclization of protected 2,3-syn-3,4-syn-4-amino-1,3-dihydroxyhept-6-en-2-yl mesylate and late-stage introduction of an alkyl side chain via olefin cross-metathesis of 4-allylazetidine with readily available terminal alkenes. This synthetic route would be useful to synthesize penaresidin side chain analogues.

Full text of DOI:10.1016/j.tet.2018.07.023

Tetrahedron xxx (2018) 1e14
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Tetrahedron
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Divergent total synthesis of penaresidin B and its straight side chain
analogue
Tomoya Fujiwara, Kazuki Hashimoto, Masanori Umeda, Saki Murayama, Yuki Ohno,
Bo Liu, Hisanori Nambu, Takayuki Yakura*
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The divergent synthesis of penaresidin B and its straight side chain analogue was accomplished by
constructing an azetidine ring via SN2 type cyclization of protected 2,3-syn-3,4-syn-4-amino-1,3-
dihydroxyhept-6-en-2-yl mesylate and late-stage introduction of an alkyl side chain via olefin cross-
metathesis of 4-allylazetidine with readily available terminal alkenes. This synthetic route would be
useful to synthesize penaresidin side chain analogues.
Received 22 May 2018
Received in revised form
4 July 2018
Accepted 10 July 2018
Available online xxx
© 2018 Elsevier Ltd. All rights reserved.
Keywords:
Analogue
Azetidine
Olefin cross-metathesis reaction
Penaresidin
SN2 cyclization
1. Introduction
However, these reactions require strongly basic reaction conditions
and prior preparation of coupling partners. As part of our synthetic
Penaresidin A (1) and B (2) are sphingosine related natural
products, which were first isolated from the Okinawan marine
sponge Penares sp. by Kobayashi et al. in 1991 (Fig. 1) [1]. These
natural products contain a 2,3,4-trisubstituted azetidine ring with
the (2S,3R,4S) absolute configuration and an alkyl side chain con-
taining one or two chiral centers with (S)-configurations [2].1 and 2
were reported to have potent actomyosin ATPase-activating activ-
ity. In addition, 2 exhibits cytotoxic activity against murine lym-
phoma L1210 cells [3]. To date, several total syntheses of 1 and 2
have been reported owing to their structural features and biological
activities [4]. Analogues and stereoisomers of 1 and 2 have also
been synthesized [3,4a-c,e,f,5], among which the straight side chain
analogue 3 was found to have cytotoxic and antimicrobial activities
similar to or better than 2 [3]. Therefore, side chain analogues of 1
and 2 would be powerful lead compounds for development of new
drugs. Despite the high potency of these analogues for drug dis-
covery, there exist few divergent methods for synthesizing them.
One such method used a Wittig reaction [4f] or JuliaeKocienski
olefination [4h-j] for the late-stage introduction of side chains.
studies on the synthesis of sphingosine related compounds [6], we
recently achieved the divergent synthesis of pachastrissamine (4)
and 2-epi-pachastrissamine (5) via the late-stage introduction of an
alkyl side chain by olefin cross-metathesis [6e]. Herein, we report
the synthesis of 2 and 3 from diethyl D-tartrate using a strategy [6e]
similar to that used to synthesize 4 and 5.
2. Results and discussion
2.1. Retrosynthetic analysis
Scheme 1 shows our previous synthesis [6e] of 4 and 5. We used
allyl ketone 7 as an intermediate for the selective synthesis of both
4 and 5 wherein 7 was readily prepared from commercially avail-
able diethyl -tartrate (6). Stereoselective reductions of 7 afforded
D
3,4-syn-homoallylic alcohol 8 and 3,4-anti-one 9, respectively. After
the conversion of 3,4-syn-alcohol 8 into 1,2,4-triol 10, the SN2 type
cyclization of the 1-tosylate of 10 followed by amination at the C-4
position of the furan ring together with the inversion of the
configuration yielded the corresponding allyltetrahydrofuran 11.
Finally, the side chain moiety was introduced via olefin cross-
metathesis with commercially available 1-tridecene to produce 4.
Using the same procedure 5 was also synthesized from 3,4-anti-
* Corresponding author.
E-mail address: yakura@pha.u-toyama.ac.jp (T. Yakura).
https://doi.org/10.1016/j.tet.2018.07.023
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
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T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
Scheme 2. Retrosynthetic analysis of
syntheses.
2 and 3 based on the pachastrissamine
however, most syntheses use 2-amino derivatives as their pre-
cursors [3,4a-f,h,i,5a,b,d] and the cyclization of 4-amino precursors
are rare [4f,g,j,5c]. Scheme 3 shows the reported cyclizations of 4-
amino precursors. Lin et al. reported that the cyclization of 4-N-
Ts-1-O-[tert-butyldimethylsilyl (TBS)]-3-O-Bn precursor 14 having
2,3-syn-3,4-syn configuration did not proceed under any conditions
and the desired azetidine 18 was not obtained (Scheme 3a) [4f]. In
2003, Yoda et al. succeeded in a similar cyclization of N-[tert-
butoxycarbonyl (Boc)]-O-MOM precursor 15 to afford 19 in 50%
yield and completed the total synthesis of 2 (Scheme 3b) [4g].
Recently, Liu et al. found that N-Ts-O-Ac precursor 16, having a
shorter alkyl side chain, afforded 20 in high yield via Mitsunobu
type SN2 cyclization (Scheme 3c) [4j]. Interestingly, 2,3-anti-3,4-
syn-precursor 17, the C-2 epimer of 14, readily cyclized under
Mitsunobu conditions to produce sterically congested all-cis
substituted azetidine 21 in excellent yield (Scheme 3d) [5c]. These
reported reactions suggest that the SN2 type cyclizations of 4-
amino precursors are influenced by hydroxy-protecting groups
[7], alkyl side chains, and the configurations of the substrate:
although the formation of 2,3-anti-3,4-syn-azetidine is somewhat
difficult, small protecting groups and short alkyl groups are better
for the azetidine ring formation. Scheme 2 shows our strategy for
the synthesis of penaresidins 2 and 3. Similar to the synthesis of
pachastrissamine [6e], in our strategy, the side chain is introduced
at a late-stage via the cross-metathesis reaction of 12 with the
Fig. 1. Structures of penaresidins A (1) and B (2), straight side chain analogue 3,
pachastrissamine (4), and 2-epi-pachastrissamine (5).
Scheme 1. Previous synthesis of 4 and 5 [6e]. PMB ¼ p-methoxybenzyl.
alcohol 9. The divergent synthetic strategy for 4 and 5 allows easy
access to their side chain analogues because cross-metathesis re-
actions tolerate a wide range of functional groups and can use
readily available terminal alkenes as coupling partners. Therefore,
we envisioned that this strategy could be applied to the synthesis of
2 and 3 (Scheme 2). Thus, 2 and 3 would be synthesized through
the final introduction of a side chain onto 4-allylazetidine 12 via
cross-metathesis and 12 would be constructed via SN2 type cycli-
zation of 2,3-syn-3,4-syn-4-amino-1,3-dihydroxyhept-6-en-2-yl
mesylate 13, which can be readily obtained from 3,4-anti-alcohol
9 following a procedure similar to that of the pachastrissamine
syntheses.
Scheme 3. Reported SN2 type cyclizations of 4-amino precursors 14e17.
Similar SN2 type construction of an azetidine ring is a popular
method used for the synthesis of penaresidins and their analogues,
DEAD ¼ diethyl
azodicarboxylate.
DIAD ¼ diisopropyl
azodicarboxylate.
THP ¼ tetrahydropyranyl.
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T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
3
allylazetidine 26 in 82% yield after 19 h. The result suggested that
the azetidine formation by the SN2 type cyclization of 4-amino-
precursors was strongly affected by the configuration at the 4-
position of the precursor.
Next, we investigated the reaction of 13 to construct the desired
2,3-anti-3,4-syn-azetidine. The 2,3-syn-3,4-syn-precursors 13aed
were prepared following a procedure similar to that of 25 (Scheme
5). Tosylation of the 4-hydroxy group of 9 followed by nucleophilic
substitution with NaN3 produced 27. Reduction of the azide group
of 27 under Staudinger conditions yielded the corresponding
amine, which was subjected to the protection of the amino group
with a tosyl or 2-nitrobenzenesulfonyl (nosyl, Ns) group and
removal of the diol protecting group to afford diols 28 and 29,
respectively. Selective protection of the primary hydroxy group of
28 with TBS group followed by mesylation of the secondary OH
group of 30 led to 1-O-TBS-3-O-PMB-precursor 13a, whereas se-
lective Bn protection of 1-OH group of 29 with BnBr in the presence
of Bu2SnO afforded 31, which was converted to 1-O-Bn-3-O-PMB-
precursor 13b. Removal of the PMB group of 27 with 2,3-dichloro-
5,6-dicyano-p-benzoquinone (DDQ) followed by MOM protection
afforded azide 32, which was converted into 13c and 13d by sub-
sequent selective protections of diol 33 through 34 or 35, respec-
tively. Table 1 summarizes the results of SN2 type cyclization of
13aed with NaH. When 1-O-TBS-3-O-PMB-precursor 13a was
reacted with NaH under reflux conditions in THF, the corre-
sponding azetidine 12a was obtained in 11% yield after 24 h (entry
1). The reaction of 1-O-TBS-3-O-MOM-precursor 13c under the
same reaction conditions afforded azetidine 12c in higher yield
(20%, entry 2). The cyclization of 13c at 120 ꢀC in DMF led to a
shorter reaction time (1 h) and an increased yield (50%) of 12c
(entry 3). The reaction of 1-O-Bn-3-O-MOM-precursor 13d at
120 ꢀC in DMF required a longer reaction time (24 h), but afforded
12d in 72% yield (entry 4). The best result was obtained when 1-O-
Bn-3-O-PMB-precursor 13b was used for cyclization: 13b was
reacted at 80 ꢀC in DMF to afford azetidine 12b in 92% yield after
45 min (entry 5). These results suggest that the SN2 type cycliza-
tion of 2,3-syn-3,4-syn-4-amino-1,3-dihydroxyhept-6-en-2-yl
Scheme 4. Synthesis and SN2 type cyclization of 2,3-syn-3,4-anti-precursor 25.
TBSOTf ¼ tert-butyldimethylsilyl trifluoromethanesulfonate.
alkene. The cyclization precursor 13, which can be prepared from
3,4-anti-alcohol 9, has a short allyl group as an alkene unit; this
should be good for an SN2 type cyclization.
2.2. SN2 type cyclization of 4-amino-1,3-dihydroxyhept-6-en-2-yl
mesylates to 4-allylazetidines
First, we examined the SN2 type cyclization of 2,3-syn-3,4-anti-
precursor 25, which has 1- and 3-hydroxy protecting groups nearly
identical to those of 14, to investigate the effects of the configura-
tion at the 4-position of the precursor (Scheme 4). Preparation of 25
began from 3,4-anti-amine 22 that was used as an intermediate for
the synthesis of 2-epi-pyrrolidine analogue of 4 [6e]. After tosyla-
tion of the amino group of 22, removal of the diol protecting group
yielded 23, whose primary hydroxy group was selectively protected
by the TBS group to afford 24. The subsequent mesylation of the
secondary hydroxy group produced precursor 25. In the case of the
reaction of 25 with NaH in THF at room temperature, the cyclization
reaction took place quite smoothly to afford 2,3-trans-3,4-trans-4-
Scheme 5. Synthesis of 2,3-syn-3,4-syn-precursors 13aed. Reagents and conditions: (a) TsCl, 4-dimethylaminopyridine (DMAP), pyridine, rt, 92%; (b) NaN3, DMF, 60 ꢀC, 77%;
(c) Ph3P, THF-H2O, 50 ꢀC, 87%; (d) TsCl, Et3N, CH2Cl2, rt, 94%; (e) 2% H2SO4, MeOH, rt, 28, 93%, 29, 81%; (f) 2-nitrobenzenesulfonyl (Ns) chloride, Et3N, CH2Cl2, rt, 89%; (g) TBSCl,
Et3N, DMAP, DMF, rt, 30, 92%, 34, 74%; (h) MsCl, Et3N, CH2Cl2, rt, 13a, 98%, 13b, 96%, 13c, 97%, 13d, 87%; (i) BnBr, Bu2SnO, tetrabutylammonium iodide (TBAI), toluene, reflux, 89%;
(j) DDQ, CH2Cl2-H2O, rt, 96%; (k) MOMCl, i-Pr2NEt, TBAI, THF, reflux, 93%; (l) Ph3P, THF-H2O, 50 ꢀC, 96%; (m) NsCl, Et3N, CH2Cl2, rt, quant; (n) pyridinium p-toluenesulfonate
(PPTS), MeOH, rt, 64%; (o) BnBr, Bu2SnO, TBAI, Et3N, toluene, reflux, 58%.
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T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
Table 1
SN2 type cyclizations of precursors 13aed.
entry
precursor
R1
R2
R3
solvent
temp. (ꢀC)
time (h)
azetidine
yield (%)
1
2
3
4
5
13a
13c
13c
13d
13b
TBS
TBS
TBS
Bn
PMB
Ts
THF
THF
DMF
DMF
DMF
reflux
reflux
120
120
80
24
24
1
24
0.75
12a
12c
12c
12d
12b
11
20
50
72
92
MOM
MOM
MOM
PMB
Ns
Ns
Ns
Ns
Bn
mesylates 13 is strongly influenced by the steric bulkiness of the 1-
hydroxy protecting group.
however, a complex mixture was formed. Fortunately, protection of
the amino group of 38 with the Boc group followed by catalytic
hydrogenation of 39 produced N-Boc penaresidin analogue 40 in
high yield. Removal of the Boc group of 40 with conc. HCl in MeOH
successfully afforded 3 [9] in 50% yield.
2.3. Synthesis of penaresidin B and its straight side chain analogue
Finally, we focused on the completion of the total synthesis of 2
(Scheme 7). Coupling partner 46 for olefin cross-metathesis was
Following the successful synthesis of the desired azetidine 12b
we investigated the introduction of the alkyl side chain using olefin
cross-metathesis (Scheme 6). When 12b was treated with 8 equiv of
1-tridecene in the presence of 5 mol% of Grubbs 2nd generation
catalyst in CH2Cl2 under reflux conditions for 24 h, the reaction did
not occur and 12b was recovered. Although the reaction with 12
equiv of 1-tridecene and 20 mol% of the catalyst in refluxing 1,2-
dichloroethane for 48 h produced coupling product 36, the yield
of 36 was very low (<30%). These results could be attributed to the
steric hindrance of the 3-O-PMB group. Next, we employed 3-
hydroxyazetidine 12e as a substrate for the reaction. The PMB
group of 12b was removed with DDQ to afford 12e [8] that was
subjected to the cross-metathesis reaction with 4 equiv of 1-
tridecene and 5 mol% of the catalyst in CH2Cl2 under reflux condi-
tions. We found that the reaction proceeded smoothly and pro-
duced the desired coupling product 37 in 63% yield after 2 h. The Ns
group of 37 was removed with PhSH in the presence of Cs2CO3 to
afford amine 38 and the catalytic hydrogenation of 38 was
attempted to reduce the olefin moiety and remove the Bn group;
readily prepared from -leucine (41). After the conversion of 41 to
L
epoxide 42 according to literature [10], the treatment of 42 with
lithium acetylide, which was derived from 1-octyne and butyl-
lithium, in the presence of BF3$OEt2 produced internal alkyne 43.
Isomerization of 43 to terminal alkyne 44 was achieved in 85% yield
via an alkyne zipper reaction with KH and 1,3-diaminopropane
under solvent free conditions [11]. Partial hydrogenation of 44 us-
ing Lindlar catalyst afforded alkene 45, whose hydroxy group was
Scheme 6. Olefin cross-metathesis of azetidine 12b,e and the synthesis of straight side
chain analogue 3.
Scheme 7. Total synthesis of penaresidin B (2).
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T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
5
protected with a benzyl group to afford 46. When the olefin cross-
metathesis reaction of 3-hydroxy-4-allylazetidine 12e and 46 was
conducted with Grubbs 2nd catalyst in refluxing CH2Cl2, the
coupling product 47 was obtained in 74% yield after 3.5 h. After
changing the amino protecting group of 47 to a Boc group, reduc-
tion of the olefin moiety and removal of the Bn group of 48 via
catalytic hydrogenation afforded N-Boc-penaresidin B (49) in high
yield. Finally, the deprotection of 49 under acidic conditions suc-
cessfully produced penaresidin B (2) in 92% yield. The synthetic 2
temperature for 24 h, K2CO3 (160 mg, 1.16 mmol) was added to the
resulting solution at 0 ꢀC. The mixture was stirred for 0.5 h, dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(eluent: EtOAceCH2Cl2 ¼ 1:1) to give 23 (87 mg, 86%) as a colorless
19
oil: [
a
]
D
e22.2 (c 1.00, CHCl3); IR (neat) nmax ¼ 3487, 3324, 2933,
2879, 1613, 1514, 1442, 1324, 1304, 1250, 1158, 1092, 1035, 922, 816,
737, 706, 665 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
7.77e7.75 (2H, m),
7.28 (2H, d, J ¼ 8.0 Hz), 7.18e7.15 (2H, m), 6.87e6.84 (2H, m), 5.51
(1H, br d, J ¼ 7.5 Hz), 5.50e5.42 (1H, m), 4.99e4.94 (2H, m), 4.46
(1H, d, J ¼ 10.9 Hz), 4.29 (1H, d, J ¼ 10.9 Hz), 3.93e3.88 (1H, m), 3.80
(3H, s), 3.67e3.58 (2H, m), 3.52e3.45 (2H, m), 2.93 (1H, br d,
J ¼ 7.5 Hz), 2.41 (3H, s), 2.39e2.33 (1H, m), 2.20e2.11 (2H, m); 13C
was spectroscopically identical to previously synthesized 2 [4c],
23
including its optical rotation ([
a
]
D
¼ ꢁ7.1 (c 0.59, MeOH); lit [4c].
25
[
a]
¼ ꢁ6.8 (c 0.35, MeOH) (AcOH salt)).
D
3. Conclusion
NMR (126 MHz, CDCl3) d 159.6, 143.4, 137.9, 133.3, 129.9, 129.6,
129.2, 127.1, 119.0, 114.0, 77.9, 72.4, 70.5, 64.4, 55.3, 53.5, 36.1, 21.5;
We successfully performed the total synthesis of 2 via SN2 type
cyclization of 2,3-syn-3,4-syn-4-amino-1,3-dihydroxyhept-6-en-2-
yl mesylate 13b and olefin cross-metathesis of 4-allyazetidine 12e
HRMS (EI) calcd for C22H29NO6S ([M]þ): 435.1716; found 435.1704.
4.1.3. N-[(2R,3R,4R)-1-tert-Butyldimethylsilyloxy-2-hydroxy-3-(4-
methoxyphenylmethoxy)hept-6-en-4-yl]-4-methylbenzene
sulfonamide (24)
with terminal alkene 46 that was readily prepared from L-leucine
(41). Straight side chain analogue 3 was also synthesized using 12e
with commercially available 1-tridecene as a coupling partner. We
found that the cyclization of 2,3-syn-3,4-syn-precursors 13aed was
strongly influenced by the 1-hydroxy protecting groups. In
contrast, the cross-metathesis of 4-allylazetidines 12 depended on
the steric bulkiness of the 3-OH group. This synthetic procedure for
2 and 3 will be applicable to the synthesis of other penaresidin
analogues with various alkyl side chains.
tert-Butyldimethylsilyl trifluoromethanesulfonate (0.14 mL,
0.61 mmol) was added to a solution of 23 (333 mg, 0.77 mmol)
and i-Pr2NEt (0.27 mL, 1.53 mmol) in anhydrous CH2Cl2 (6.6 mL)
at ꢁ40 ꢀC under a nitrogen atmosphere. After stirring for 0.5 h,
the resulting mixture was treated with sat. aq. NaHCO3 and then
extracted with EtOAc. The organic layer was washed with water
and brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel column
4. Experimental section
chromatography (eluent: EtOAcehexane ¼ 1:4) to give 24
19
(353 mg, 84%) as a colorless oil: [
a
]
e25.7 (c 1.00, CHCl3); IR
D
4.1. SN2 type cyclization of 4-amino-1,3-dihydroxyhept-6-en-2-yl
mesylates to 4-allylazetidines
(neat) nmax ¼ 3500, 3296, 2928, 1643, 1613, 1515, 1464, 1326, 1250,
1160, 1094, 920, 838, 779, 738, 666 cmꢁ1 1H NMR (400 MHz,
CDCl3)
m), 6.86e6.82 (2H, m), 5.57e5.47 (2H, m), 5.00e4.96 (2H, m),
4.35 (1H, d, J ¼ 11.0 Hz), 4.28 (1H, d, J ¼ 11.0 Hz), 3.87e3.81 (1H,
m), 3.80 (3H, s), 3.64e3.50 (3H, m), 3.39 (1H, dd, J ¼ 9.6, 7.3 Hz),
2.62 (1H, br d, J ¼ 6.4 Hz), 2.45e2.38 (1H, m), 2.40 (3H, s),
2.21e2.13 (1H, m), 0.87 (9H, s), 0.03 (3H, s), 0.02 (3H, s); 13C NMR
;
d
7.77e7.73 (2H, m), 7.25 (2H, d, J ¼ 8.2 Hz), 7.14e7.10 (2H,
4.1.1. N-{(1R,2R)-1-[(4R)-2,2-Diethyl-1,3-dioxolan-4-yl]-1-(4-
methoxyphenylmethoxy)pent-4-en-2-yl}-4-methylbenzenesulfon-
amide
p-Toluenesulfonyl chloride (83 mg, 0.44 mmol) was added to a
solution of 22 [6e] (122 mg, 0.35 mmol) and Et3N (0.12 mL,
0.88 mmol) in anhydrous CH2Cl2 (1.5 mL) at 0 ꢀC under a nitrogen
atmosphere. After stirring at room temperature for 4.5 h, the
mixture was diluted with EtOAc. The resulting mixture was washed
with water and brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (eluent: EtOAcehexane ¼ 1:3) to give the
(100 MHz, CDCl3)
d 159.4, 143.1, 138.0, 133.6, 129.71, 129.67, 129.5,
127.2, 118.6, 113.8, 75.9, 72.4, 70.8, 63.8, 55.2, 54.0, 36.5, 25.8, 21.5,
18.2, ꢁ5.4, ꢁ5.5; HRMS (EI) calcd for C28H43NO6SSi ([M]þ):
549.2580; found 549.2616.
4.1.4. (2R,3R,4R)-1-tert-Butyldimethylsilyloxy-3-(4-
methoxyphenylmethoxy)-4-[(4-methylbenzenesulfonyl)amino]
hept-6-en-2-yl methanesulfonate (25)
title compound (154 mg, 87%) as a colorless oil: [
a
]
18 þ30.6 (c 0.75,
D
CHCl3); IR (neat) nmax ¼ 3297, 2973, 2938, 2881, 1613, 1514, 1464,
1335, 1304, 1249, 1163, 1092, 1036, 919, 816, 758, 737, 665 cmꢁ1; 1H
Methanesulfonyl chloride (80 mL, 1.09 mmol) was added to a
NMR (500 MHz, CDCl3)
d
7.66e7.63 (2H, m), 7.22 (2H, d, J ¼ 8.0 Hz),
solution of 24 (200 mg, 0.36 mmol) in pyridine (1.6 mL) at 0 ꢀC
under a nitrogen atmosphere. After stirring at room temperature
for 14 h, the resulting mixture was treated with water and then
extracted with Et2O. The organic layer was washed with 1 M HCl,
water, and brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (eluent: EtOAcehexane ¼ 1:4) to give 25
(201 mg, 88%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
7.16e7.13 (2H, m), 6.89e6.86 (2H, m), 5.66e5.58 (1H, m), 5.26 (1H,
br d, J ¼ 8.0 Hz), 5.02e4.98 (2H, m), 4.44 (1H, d, J ¼ 11.5 Hz), 4.26
(1H, d, J ¼ 11.5 Hz), 4.19e4.15 (1H, m), 3.89 (1H, dd, J ¼ 8.0, 6.3 Hz),
3.82 (3H, s), 3.49 (1H, t, J ¼ 8.0 Hz), 3.32e3.27 (1H, m), 3.19 (1H, dd,
J ¼ 5.2, 3.4 Hz), 2.44e2.37 (1H, m), 2.38 (3H, s), 2.18e2.12 (1H, m),
1.65e1.58 (4H, m), 0.88 (3H, t, J ¼ 7.5 Hz), 0.86 (3H, t, J ¼ 7.5 Hz); 13
C
NMR (126 MHz, CDCl3)
d 159.3, 143.2, 137.91, 137.88, 133.9, 130.0,
129.5, 127.1, 118.2, 113.8, 113.7, 78.28, 78.26, 72.3, 66.4, 55.3, 54.3,
35.8, 29.55, 29.49, 21.5, 8.1, 8.0; HRMS (EI) calcd for C27H37NO6S
([M]þ): 503.2342; found 503.2352.
d
7.73e7.69 (2H, m), 7.28 (2H, d, J ¼ 7.8 Hz), 7.25e7.21 (2H, m),
6.90e6.86 (2H, m), 5.34 (1H, ddt, J ¼ 17.4, 10.1, 7.3 Hz), 4.99e4.94
(2H, m), 4.74 (1H, br d, J ¼ 7.3 Hz), 4.62 (1H, q, J ¼ 5.5 Hz), 4.57 (1H,
d, J ¼ 11.5 Hz), 4.56 (1H, d, J ¼ 11.5 Hz), 3.90 (1H, dd, J ¼ 5.5, 3.2 Hz),
3.83 (1H, dd, J ¼ 11.5, 5.5 Hz), 3.81 (3H, s), 3.73 (1H, dd, J ¼ 11.5,
5.5 Hz), 3.59e3.53 (1H, m), 2.97 (3H, s), 2.42 (3H, s), 2.32e2.18 (2H,
m), 0.88 (9H, s), 0.08 (3H, s), 0.07 (3H, s); 13C NMR (100 MHz, CDCl3)
4.1.2. N-[(2R,3R,4R)-1,2-Dihydroxy-3-(4-methoxyphenylmethoxy)
hept-6-en-4-yl]-4-methylbenzenesulfonamide (23)
Diluted H2SO4 (2%, 0.46 mL) was added to a solution of N-
{(1R,2R)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-1-(4-methoxy-
phenylmethoxy)pent-4-en-2-yl}-4-methylbenzenesulfonamide
(117 mg, 0.23 mmol) in MeOH (2.5 mL) at 0 ꢀC. After stirring at room
d
159.4, 143.5, 137.3, 133.3,129.7, 129.6, 127.2, 118.9, 113.9, 82.4, 78.7,
74.2, 62.8, 55.2, 53.7, 38.4, 34.4, 25.8, 21.5, 18.2, ꢁ5.5; HRMS (EI)
calcd for C29H45NO8S2Si ([M]þ): 627.2356; found 627.2370.
Please cite this article in press as: T. Fujiwara, et al., Divergent total synthesis of penaresidin B and its straight side chain analogue, Tetrahedron
(2018), https://doi.org/10.1016/j.tet.2018.07.023

6
T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
4.1.5. (2S,3R,4R)-2-(tert-Butyldimethylsilyloxy)methyl-3-(4-
methoxyphenylmethoxy)-1-(4-methylbenzenesulfonyl)-4-(prop-2-
en-1-yl)azetidine (26)
J ¼ 7.8, 6.4 Hz), 3.81 (3H, s), 3.56 (1H, dd, J ¼ 8.7, 7.8 Hz), 3.43 (1H,
dd, J ¼ 6.9, 2.8 Hz), 3.03 (1H, ddd, J ¼ 7.8, 6.0, 2.8 Hz), 2.54e2.35 (2H,
m), 1.70e1.62 (4H, m), 0.92 (3H, t, J ¼ 7.3 Hz), 0.91 (3H, t, J ¼ 7.3 Hz);
Sodium hydride (60% dispersion in mineral oil, 2.5 mg,
0.063 mmol) was added to a solution of 25 (13 mg, 0.021 mmol) in
anhydrous THF (0.23 mL) at room temperature under a nitrogen
atmosphere. After stirring for 19 h, the resulting mixture was
treated with water and then extracted with EtOAc. The organic
layer was washed with sat. aq. NH4Cl, water, and brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (eluent:
13C NMR (100 MHz, CDCl3, major isomer)
d 159.2, 133.6, 130.3,
129.6, 118.5, 113.7, 113.4, 80.0, 78.0, 73.3, 66.5, 61.6, 55.2, 34.8, 29.7,
29.4, 8.3, 8.1; HRMS (FAB) calcd for
376.2236; found 376.2263.
C
20H30N3O4 ([MþH]þ):
4.1.8. (1R,2S)-1-[(4R)-2,2-Diethyl-1,3-dioxolan-4-yl]-1-(4-
methoxyphenylmethoxy)pent-4-en-2-amine
Triphenylphosphine (528 mg, 2.01 mmol) was added to a solu-
tion of 27 (378 mg, 1.01 mmol, dr ¼ ca. 6:1) in a 20:3 mixture of THF
and water (8.1 mL) at room temperature. After stirring at 50 ꢀC for
24 h, the resulting mixture was allowed to cool to room tempera-
ture and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (eluent:
MeOHeCH2Cl2 ¼ 3:97) to give the title compound (306 mg, 87%,
dr ¼ ca. 6:1) as a colorless oil: 1H NMR (500 MHz, CDCl3, major
EtOAcehexane ¼ 1:4) to give 26 (9 mg, 82%) as a colorless oil:
19
[
a]
þ32.5 (c 1.00, CHCl3); IR (neat) nmax ¼ 2928, 1642, 1613, 1513,
D
1462, 1347, 1250, 1162, 836, 709, 670, 606 cmꢁ1; 1H NMR (400 MHz,
CDCl3)
d
7.72e7.69 (2H, m), 7.35 (2H, d, J ¼ 7.8 Hz), 7.08e7.04 (2H,
m), 6.83e6.80 (2H, m), 5.79 (1H, ddt, J ¼ 16.9, 10.5, 6.9 Hz),
5.09e5.03 (2H, m), 4.30 (1H, d, J ¼ 11.5 Hz), 4.25 (1H, d, J ¼ 11.5 Hz),
3.80e3.78 (1H, m), 3.79 (3H, s), 3.71 (1H, dd, J ¼ 11.0, 5.5 Hz), 3.68
(1H, dd, J ¼ 11.0, 3.7 Hz), 3.63 (1H, dt, J ¼ 7.8, 5.0 Hz), 3.56 (1H, ddd,
J ¼ 5.5, 4.6, 3.7 Hz), 2.52e2.38 (2H, m), 2.45 (3H, s), 0.91 (9H, s),
isomer) d 7.32e7.29 (2H, m), 6.90e6.87 (2H, m), 5.74e5.66 (1H, m),
5.09e5.02 (2H, m), 4.86 (1H, d, J ¼ 11.5 Hz), 4.58 (1H, d, J ¼ 11.5 Hz),
4.44 (1H, ddd, J ¼ 8.6, 6.9, 6.3 Hz), 4.08 (1H, dd, J ¼ 8.0, 6.3 Hz), 3.81
(3H, s), 3.55 (1H, dd, J ¼ 8.6, 8.0 Hz), 3.32 (1H, dd, J ¼ 6.9, 2.3 Hz),
2.57 (1H, ddd, J ¼ 8.0, 5.2, 2.3 Hz), 2.28e2.22 (1H, m), 2.16e2.10 (1H,
m), 1.73e1.63 (4H, m), 1.34 (2H, br s), 0.93 (3H, t, J ¼ 7.5 Hz), 0.92
0.084 (3H, s), 0.076 (3H, s); 13C NMR (100 MHz, CDCl3)
d 159.3,
143.9, 132.8, 132.3, 129.7, 129.5, 129.2, 128.3, 118.1, 113.7, 74.0, 70.9,
69.4, 67.7, 62.7, 55.2, 37.6, 25.9, 21.6, 18.3, ꢁ5.3, ꢁ5.5; HRMS (EI)
calcd for C28H41NO5SSi ([M]þ): 531.2475; found 531.2472.
(3H, t, J ¼ 7.5 Hz); 13C NMR (126 MHz, CDCl3, major isomer)
d 159.1,
4.1.6. (1S,2R)-1-[(4R)-2,2-Diethyl-1,3-dioxolan-4-yl]-1-(4-
135.6, 130.9, 129.7, 117.7, 113.6, 113.1, 81.4, 79.0, 73.5, 66.9, 55.2, 52.8,
methoxyphenylmethoxy)pent-4-en-2-yl 4-methylbenzenesulfonate
p-Toluenesulfonyl chloride (983 mg, 5.15 mmol) was added to a
solution of 9 [6e] (602 mg, 1.72 mmol, dr ¼ ca. 8:1) in pyridine
(9 mL), followed by DMAP (21 mg, 0.17 mmol) at room temperature
under a nitrogen atmosphere. After stirring for 48 h, the mixture
was concentrated under reduced pressure and then diluted with
EtOAc. The organic layer was washed with sat. aq. NH4Cl, water, and
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (eluent: EtOAcehexane ¼ 1:9) to give the title compound
(794 mg, 92%, dr ¼ ca. 7:1) as a colorless oil: 1H NMR (400 MHz,
40.9, 29.8, 29.5, 8.3, 8.1; HRMS (FAB) calcd for C20H32NO4
([MþH]þ): 350.2331; found 350.2347.
4.1.9. N-{(1R,2S)-1-[(4R)-2,2-Diethyl-1,3-dioxolan-4-yl]-1-(4-
methoxyphenylmethoxy)pent-4-en-2-yl}-4-methylbenzene-
sulfonamide
p-Toluenesulfonyl chloride (84 mg, 0.44 mmol) was added to a
solution of (1R,2S)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-1-(4-
methoxyphenylmethoxy)pent-4-en-2-amine (122 mg, 0.35 mmol,
dr ¼ ca. 6:1) and Et3N (0.12 mL, 0.88 mmol) in anhydrous CH2Cl2
(1.5 mL) at 0 ꢀC under a nitrogen atmosphere. After stirring at room
temperature for 5 h, the resulting mixture was diluted with EtOAc.
The solution was washed with water and brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluent:
EtOAcehexane ¼ 1:4) to give the title compound (166 mg, 94%,
dr ¼ ca. 6:1) as a colorless oil: 1H NMR (400 MHz, CDCl3, major
CDCl3, major isomer)
d
7.75e7.72 (2H, m), 7.31 (2H, d, J ¼ 8.2 Hz),
7.29e7.25 (2H, m), 6.88e6.85 (2H, m), 5.55 (1H, ddt, J ¼ 16.9, 10.1,
6.9 Hz), 5.03e4.94 (2H, m), 4.67 (1H, d, J ¼ 11.5 Hz), 4.64 (1H, d,
J ¼ 11.5 Hz), 4.45 (1H, dt, J ¼ 7.8, 3.7 Hz), 4.06 (1H, dt, J ¼ 7.8, 6.4 Hz),
3.92 (1H, dd, J ¼ 7.8, 6.4 Hz), 3.80 (3H, s), 3.64 (1H, dd, J ¼ 6.4,
3.7 Hz), 3.54 (1H, t, J ¼ 7.8 Hz), 2.59e2.42 (2H, m), 2.44 (3H, s),
1.63e1.55 (4H, m), 0.87 (3H, t, J ¼ 7.3 Hz), 0.84 (3H, t, J ¼ 7.3 Hz); 13
C
isomer) d 7.72e7.69 (2H, m), 7.30e7.24 (4H, m), 6.90e6.87 (2H, m),
NMR (100 MHz, CDCl3, major isomer)
d
159.2, 144.9, 133.8, 132.7,
5.40 (1H, dddd, J ¼ 16.9, 10.1, 8.2, 6.4 Hz), 4.96e4.93 (1H, m), 4.93
(1H, br d, J ¼ 9.2 Hz), 4.87 (1H, d, J ¼ 11.0 Hz), 4.85e4.80 (1H, m),
4.51 (1H, d, J ¼ 11.0 Hz), 4.08 (1H, td, J ¼ 8.2, 6.4 Hz), 3.82 (3H, s),
3.75 (1H, dd, J ¼ 8.2, 6.4 Hz), 3.35 (1H, dd, J ¼ 8.2, 1.4 Hz), 3.31 (1H, t,
J ¼ 8.2 Hz), 2.99 (1H, tdd, J ¼ 9.2, 5.0, 1.4 Hz), 2.42 (3H, s), 2.26e2.16
(1H, m), 2.10e2.03 (1H, m), 1.67e1.52 (4H, m), 0.90 (3H, t,
J ¼ 7.3 Hz), 0.86 (3H, t, J ¼ 7.3 Hz); 13C NMR (100 MHz, CDCl3, major
130.1, 129.7, 129.6, 128.0, 118.5, 113.7, 113.3, 83.2, 79.9, 77.1, 73.8,
66.5, 55.2, 34.2, 29.4, 29.2, 21.6, 8.2, 8.0; HRMS (FAB) calcd for
C
27H37O7S ([MþH]þ): 505.2260; found 505.2234.
4.1.7. (4R)-4-[(1R,2S)-2-Azido-1-(4-methoxyphenylmethoxy)pent-
4-en-1-yl]-2,2-diethyl-1,3-dioxolane (27)
Sodium azide (255 mg, 3.92 mmol) was added to a solution of
(1S,2R)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-1-(4-methoxyphe-
nylmethoxy)pent-4-en-2-yl 4-methylbenzenesulfonate (660 mg,
1.31 mmol, dr ¼ ca. 7:1) in anhydrous DMF (5.2 mL) at room tem-
perature under a nitrogen atmosphere. After stirring at 60 ꢀC for
24 h, the mixture was allowed to cool to room temperature, treated
with water, and then extracted with Et2O. The organic layer was
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (eluent: CH2Cl2) to give 27 (378 mg, 77%,
dr ¼ ca. 6:1) as a colorless oil: 1H NMR (400 MHz, CDCl3, major
isomer) d 159.4, 143.5, 138.3, 133.7, 130.0, 129.6, 129.5, 127.0, 118.6,
113.8, 113.5, 78.8, 78.4, 73.7, 66.7, 55.3, 54.7, 37.7, 29.7, 29.1, 21.5, 8.2,
8.0; HRMS (FAB) calcd for C27H38NO6S ([MþH]þ): 504.2420; found
504.2407.
4.1.10. N-[(2R,3R,4S)-1,2-Dihydroxy-3-(4-methoxyphenylmethoxy)
hept-6-en-4-yl]-4-methylbenzenesulfonamide (28)
Diluted H2SO4 (2%, 0.64 mL) was added to a solution of N-
{(1R,2S)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-1-(4-methoxyphe-
nylmethoxy)pent-4-en-2-yl}-4-methylbenzenesulfonamide
(160 mg, 0.32 mmol, dr ¼ ca. 6:1) in MeOH (3.5 mL) at 0 ꢀC. After
stirring at room temperature for 24 h, K2CO3 (220 mg, 1.59 mmol)
was added to the resulting solution at 0 ꢀC. The mixture was stirred
for 0.5 h, dried over MgSO4, filtered, and concentrated under
isomer)
d 7.32e7.28 (2H, m), 6.90e6.87 (2H, m), 5.71 (1H, ddt,
J ¼ 17.6, 10.1, 6.9 Hz), 5.14e5.09 (2H, m), 4.83 (1H, d, J ¼ 11.5 Hz),
4.63 (1H, d, J ¼ 11.5 Hz), 4.36 (1H, dt, J ¼ 8.7, 6.4 Hz), 4.02 (1H, dd,
Please cite this article in press as: T. Fujiwara, et al., Divergent total synthesis of penaresidin B and its straight side chain analogue, Tetrahedron
(2018), https://doi.org/10.1016/j.tet.2018.07.023

T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
7
reduced pressure. The residue was purified by silica gel column
chromatography (eluent: acetoneeCHCl3 ¼ 1:6 to 1:3) to give 28
(128 mg, 93%, dr ¼ ca. 6:1) as a colorless oil. Diastereomerically pure
28 gave the following data after partial separation by silica gel
18.2, ꢁ5.4, ꢁ5.5; HRMS (FAB) calcd for C29H46NO8S2Si ([MþH]þ):
628.2434; found 628.2415.
4.1.13. N-{(1R,2S)-1-[(4R)-2,2-Diethyl-1,3-dioxolan-4-yl]-1-(4-
methoxyphenylmethoxy)pent-4-en-2-yl}-2-nitrobenzene-
sulfonamide
2-Nitrobenzenesulfonyl chloride (204 mg, 0.92 mmol) was
added to a solution of (1R,2S)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-
column chromatography (eluent: EtOAceCH2Cl2 ¼ 1:3): colorless
19
oil; [
a]
e9.0 (c 0.51, CHCl3); IR (neat) nmax ¼ 3468, 3381, 3289,
D
2927, 1612, 1514, 1464, 1442, 1325, 1304, 1250, 1159, 1092, 1035, 920,
817, 737, 707, 667 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
7.71e7.68 (2H,
m), 7.28 (2H, d, J ¼ 8.0 Hz), 7.26e7.24 (2H, m), 6.91e6.88 (2H, m),
5.38 (1H, ddt, J ¼ 17.2, 10.3, 6.9 Hz), 4.97e4.91 (3H, m), 4.59 (1H, d,
J ¼ 10.9 Hz), 4.58 (1H, d, J ¼ 10.9 Hz), 3.82 (3H, s), 3.76e3.72 (1H, m),
3.59 (1H, dd, J ¼ 5.7, 2.9 Hz), 3.57e3.50 (2H, m), 3.42e3.37 (1H, m),
2.57 (1H, br d, J ¼ 3.4 Hz), 2.42 (3H, s), 2.34e2.28 (1H, m), 2.16e2.10
yl]-1-(4-methoxyphenylmethoxy)pent-4-en-2-amine
(306 mg,
0.88 mmol, dr ¼ ca. 6:1) and Et3N (0.24 mL, 1.75 mmol) in anhy-
drous CH2Cl2 (3.5 mL) at 0 ꢀC under a nitrogen atmosphere. After
stirring at room temperature for 1.5 h, the resulting mixture was
treated with 1 M HCl and then extracted with CH2Cl2. The organic
layer was washed with sat. aq. NaHCO3, water, and brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (eluent:
EtOAcehexane ¼ 1:4) to give the title compound (417 mg, 89%,
dr ¼ ca. 6:1) as a colorless oil: 1H NMR (400 MHz, CDCl3, major
(1H, m), 2.08 (1H, br s); 13C NMR (126 MHz, CDCl3)
d 159.6, 143.5,
137.6, 133.8, 129.9, 129.62, 129.58, 127.1, 118.6, 114.0, 78.6, 74.4, 71.1,
63.6, 55.3, 54.0, 36.4, 21.5; HRMS (EI) calcd for C22H29NO6S ([M]þ):
435.1716; found 435.1701.
4.1.11. N-[(2R,3R,4S)-1-tert-Butyldimethylsilyloxy-2-hydroxy-3-(4-
methoxyphenylmethoxy)hept-6-en-4-yl]-4-methylbenzene-
sulfonamide (30)
isomer) d 8.09e8.05 (1H, m), 7.88e7.83 (1H, m), 7.74e7.69 (2H, m),
7.29e7.26 (2H, m), 6.90e6.87 (2H, m), 5.77 (1H, br d, J ¼ 9.2 Hz),
5.36 (1H, ddt, J ¼ 16.9, 10.1, 7.3 Hz), 4.89 (1H, d, J ¼ 11.5 Hz),
4.82e4.75 (2H, m), 4.58 (1H, d, J ¼ 11.5 Hz), 4.25 (1H, td, J ¼ 7.8,
6.4 Hz), 4.03 (1H, dd, J ¼ 7.8, 6.4 Hz), 3.81 (3H, s), 3.45 (1H, t,
J ¼ 7.8 Hz), 3.41 (1H, dd, J ¼ 7.8, 1.8 Hz), 3.35e3.29 (1H, m),
2.28e2.21 (1H, m), 2.12e2.05 (1H, m), 1.67 (1H, q, J ¼ 7.3 Hz), 1.66
(1H, q, J ¼ 7.3 Hz), 1.57 (2H, q, J ¼ 7.3 Hz), 0.92 (3H, t, J ¼ 7.3 Hz), 0.85
tert-Butylchlorodimethylsilane (26 mg, 0.17 mmol) was added
to a solution of 28 (67 mg, 0.15 mmol, dr ¼ ca. 9:1) and Et3N (32
mL,
0.23 mmol) in anhydrous DMF (1.2 mL), followed by DMAP (4 mg,
0.031 mmol) at 0 ꢀC under a nitrogen atmosphere. After stirring at
room temperature for 4 h, tert-butylchlorodimethylsilane (5 mg,
0.031 mmol) was added to the mixture. After stirring for 1.5 h, the
resulting mixture was diluted with Et2O, washed with water and
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (eluent: EtOAcehexane ¼ 1:4 to acetoneeCHCl3 ¼ 1:2) to
give 30 (78 mg, 92%, dr ¼ ca. 12:1) as a colorless solid: 1H NMR
(3H, t, J ¼ 7.3 Hz); 13C NMR (100 MHz, CDCl3, major isomer)
d 159.3,
147.6, 135.5, 133.4, 132.8,130.3,130.1, 129.9,129.2, 125.3,118.7, 113.7,
113.6, 78.7, 78.2, 73.3, 66.7, 56.0, 55.3, 37.5, 29.7, 29.2, 8.2, 8.1; HRMS
(FAB) calcd for C26H35N2O8S ([MþH]þ): 535.2114; found 535.2128.
4.1.14. N-[(2R,3R,4S)-1,2-Dihydroxy-3-(4-methoxyphenylmethoxy)
hept-6-en-4-yl]-2-nitrobenzenesulfonamide (29)
(400 MHz, CDCl3, major isomer) d 7.71e7.68 (2H, m), 7.28e7.23 (4H,
m), 6.91e6.87 (2H, m), 5.44 (1H, ddt, J ¼ 16.9, 10.1, 6.9 Hz), 5.04 (1H,
br d, J ¼ 8.7 Hz), 4.96e4.90 (2H, m), 4.63 (1H, d, J ¼ 11.0 Hz), 4.55
(1H, d, J ¼ 11.0 Hz), 3.82 (3H, s), 3.68e3.63 (1H, m), 3.58 (1H, dd,
J ¼ 5.5, 2.8 Hz), 3.56e3.50 (2H, m), 3.43e3.37 (1H, m), 2.42 (3H, s),
2.40 (1H, br d, J ¼ 5.0 Hz), 2.36e2.28 (1H, m), 2.19e2.11 (1H, m),
0.90 (9H, s), 0.072 (3H, s), 0.068 (3H, s); 13C NMR (100 MHz, CDCl3,
Diluted H2SO4 (2%,1.6 mL) was added to a solution of N-{(1R,2S)-
1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-1-(4-
methoxyphenylmethoxy)pent-4-en-2-yl}-2-
nitrobenzenesulfonamide (432 mg, 0.81 mmol, dr ¼ ca. 6:1) in
MeOH (8.1 mL) at room temperature. After stirring for 18 h, K2CO3
(558 mg, 4.0 mmol) was added to the resulting solution at 0 ꢀC. The
mixture was stirred for 0.5 h, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent: EtOAceCH2Cl2e
hexane ¼ 4:3:3) to give 29 (305 mg, 81%) and N-[(2R,3R,4R)-1,2-
dihydroxy-3-(4-methoxyphenylmethoxy)hept-6-en-4-yl]-2-
nitrobenzenesulfonamide [6e] (41 mg, 11%). 29: colorless oil:
major isomer)
d 159.5, 143.3, 138.1, 134.1, 130.0, 129.8, 129.6, 127.1,
118.3, 113.9, 78.6, 74.2, 71.8, 63.9, 55.3, 54.2, 36.5, 25.8, 21.5,
18.2, ꢁ5.4; HRMS (FAB) calcd for
C
28H44NO6SSi ([MþH]þ):
550.2659; found 550.2653.
4.1.12. (2R,3R,4S)-1-tert-Butyldimethylsilyloxy-3-(4-methoxyphe-
nylmethoxy)-4-[(4-methylbenzenesulfonyl)amino]hept-6-en-2-yl
methanesulfonate (13a)
[
a
]
23 þ72.9 (c 1.00, CHCl3); IR (neat) nmax ¼ 3528, 3381, 3077, 2935,
D
1613, 1540, 1514, 1442, 1411, 1361, 1303, 1250, 1168, 1062, 1033, 924,
Methanesulfonyl chloride (27
mL, 0.35 mmol) was added to a
853, 822, 784, 742, 656 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
solution of 30 (65 mg, 0.12 mmol, dr ¼ ca. 12:1) and Et3N (99
m
L,
d
8.07e8.03 (1H, m), 7.88e7.83 (1H, m), 7.73e7.69 (2H, m),
0.71 mmol) in anhydrous CH2Cl2 (2.5 mL) at 0 ꢀC under a nitrogen
atmosphere. After stirring at room temperature for 1.5 h, the
resulting mixture was diluted with CH2Cl2, washed with water and
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (eluent: EtOAcehexane ¼ 1:3) to give 13a (73 mg, 98%,
dr ¼ ca. 12:1) as a colorless oil: 1H NMR (500 MHz, CDCl3, major
7.29e7.26 (2H, m), 6.93e6.89 (2H, m), 5.74 (1H, br d, J ¼ 8.2 Hz),
5.40 (1H, ddt, J ¼ 16.9, 10.1, 7.3 Hz), 4.93e4.88 (1H, m), 4.82e4.79
(1H, m), 4.66 (1H, d, J ¼ 11.0 Hz), 4.62 (1H, d, J ¼ 11.0 Hz), 3.82 (3H,
s), 3.79e3.74 (1H, m), 3.70e3.57 (4H, m), 2.42 (1H, br d, J ¼ 5.0 Hz),
2.43e2.35 (1H, m), 2.27e2.20 (1H, m), 1.95 (1H, br t, J ¼ 5.5 Hz); 13
C
NMR (100 MHz, CDCl3)
d 159.6, 147.6, 135.0, 133.5, 133.4, 132.8,
130.3, 129.8, 129.5, 125.3, 118.6, 114.1, 79.1, 74.5, 71.2, 63.6, 55.5,
55.3, 36.8; HRMS (EI) calcd for C21H26N2O8S ([M]þ): 466.1410;
found 466.1384.
isomer)
d
7.73e7.70 (2H, m), 7.30 (2H, d, J ¼ 7.5 Hz), 7.25e7.23 (2H,
m), 6.90e6.87 (2H, m), 5.45 (1H, dddd, J ¼ 17.5, 10.0, 8.0, 6.3 Hz),
4.98e4.95 (1H, m), 4.90e4.85 (1H, m), 4.89 (1H, d, J ¼ 10.3 Hz), 4.68
(1H, d, J ¼ 10.3 Hz), 4.61 (1H, ddd, J ¼ 8.0, 4.0, 2.3 Hz), 4.48 (1H, d,
J ¼ 10.3 Hz), 3.90e3.84 (3H, m), 3.81 (3H, s), 3.54e3.49 (1H, m),
2.92 (3H, s), 2.42 (3H, s), 2.20e2.13 (1H, m), 2.06e2.01 (1H, m), 0.91
(9H, s), 0.11 (3H, s), 0.09 (3H, s); 13C NMR (126 MHz, CDCl3, major
4.1.15. N-[(2R,3R,4S)-1-Benzyloxy-2-hydroxy-3-(4-methoxyphenyl-
methoxy)hept-6-en-4-yl]-2-nitrobenzenesulfonamide (31)
Dibutyltin oxide (107 mg, 0.43 mmol), BnBr (76 mL, 0.64 mmol),
and TBAI (158 mg, 0.43 mmol) were added to a solution of 29
(200 mg, 0.43 mmol) in anhydrous toluene (5 mL) at 0 ꢀC under a
nitrogen atmosphere. After heating under reflux with stirring for
isomer)
d 159.6, 143.7, 138.2, 133.5, 129.8, 129.6, 129.4, 127.0, 118.6,
114.0, 84.0, 76.6, 74.8, 62.3, 55.3, 53.2, 38.1, 37.1, 25.8, 21.5,
Please cite this article in press as: T. Fujiwara, et al., Divergent total synthesis of penaresidin B and its straight side chain analogue, Tetrahedron
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8
T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
3 h, the mixture was allowed to cool to room temperature and then
filtered through a pad of silica gel (eluent: EtOAc). The filtrate was
concentrated under reduced pressure, diluted with CH2Cl2, washed
with sat. aq. NaHCO3, water, and brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (eluent: EtOAce
CH2Cl2ehexane ¼ 1:5:4) to give 31 (212 mg, 89%) as a colorless oil:
CDCl3, major isomer) d 133.5,118.6,113.6, 76.4, 73.2, 66.4, 62.9, 34.9,
29.5, 29.0, 8.1, 8.0; HRMS (FAB) calcd for C12H22N3O3 ([MþH]þ):
256.1661; found 256.1638.
4.1.18. (4R)-4-[(1R,2S)-2-Azido-1-methoxymethoxypent-4-en-1-
yl]-2,2-diethyl-1,3-dioxolane (32)
Chloromethyl methyl ether (0.17 mL, 2.26 mmol) was added to a
solution of (1R,2S)-2-azido-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]
pent-4-en-1-ol (192 mg, 0.75 mmol, dr ¼ ca. 7:1) and i-Pr2NEt
(0.77 mL, 4.51 mmol) in anhydrous THF (4 mL), followed by TBAI
(139 mg, 0.38 mmol) at 0 ꢀC under nitrogen atmosphere. After
heating under reflux with stirring for 12 h, the mixture was allowed
to cool to room temperature and then treated with MeOH. The
resulting mixture was concentrated under reduced pressure and
then dissolved in EtOAc. The mixture was washed with water and
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (eluent: EtOAcehexane ¼ 1:9) to give 32 (210 mg, 93%,
dr ¼ ca. 6:1) as a colorless oil: 1H NMR (400 MHz, CDCl3, major
[
a]
23 þ47.8 (c 1.00, CHCl3); IR (neat) nmax ¼ 3546, 3370, 3068, 2921,
D
2867, 1612,1541, 1514, 1442, 1410,1361, 1303, 1250,1170, 1090,1034,
;
923, 853, 822, 784, 738, 701, 656 cmꢁ1 1H NMR (500 MHz, CDCl3)
d
8.00e7.96 (1H, m), 7.82e7.77 (1H, m), 7.68e7.63 (2H, m),
7.38e7.29 (5H, m), 7.24e7.21 (2H, m), 6.89e6.86 (2H, m), 5.77 (1H,
br d, J ¼ 8.0 Hz), 5.39 (1H, ddt, J ¼ 17.2, 9.7, 6.9 Hz), 4.88e4.84 (1H,
m), 4.81e4.78 (1H, m), 4.62 (1H, d, J ¼ 10.9 Hz), 4.59 (1H, d,
J ¼ 10.9 Hz), 4.53 (1H, d, J ¼ 12.0 Hz), 4.48 (1H, d, J ¼ 12.0 Hz), 3.87
(1H, br quint, J ¼ 5.2 Hz), 3.81 (3H, s), 3.68e3.63 (2H, m), 3.53 (1H,
dd, J ¼ 9.7, 5.7 Hz), 3.50 (1H, dd, J ¼ 9.7, 5.2 Hz), 2.38 (1H, br d,
J ¼ 5.7 Hz), 2.38e2.33 (1H, m), 2.22e2.16 (1H, m); 13C NMR
(126 MHz, CDCl3)
d 159.5, 147.6, 137.8, 135.2, 133.6, 133.2, 132.7,
130.3, 129.8, 129.7, 128.4, 127.9, 127.8, 125.2, 118.4, 113.9, 79.0, 74.3,
73.4, 71.0, 70.3, 55.33, 55.27, 36.9; HRMS (EI) calcd for C28H32N2O8S
([M]þ): 556.1879; found 556.1871.
isomer)
d
5.85 (1H, ddt, J ¼ 16.9, 10.1, 6.9 Hz), 5.26e5.21 (1H, m),
5.20e5.17 (1H, m), 4.95 (1H, d, J ¼ 6.9 Hz), 4.74 (1H, d, J ¼ 6.9 Hz),
4.32 (1H, ddd, J ¼ 7.8, 6.9, 6.4 Hz), 4.04 (1H, dd, J ¼ 7.8, 6.4 Hz), 3.65
(1H, t, J ¼ 7.8 Hz), 3.61 (1H, dd, J ¼ 6.9, 3.2 Hz), 3.45 (3H, s), 3.14 (1H,
td, J ¼ 6.9, 3.2 Hz), 2.56e2.52 (2H, m), 1.68e1.60 (4H, m), 0.903 (3H,
t, J ¼ 7.3 Hz), 0.895 (3H, t, J ¼ 7.3 Hz); 13C NMR (100 MHz, CDCl3,
4.1.16. (2R,3R,4S)-1-Benzyloxy-3-(4-methoxyphenylmethoxy)-4-
[(2-nitrobenzenesulfonyl)amino]hept-6-en-2-yl methanesulfonate
(13b)
major isomer)
d 133.5, 118.7, 113.4, 97.6, 79.6, 77.2, 66.4, 61.6, 56.3,
Methanesulfonyl chloride (89
m
L, 1.14 mmol) was added to a
34.9, 29.6, 29.2, 8.2, 8.0; HRMS (FAB) calcd for C14H26N3O4
solution of 31 (212 mg, 0.38 mmol) and Et3N (0.32 mL, 2.29 mmol)
in anhydrous CH2Cl2 (7.6 mL) at 0 ꢀC under nitrogen atmosphere.
After stirring at room temperature for 1 h, the mixture was filtered
through a pad of silica gel (eluent: EtOAc). The filtrate was
concentrated under reduced pressure, diluted with CH2Cl2, washed
with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (eluent: EtOAcehexane ¼ 2:3) to give 13b
(233 mg, 96%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
([MþH]þ): 300.1923; found 300.1946.
4.1.19. (1R,2S)-1-[(4R)-2,2-Diethyl-1,3-dioxolan-4-yl]-1-
methoxymethoxypent-4-en-2-amine
Triphenylphosphine (368 mg, 1.40 mmol) was added to a solu-
tion of 32 (210 mg, 0.70 mmol, dr ¼ ca. 6:1) in a 20:3 mixture of THF
and water (6 mL) at room temperature. After stirring at 50 ꢀC for
16 h, the resulting mixture was allowed to cool to room tempera-
ture and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (eluent: MeOH-
CH2Cl2 ¼ 1:19) to give the title compound (184 mg, 96%, dr ¼ ca.
7:1) as a colorless oil. The diastereomerically pure compound gave
the following data after partial separation by silica gel column
chromatography (eluent: MeOH-CH2Cl2 ¼ 1:19): colorless oil;
d
8.01e7.96 (1H, m), 7.86e7.81 (1H, m), 7.72e7.65 (2H, m),
7.40e7.31 (5H, m), 7.27e7.23 (2H, m), 6.90e6.87 (2H, m), 5.76 (1H,
br d, J ¼ 9.6 Hz), 5.39 (1H, ddt, J ¼ 16.9, 9.6, 7.3 Hz), 4.84e4.77 (2H,
m), 4.74 (1H, ddd, J ¼ 7.3, 5.0, 2.8 Hz), 4.70 (1H, d, J ¼ 11.5 Hz), 4.57
(1H, d, J ¼ 11.9 Hz), 4.54 (1H, d, J ¼ 11.9 Hz), 4.46 (1H, d, J ¼ 11.5 Hz),
3.86 (1H, dd, J ¼ 7.3, 1.8 Hz), 3.83e3.76 (2H, m), 3.80 (3H, s),
3.75e3.68 (1H, m), 2.90 (3H, s), 2.26e2.18 (1H, m), 2.13e2.05 (1H,
[
a
]
22 þ75.5 (c 1.00, CHCl3); IR (neat) nmax ¼ 3380, 3077, 2974, 2940,
D
1639, 1591, 1464, 1357, 1288, 1273, 1200, 1153, 1096, 1079, 1031, 920,
m); 13C NMR (100 MHz, CDCl3)
d
159.6, 147.6, 137.3, 135.2, 133.5,
840, 766 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 5.84e5.73 (1H, m),
133.0, 132.9, 130.3, 129.6, 129.2, 128.5, 128.0, 125.4, 118.7, 114.0, 81.8,
76.9, 74.5, 73.5, 68.7, 55.3, 54.1, 38.1, 37.4; HRMS (FAB) calcd for
C
5.15e5.09 (2H, m), 4.97 (1H, d, J ¼ 6.9 Hz), 4.73 (1H, d, J ¼ 6.9 Hz),
4.39 (1H, ddd, J ¼ 8.2, 6.9, 6.4 Hz), 4.07 (1H, dd, J ¼ 8.2, 6.4 Hz), 3.61
(1H, t, J ¼ 8.2 Hz), 3.49 (1H, dd, J ¼ 6.9, 2.8 Hz), 3.44 (3H, s), 2.65 (1H,
ddd, J ¼ 8.2, 5.5, 2.8 Hz), 2.40e2.33 (1H, m), 2.20e2.11 (1H, m),
1.68e1.59 (4H, m), 1.53 (2H, br s), 0.91 (3H, t, J ¼ 7.3 Hz), 0.89 (3H, t,
29H35N2O10S2 ([MþH]þ): 635.1733; found 635.1764.
4.1.17. (1R,2S)-2-Azido-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]pent-
4-en-1-ol
J ¼ 7.3 Hz); 13C NMR (100 MHz, CDCl3)
d 135.4, 117.9, 113.1, 97.5,
2,3-Dichloro-5,6-dicyano-p-benzoquinone (93 mg, 0.41 mmol)
was added to a solution of 27 (103 mg, 0.27 mmol, dr ¼ ca. 7:1) in a
9:1 mixture of CH2Cl2 and water (1.5 mL) at room temperature.
After stirring for 1 h, the resulting mixture was treated with sat. aq.
NaHCO3 and then extracted with CH2Cl2. The organic layer was
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (eluent: EtOAcehexane ¼ 1:9) to give the
title compound (67 mg, 96%, dr ¼ ca. 9:1) as a colorless oil: 1H NMR
80.4, 78.1, 66.8, 56.1, 52.6, 40.6, 29.7, 29.3, 8.2, 8.0; HRMS (EI) calcd
for C14H27NO4 ([M]þ): 273.1940; found 273.1929.
4.1.20. N-{(1R,2S)-1-[(4R)-2,2-Diethyl-1,3-dioxolan-4-yl]-1-
methoxymethoxypent-4-en-2-yl}-2-nitrobenzenesulfonamide
2-Nitrobenzenesulfonyl chloride (194 mg, 0.88 mmol) was
added to a solution of (1R,2S)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-
yl]-1-methoxymethoxypent-4-en-2-amine (184 mg, 0.67 mmol,
dr ¼ ca. 7:1) and Et3N (0.19 mL, 1.35 mmol) in anhydrous CH2Cl2
(5.4 mL) at 0 ꢀC under a nitrogen atmosphere. After stirring at room
temperature for 3 h, the resulting mixture was treated with sat. aq.
NH4Cl and then extracted with CH2Cl2. The organic layer was
washed with water and brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent: EtOAcehexane ¼ 1:3) to
(400 MHz, CDCl3, major isomer)
d
5.84 (1H, ddt, J ¼ 16.9, 10.1,
6.9 Hz), 5.25e5.20 (1H, m), 5.19e5.16 (1H, m), 4.23 (1H, ddd, J ¼ 6.9,
6.4, 5.5 Hz), 4.06 (1H, dd, J ¼ 8.2, 6.4 Hz), 3.71 (1H, dd, J ¼ 8.2,
6.9 Hz), 3.56 (1H, td, J ¼ 5.5, 3.7 Hz), 3.20 (1H, td, J ¼ 6.9, 3.7 Hz),
2.57 (1H, br d, J ¼ 5.5 Hz), 2.53e2.49 (2H, m), 1.71e1.62 (4H, m),
0.92 (3H, t, J ¼ 7.3 Hz), 0.91 (3H, t, J ¼ 7.3 Hz); 13C NMR (100 MHz,
Please cite this article in press as: T. Fujiwara, et al., Divergent total synthesis of penaresidin B and its straight side chain analogue, Tetrahedron
(2018), https://doi.org/10.1016/j.tet.2018.07.023

T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
9
give the title compound (309 mg, quant, dr ¼ ca. 7:1) as a colorless
oil: 1H NMR (400 MHz, CDCl3, major isomer)
8.14e8.10 (1H, m),
anhydrous CH2Cl2 (0.6 mL) at 0 ꢀC under nitrogen atmosphere. Af-
ter stirring at room temperature for 3 h, the mixture was treated
with water and then extracted with CH2Cl2. The organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (eluent: EtOAcehexane ¼ 2:3) to give 13c
d
7.91e7.87 (1H, m), 7.77e7.70 (2H, m), 5.79 (1H, br d, J ¼ 9.2 Hz), 5.52
(1H, ddt, J ¼ 16.9, 10.1, 7.3 Hz), 5.00e4.95 (1H, m), 4.98 (1H, d,
J ¼ 6.9 Hz), 4.90e4.87 (1H, m), 4.72 (1H, d, J ¼ 6.9 Hz), 4.20 (1H, ddd,
J ¼ 8.2, 7.8, 6.9 Hz), 4.04 (1H, dd, J ¼ 8.2, 6.9 Hz), 3.60 (1H, dd, J ¼ 7.8,
1.8 Hz), 3.50 (1H, t, J ¼ 8.2 Hz), 3.43 (3H, s), 3.42e3.37 (1H, m),
2.44e2.37 (1H, m), 2.23e2.16 (1H, m), 1.65e1.58 (2H, m), 1.54 (2H,
q, J ¼ 7.3 Hz), 0.88 (3H, t, J ¼ 7.3 Hz), 0.81 (3H, t, J ¼ 7.3 Hz); 13C NMR
(18 mg, 97%) as
8.17e8.13 (1H, m), 7.91e7.87 (1H, m), 7.78e7.73 (2H, m), 5.80 (1H,
a
colorless oil: 1H NMR (400 MHz, CDCl3)
d
br d, J ¼ 9.6 Hz), 5.54 (1H, ddt, J ¼ 16.9, 10.1, 7.3 Hz), 5.00e4.95 (1H,
m), 4.92e4.89 (1H, m), 4.75 (1H, d, J ¼ 6.9 Hz), 4.72 (1H, d,
J ¼ 6.9 Hz), 4.65 (1H, ddd, J ¼ 7.3, 4.6, 3.2 Hz), 4.01 (1H, dd, J ¼ 12.4,
4.6 Hz), 3.97e3.93 (2H, m), 3.85e3.78 (1H, m), 3.44 (3H, s), 3.05
(3H, s), 2.42e2.34 (1H, m), 2.17e2.10 (1H, m), 0.90 (9H, s), 0.102 (3H,
(100 MHz, CDCl3, major isomer)
d 147.6, 135.5, 133.4, 133.3, 132.9,
130.2, 125.4, 119.0, 113.6, 97.4, 78.2, 77.4, 66.6, 56.3, 55.9, 37.5, 29.7,
29.1, 8.1, 8.0; HRMS (FAB) calcd for C20H31N2O8S ([MþH]þ):
459.1801; found 459.1806.
s), 0.096 (3H, s); 13C NMR (100 MHz, CDCl3)
d 147.7, 135.5, 133.6,
4.1.21. N-[(2R,3R,4S)-1,2-Dihydroxy-3-methoxymethoxyhept-6-en-
4-yl]-2-nitrobenzenesulfonamide (33)
133.02, 132.99, 130.3, 125.5, 119.0, 98.7, 83.5, 77.2, 62.2, 56.5, 54.1,
38.2, 37.1, 25.8, 18.2, ꢁ5.46, ꢁ5.52; HRMS (FAB) calcd for
Pyridinium p-toluenesulfonate (8.9 mg, 0.035 mmol) was added
to a solution of N-{(1R,2S)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-
1-methoxymethoxypent-4-en-2-yl}-2-nitrobenzenesulfonamide
(81 mg, 0.18 mmol, dr ¼ ca. 7:1) in anhydrous MeOH (1.8 mL) at
room temperature. After stirring for 9 h, the resulting mixture was
treated with sat. aq. NaHCO3 and then filtered through a pad of
celite. The filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (eluent:
EtOAcehexane ¼ 2:3) to give 33 (44 mg, 64%, dr ¼ ca. 14:1) and the
recovered starting material (13 mg, 16%, dr ¼ ca. 6:1). 33: colorless
C
22H39N2O10S2Si ([MþH]þ): 583.1815; found 583.1832.
4.1.24. N-[(2R,3R,4S)-1-Benzyloxy-2-hydroxy-3-
methoxymethoxyhept-6-en-4-yl]-2-nitrobenzenesulfonamide (35)
Dibutyltin oxide (9.6 mg, 0.038 mmol), BnBr (7
mL, 0.058 mmol),
Et3N (13 L, 0.096 mmol), and TBAI (14 mg, 0.038 mmol) were
m
added to a solution of 33 (15 mg, 0.038 mmol, dr ¼ ca. 10:1) in
anhydrous toluene (0.4 mL) at 0 ꢀC under a nitrogen atmosphere.
After heating under reflux with stirring for 3 h, the mixture was
allowed to cool to room temperature and then filtered through a
pad of silica gel (eluent: EtOAc). The filtrate was concentrated under
reduced pressure, diluted with CH2Cl2, washed with sat. aq.
NaHCO3, water, and brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent: EtOAcehexane ¼ 1:1 to
9:1) to give 35 (11 mg, 58%, dr ¼ ca. 10:1) and the recovered 33
(2.3 mg, 15%, dr ¼ ca. 10:1). 35: colorless oil; 1H NMR (400 MHz,
oil; 1H NMR (500 MHz, CDCl3, major isomer)
d 8.16e8.13 (1H, m),
7.91e7.87 (1H, m), 7.77e7.72 (2H, m), 5.74 (1H, br d, J ¼ 9.2 Hz), 5.52
(1H, dddd, J ¼ 17.8, 10.3, 7.5, 6.9 Hz), 4.97e4.93 (1H, m), 4.89e4.87
(1H, m), 4.79 (1H, d, J ¼ 6.9 Hz), 4.69 (1H, d, J ¼ 6.9 Hz), 3.84e3.79
(1H, m), 3.75e3.61 (5H, m), 3.47 (3H, s), 2.38e2.32 (1H, m),
2.24e2.18 (1H, m); 13C NMR (126 MHz, CDCl3, major isomer)
d
147.6, 135.4, 133.5, 133.2, 133.0, 130.3, 125.4, 118.7, 98.9, 82.7, 71.3,
62.8, 56.4, 55.2, 37.4; HRMS (FAB) calcd for C15H23N2O8S ([MþH]þ):
CDCl3, major isomer) d 8.02e7.98 (1H, m), 7.87e7.83 (1H, m),
391.1175; found 391.1186.
7.72e7.65 (2H, m), 7.40e7.30 (5H, m), 5.76 (1H, br d, J ¼ 8.7 Hz),
5.48 (1H, ddt, J ¼ 16.9, 10.1, 6.9 Hz), 4.95e4.90 (1H, m), 4.88e4.85
(1H, m), 4.76 (1H, d, J ¼ 6.9 Hz), 4.68 (1H, d, J ¼ 6.9 Hz), 4.61 (1H, d,
J ¼ 11.9 Hz), 4.47 (1H, d, J ¼ 11.9 Hz), 3.84e3.79 (1H, m), 3.76e3.69
(2H, m), 3.62 (1H, dd, J ¼ 10.5, 4.6 Hz), 3.57 (1H, dd, J ¼ 10.5, 3.7 Hz),
3.43 (3H, s), 3.24 (1H, br d, J ¼ 3.7 Hz), 2.39e2.31 (1H, m), 2.21e2.14
4.1.22. N-[(2R,3R,4S)-1-tert-Butyldimethylsilyloxy-2-hydroxy-3-
methoxymethoxyhept-6-en-4-yl]-2-nitrobenzenesulfonamide (34)
tert-Butylchlorodimethylsilane (10.2 mg, 0.068 mmol) was
added to a solution of 33 (24 mg, 0.062 mmol, dr ¼ ca. 14:1) and
Et3N (10
m
L, 0.074 mmol) in anhydrous DMF (0.6 mL), followed by
(1H, m); 13C NMR (100 MHz, CDCl3, major isomer)
d 147.6, 137.8,
DMAP (1.9 mg, 0.015 mmol) at 0 ꢀC under a nitrogen atmosphere.
After stirring at room temperature for 16 h, the resulting mixture
was treated with water and then extracted with Et2O. The organic
layer was washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent: EtOAcehexane ¼ 2:3) to
135.5, 133.4, 133.3,132.8,130.3,128.4,128.0,127.8,125.3,118.5, 98.6,
81.8, 73.5, 70.5, 70.4, 56.3, 55.1, 37.3; HRMS (FAB) calcd for
C
22H29N2O8S ([MþH]þ): 481.1645; found 481.1656.
4.1.25. (2R,3R,4S)-1-Benzyloxy-3-methoxymethoxy-4-[(2-
nitrobenzenesulfonyl)amino]hept-6-en-2-yl methanesulfonate
(13d)
give 34 (23 mg, 74%) as a colorless oil: [
a
]
D
22 þ70.3 (c 1.00, CHCl3); IR
(neat) nmax ¼ 3379, 2952, 2929, 2857, 1542, 1471, 1442, 1415, 1361,
Methanesulfonyl chloride (3
mL, 0.042 mmol) was added to a
1255, 1169, 1122, 1031, 919, 837, 780, 742, 655 cmꢁ1
;
1H NMR
solution of 35 (16 mg, 0.033 mmol, dr ¼ ca. 10:1) and Et3N (27
m
L,
(400 MHz, CDCl3) 8.16e8.12 (1H, m), 7.89e7.86 (1H, m), 7.76e7.70
d
0.20 mmol) in anhydrous CH2Cl2 (1 mL) at 0 ꢀC under nitrogen at-
mosphere. After stirring at room temperature for 2 h, the mixture
was treated with water and then extracted with CH2Cl2. The organic
layer was washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent: EtOAcehexane ¼ 1:2) to
give 13d (16 mg, 87%, dr ¼ ca. 10:1) as a colorless oil: 1H NMR
(2H, m), 5.84 (1H, br d, J ¼ 8.6 Hz), 5.53 (1H, ddt, J ¼ 17.2, 9.7, 6.9 Hz),
4.98e4.93 (1H, m), 4.90e4.87 (1H, m), 4.78 (1H, d, J ¼ 6.9 Hz), 4.70
(1H, d, J ¼ 6.9 Hz), 3.82e3.67 (5H, m), 3.44 (3H, s), 2.92 (1H, br s),
2.42e2.36 (1H, m), 2.23e2.18 (1H, m), 0.90 (9H, s), 0.09 (6H, s); 13
C
NMR (100 MHz, CDCl3)
d 147.7, 135.6, 133.5, 133.3, 132.8, 130.3,
125.3, 118.6, 98.5, 80.7, 71.6, 63.7, 56.3, 55.3, 37.1, 25.9,
18.2, ꢁ5.4, ꢁ5.5; HRMS (FAB) calcd for C21H37N2O8SSi ([MþH]þ):
505.2040; found 505.2085.
(500 MHz, CDCl3, major isomer)
d 8.07e8.03 (1H, m), 7.89e7.85
(1H, m), 7.74e7.69 (2H, m), 7.39e7.31 (5H, m), 5.75 (1H, br d,
J ¼ 9.7 Hz), 5.49 (1H, ddt, J ¼ 17.2, 9.7, 6.9 Hz), 4.97e4.92 (1H, m),
4.89e4.86 (1H, m), 4.82e4.79 (1H, m), 4.74 (1H, d, J ¼ 6.9 Hz), 4.71
(1H, d, J ¼ 6.9 Hz), 4.57 (1H, d, J ¼ 12.0 Hz), 4.49 (1H, d, J ¼ 12.0 Hz),
3.91 (1H, dd, J ¼ 6.9, 2.3 Hz), 3.85 (1H, dd, J ¼ 11.5, 5.7 Hz), 3.80 (1H,
dd, J ¼ 11.5, 2.9 Hz), 3.78e3.72 (1H, m), 3.41 (3H, s), 3.00 (3H, s),
2.39e2.33 (1H, m), 2.16e2.10 (1H, m); 13C NMR (126 MHz, CDCl3,
4.1.23. (2R,3R,4S)-1-tert-Butyldimethylsilyloxy-3-methoxy
methoxy-4-[(2-nitrobenzenesulfonyl)amino]hept-6-en-2-yl
methanesulfonate (13c)
Methanesulfonyl chloride (8
solution of 34 (16 mg, 0.032 mmol) and Et3N (30
m
L, 0.095 mmol) was added to a
L, 0.19 mmol) in
m
Please cite this article in press as: T. Fujiwara, et al., Divergent total synthesis of penaresidin B and its straight side chain analogue, Tetrahedron
(2018), https://doi.org/10.1016/j.tet.2018.07.023

10
T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
major isomer)
d
147.7, 137.2, 135.3, 133.6, 133.0, 132.9, 130.4, 128.5,
anhydrous DMF (0.6 mL) at 0 ꢀC under nitrogen atmosphere. The
mixture was heated to 120 ꢀC with stirring for 1 h and then allowed
to cool to room temperature. The resulting mixture was treated
with sat. aq. NH4Cl and then extracted with Et2O. The organic layer
was washed with water and brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent: EtOAcehexane ¼ 1:4) to
128.01, 127.99, 125.5, 119.0, 98.7, 81.8, 77.4, 73.5, 68.6, 56.5, 54.0,
38.4, 37.1; HRMS (FAB) calcd for
559.1420; found 559.1421.
C
23H31N2O10S2 ([MþH]þ):
4.1.26. (2S,3R,4S)-2-(tert-Butyldimethylsilyloxy)methyl-3-(4-
methoxyphenylmethoxy)-1-(4-methylbenzenesulfonyl)-4-(prop-2-
en-1-yl)azetidine (12a)
give 12c (3.9 mg, 50%) as a colorless oil: [
a
]
D
19 þ122.5 (c 0.44, CHCl3);
Sodium hydride (60% dispersion in mineral oil, 12 mg,
0.30 mmol) was added to a solution of 13a (62 mg, 0.099 mmol,
dr ¼ ca.12:1) in anhydrous THF (2 mL) at room temperature under a
nitrogen atmosphere. After heating under reflux with stirring for
24 h, the resulting mixture was allowed to cool to room tempera-
ture, diluted with EtOAc, washed with sat. aq. NH4Cl, water, and
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
IR (neat) nmax ¼ 2928, 2855, 1733, 1544, 1470, 1441, 1351, 1257, 1157,
1103, 1052, 994, 948, 920, 837, 779, 742, 667 cmꢁ1
;
1H NMR
(500 MHz, CDCl3) 8.10e8.07 (1H, m), 7.72e7.68 (1H, m), 7.66e7.63
d
(2H, m), 5.73 (1H, ddt, J ¼ 17.2, 10.3, 6.9 Hz), 5.00e4.92 (2H, m), 4.73
(1H, ddd, J ¼ 9.2, 6.9, 4.6 Hz), 4.64 (1H, d, J ¼ 6.9 Hz), 4.57 (1H, d,
J ¼ 6.9 Hz), 4.44e4.42 (1H, m), 4.37 (1H, dd, J ¼ 6.9, 3.4 Hz), 4.06
(1H, dd, J ¼ 11.5, 4.0 Hz), 3.80 (1H, dd, J ¼ 11.5, 2.3 Hz), 3.36 (3H, s),
2.65e2.58 (1H, m), 2.54e2.48 (1H, m), 0.87 (9H, s), 0.06 (3H, s), 0.04
tography
(eluent:
EtOAceCHCl3ehexane ¼ 1:1:4
and
(3H, s); 13C NMR (126 MHz, CDCl3)
d 147.7, 136.7, 133.7, 132.8, 132.1,
EtOAcehexane ¼ 1:4) to give 12a (5.9 mg, 11%) and 26 (3.0 mg, 6%).
130.0, 124.3, 117.5, 96.2, 74.8, 70.4, 68.5, 61.4, 55.8, 32.9, 25.8,
18.2, ꢁ5.5, ꢁ5.7; HRMS (FAB) calcd for C21H35N2O7SSi ([MþH]þ):
487.1934; found 487.1963.
12a: colorless oil: [
a
]
23 þ72.0 (c 0.30, CHCl3); IR (neat) nmax ¼ 2952,
D
2928, 2856, 1613, 1514, 1464, 1344, 1304, 1250, 1157, 1106, 1036,
1005, 939, 918, 837, 815, 779, 675 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
7.72e7.70 (2H, m), 7.27 (2H, d, J ¼ 8.0 Hz), 7.19e7.16 (2H, m),
4.1.29. (2S,3R,4S)-2-Benzyloxymethyl-3-methoxymethoxy-1-(2-
nitrobenzenesulfonyl)-4-(prop-2-en-1-yl)azetidine (12d)
6.86e6.83 (2H, m), 5.75 (1H, ddt, J ¼ 17.2, 10.3, 6.9 Hz), 5.06e5.00
(2H, m), 4.43 (1H, d, J ¼ 11.5 Hz), 4.43e4.40 (1H, m), 4.36 (1H, d,
J ¼ 11.5 Hz), 4.14 (1H, dd, J ¼ 6.9, 3.4 Hz), 4.09 (1H, quint, J ¼ 3.4 Hz),
3.82 (1H, dd, J ¼ 10.9, 3.4 Hz), 3.79 (3H, s), 3.76 (1H, dd, J ¼ 10.9,
Sodium hydride (60% dispersion in mineral oil, 4.8 mg,
0.12 mmol) was added to a solution of 13d (19 mg, 0.034 mmol,
dr ¼ ca. 17:1) in anhydrous DMF (0.7 mL) at room temperature
under nitrogen atmosphere. The mixture was heated to 120 ꢀC with
stirring for 24 h and then allowed to cool to room temperature. The
resulting mixture was treated with sat. aq. NH4Cl and then
extracted with Et2O. The organic layer was washed with water and
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (eluent: EtOAcehexane ¼ 1:3) to give 12d (11 mg, 72%) as
6.9 Hz), 2.61e2.53 (2H, m), 2.41 (3H, s), 0.88 (9H, s), 0.04 (6H, s); 13
C
NMR (126 MHz, CDCl3)
129.0, 127.2, 117.3, 113.8, 72.2, 71.6, 71.2, 67.6, 62.0, 55.3, 31.8, 25.9,
21.5, 18.3, ꢁ5.4, ꢁ5.5; HRMS (FAB) calcd for
([MþH]þ): 532.2553; found 532.2562.
d 159.3, 143.2, 138.1, 134.3, 129.8, 129.5,
C28H42NO5SSi
4.1.27. (2S,3R,4S)-2-Benzyloxymethyl-3-(4-methoxyphenyl
methoxy)-1-(2-nitrobenzenesulfonyl)-4-(prop-2-en-1-yl)azetidine
(12b)
a pale yellow oil: [
a
]
20 þ115.5 (c 0.48, CHCl3); IR (neat) nmax ¼ 2932,
D
2853, 1542, 1454, 1348, 1156, 1101, 1052, 994, 919, 852, 781, 742,
Sodium hydride (60% dispersion in mineral oil, 82 mg,
2.06 mmol) was added to a solution of 13b (218 mg, 0.34 mmol) in
anhydrous DMF (7 mL) at 0 ꢀC under nitrogen atmosphere. The
mixture was heated to 80 ꢀC with stirring for 45 min and then
allowed to cool to room temperature. The resulting mixture was
treated with sat. aq. NH4Cl and then extracted with EtOAc. The
organic layer was washed with water and brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluent:
EtOAcehexane ¼ 1:3) to give 12b (170 mg, 92%) as a colorless oil:
699, 660 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 8.09e8.05 (1H, m),
7.68e7.63 (1H, m), 7.61e7.54 (2H, m), 7.34e7.24 (5H, m), 5.75 (1H,
ddt, J ¼ 16.9, 10.1, 6.9 Hz), 5.03e4.98 (1H, m), 4.98e4.94 (1H, m),
4.78 (1H, ddd, J ¼ 9.2, 7.3, 4.6 Hz), 4.61 (1H, d, J ¼ 6.9 Hz), 4.55 (1H,
d, J ¼ 6.9 Hz), 4.53e4.50 (1H, m), 4.49 (1H, d, J ¼ 11.9 Hz), 4.42 (1H,
dd, J ¼ 7.3, 3.7 Hz), 4.40 (1H, d, J ¼ 11.9 Hz), 3.90 (1H, dd, J ¼ 10.5,
3.7 Hz), 3.69 (1H, dd, J ¼ 10.5, 2.8 Hz), 3.33 (3H, s), 2.71e2.54 (2H,
m); 13C NMR (100 MHz, CDCl3)
d 147.7, 137.9, 136.3, 133.7, 132.8,
131.9, 130.0, 128.3, 127.5, 127.4, 124.2, 117.7, 96.3, 73.1, 72.9, 70.5,
68.7, 68.5, 55.8, 33.0; HRMS (FAB) calcd for C22H27N2O7S ([MþH]þ):
463.1539; found 463.1558.
[
a
]
18 þ98.4 (c 1.00, CHCl3); IR (neat) nmax ¼ 2925, 2856, 1612, 1542,
D
1514, 1455, 1349, 1249, 1161, 1033, 920, 852, 821, 743, 699,
659 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
8.07e8.03 (1H, m),
4.2. Synthesis of penaresidin B and its straight side chain analogue
7.68e7.64 (1H, m), 7.61e7.54 (2H, m), 7.35e7.28 (3H, m), 7.26e7.23
(2H, m), 7.19e7.15 (2H, m), 6.85e6.81 (2H, m), 5.79 (1H, ddt,
J ¼ 16.9, 10.5, 6.9 Hz), 5.04e4.95 (2H, m), 4.74 (1H, ddd, J ¼ 9.2, 6.9,
4.6 Hz), 4.50 (1H, br q, J ¼ 3.7 Hz), 4.47 (1H, d, J ¼ 11.9 Hz), 4.43 (1H,
d, J ¼ 11.5 Hz), 4.39 (1H, d, J ¼ 11.5 Hz), 4.36 (1H, d, J ¼ 11.9 Hz), 4.26
(1H, dd, J ¼ 6.9, 3.7 Hz), 3.79 (3H, s), 3.78 (1H, dd, J ¼ 10.5, 4.6 Hz),
3.52 (1H, dd, J ¼ 10.5, 2.8 Hz), 2.73e2.65 (1H, m), 2.59e2.52 (1H,
4.2.1. (2S,3R,4S)-2-Benzyloxymethyl-3-(4-methoxyphenyl
methoxy)-1-(2-nitrobenzenesulfonyl)-4-(tetradec-2-en-1-yl)-
azetidine (36)
Grubbs 2nd generation catalyst (8.8 mg, 0.010 mmol) and 1-
tridecene (0.15 mL, 0.62 mmol) were added to a solution of 12b
(28 mg, 0.052 mmol) in anhydrous (CH2Cl)2 (1 mL) under a nitrogen
atmosphere. After heating under reflux with stirring for 48 h, the
resulting mixture was cooled to room temperature and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (eluent: EtOAcehexane ¼ 1:4) to give
an inseparable mixture of 36 and unknown byproducts (12 mg) as a
colorless oil. The E/Z ratio of 36 could not be determined by NMR
due to overlapping peaks. 36: colorless oil; 1H NMR (500 MHz,
m); 13C NMR (100 MHz, CDCl3)
d 159.3, 147.7, 137.9, 136.3, 133.9,
132.8, 132.0, 130.0, 129.6, 129.3, 128.3, 127.6, 127.5, 124.2, 117.6,
113.8, 73.1, 72.4, 71.7, 71.6, 69.0, 68.7, 55.2, 32.9; HRMS (FAB) calcd
for C28H31N2O7S ([MþH]þ): 539.1852; found 539.1835.
4.1.28. (2S,3R,4S)-2-(tert-Butyldimethylsilyloxy)methyl-3-
methoxymethoxy-1-(2-nitrobenzenesulfonyl)-4-(prop-2-en-1-yl)
azetidine (12c)
CDCl3, major isomer)
d 8.07e8.03 (1H, m), 7.67e7.64 (1H, m),
Sodium hydride (60% dispersion in mineral oil, 2.3 mg,
0.058 mmol) was added to a solution of 13c (9.4 mg, 0.016 mmol) in
7.60e7.55 (2H, m), 7.35e7.23 (5H, m), 7.18e7.15 (2H, m), 6.84e6.81
(2H, m), 5.43 (1H, dt, J ¼ 14.9, 6.9 Hz), 5.35 (1H, dt, J ¼ 14.9, 6.9 Hz),
Please cite this article in press as: T. Fujiwara, et al., Divergent total synthesis of penaresidin B and its straight side chain analogue, Tetrahedron
(2018), https://doi.org/10.1016/j.tet.2018.07.023

T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
11
4.68 (1H, ddd, J ¼ 9.7, 6.9, 3.4 Hz), 4.50e4.48 (1H, m), 4.48 (1H, d,
J ¼ 11.5 Hz), 4.42 (1H, d, J ¼ 12.0 Hz), 4.39 (1H, d, J ¼ 12.0 Hz), 4.38
(1H, d, J ¼ 11.5 Hz), 4.24 (1H, dd, J ¼ 6.9, 3.4 Hz), 3.79 (3H, s), 3.78
(1H, dd, J ¼ 10.9, 4.6 Hz), 3.53 (1H, dd, J ¼ 10.9, 3.4 Hz), 2.64e2.59
(1H, m), 2.51e2.45 (1H, m), 1.90 (2H, br q, J ¼ 6.9 Hz), 1.31e1.25
(18H, m), 0.88 (3H, t, J ¼ 6.9 Hz); 13C NMR (126 MHz, CDCl3, major
was cooled to room temperature, treated with sat. aq. NH4Cl and
then extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (eluent: EtOAc to MeOHeCH2Cl2 ¼ 1:10) to give 38
(16 mg, 92%) as a colorless oil. The E/Z ratio of 38 could not be
determined by NMR due to overlapping and broadening peaks. 38:
isomer)
d 159.3, 147.7, 138.0, 136.4, 134.1, 132.8, 132.0, 130.0, 129.7,
129.2, 128.3, 127.58, 127.55, 124.8, 124.2, 113.8, 73.2, 72.3, 71.8, 71.6,
69.4, 68.8, 55.2, 32.7, 31.9, 31.6, 29.7, 29.6, 29.5, 29.35, 29.32, 29.2,
22.7, 14.1; HRMS (FAB) calcd for C39H53N2O7S ([MþH]þ): 693.3573;
found 693.3588.
colorless oil; 1H NMR (400 MHz, CDCl3, major isomer)
d 7.37e7.28
(5H, m), 5.55 (1H, dt, J ¼ 15.1, 6.9 Hz), 5.41e5.34 (1H, m), 4.57 (1H, d,
J ¼ 11.9 Hz), 4.54 (1H, d, J ¼ 11.9 Hz), 4.42 (1H, dd, J ¼ 6.9, 5.0 Hz),
3.92 (1H, br q, J ¼ 5.0 Hz), 3.86e3.81 (1H, m), 3.65e3.58 (4H, m),
2.55e2.49 (1H, m), 2.43e2.35 (1H, m), 1.98 (2H, br q, J ¼ 6.9 Hz),
1.34e1.23 (18H, m), 0.88 (3H, t, J ¼ 6.9 Hz); 13C NMR (100 MHz,
4.2.2. (2S,3R,4S)-2-Benzyloxymethyl-1-(2-nitrobenzenesulfonyl)-4-
(prop-2-en-1-yl)azetidin-3-ol (12e)
CDCl3, major isomer) d 137.9, 134.0, 128.4, 127.83, 127.80, 125.1, 73.4,
2,3-Dichloro-5,6-dicyano-p-benzoquinone (96 mg, 0.42 mmol)
was added to a solution of 12b (152 mg, 0.28 mmol) in a 9:1
mixture of CH2Cl2 and water (3 mL) at room temperature. After
stirring for 5 h, the resulting mixture was diluted with CH2Cl2,
washed with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (eluent: EtOAce
70.8, 68.7, 65.6, 61.4, 32.70, 32.68, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3,
29.2, 22.7, 14.1; HRMS (FAB) calcd for C25H42NO2 ([MþH]þ):
388.3216; found 388.3219.
4.2.5. tert-Butyl (2S,3R,4S)-2-benzyloxymethyl-3-hydroxy-4-
(tetradec-2-en-1-yl)azetidine-1-carboxylate (39)
Di-tert-butyl dicarbonate (14 mg, 0.062 mmol) and Et3N (12 mL,
hexane ¼ 7:13) to give 12e (88 mg, 75%) as
a
colorless oil:
0.083 mmol) were added to a solution of 38 (16 mg, 0.041 mmol) in
anhydrous CH2Cl2 (2 mL) at 0 ꢀC under a nitrogen atmosphere. After
stirring for 2 h, the resulting mixture was diluted with CH2Cl2,
washed with water and brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent: EtOAcehexane ¼ 1:4) to
give 39 (20 mg, quant) as a colorless oil. The E/Z ratio of 39 could not
be determined by NMR due to overlapping and broadening peaks.
39: colorless oil; 1H NMR (400 MHz, CDCl3, major isomer)
19
[a]
D
þ120.5 (c 0.49, CHCl3); IR (neat) nmax ¼ 3523, 2923, 2853,
1540, 1456, 1437, 1363, 1344, 1157, 1098, 920, 853, 781, 742, 698,
656 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
8.07e8.02 (1H, m),
7.65e7.53 (3H, m), 7.33e7.22 (5H, m), 5.81 (1H, ddt, J ¼ 16.9, 10.5,
6.9 Hz), 5.11e5.05 (1H, m), 5.04e5.01 (1H, m), 4.71 (1H, ddd, J ¼ 9.2,
6.4, 4.6 Hz), 4.55e4.52 (1H, m), 4.45 (1H, d, J ¼ 11.9 Hz), 4.43 (1H, br
q, J ¼ 3.2 Hz), 4.37 (1H, d, J ¼ 11.9 Hz), 3.85 (1H, dd, J ¼ 10.5, 3.7 Hz),
3.68 (1H, dd, J ¼ 10.5, 2.8 Hz), 2.72e2.57 (2H, m), 2.49 (1H, br d,
J ¼ 3.7 Hz); 13C NMR (100 MHz, CDCl3)
d
147.6, 137.7, 135.9, 134.0,
d
7.36e7.28 (5H, m), 5.63e5.42 (2H, m), 4.59 (1H, d, J ¼ 11.9 Hz),
133.0, 132.0, 129.9, 128.3, 127.6, 127.4, 124.1, 117.8, 73.7, 73.1, 68.6,
68.5, 66.3, 32.5; HRMS (FAB) calcd for C20H23N2O6S ([MþH]þ):
419.1277; found 419.1298.
4.55e4.52 (1H, m), 4.52 (1H, d, J ¼ 11.9 Hz), 4.29e4.19 (1H, m),
4.05e3.63 (3H, m), 2.66e2.51 (2H, m), 2.21 (1H, br s), 2.13e1.96
(2H, m), 1.44 (5H, br s), 1.41 (4H, br s), 1.36e1.25 (18H, m), 0.88 (3H,
t, J ¼ 6.9 Hz); HRMS (FAB) calcd for C30H50NO4 ([MþH]þ): 488.3740;
found 488.3728.
4.2.3. (2S,3R,4S)-2-Benzyloxymethyl-1-(2-nitrobenzenesulfonyl)-4-
(tetradec-2-en-1-yl)azetidin-3-ol (37)
Grubbs 2nd generation catalyst (1.2 mg, 0.0014 mmol) and 1-
4.2.6. tert-Butyl (2S,3R,4S)-3-hydroxy-2-hydroxymethyl-4-
tridecene (27
mL, 0.12 mmol) were added to a solution of 12e
tetradecylazetidine-1-carboxylate (40)
(12 mg, 0.029 mmol) in anhydrous CH2Cl2 (1 mL) under a nitrogen
atmosphere. After heating under reflux with stirring for 2 h, the
resulting mixture was cooled to room temperature and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (eluent: EtOAcehexane ¼ 1:3) to give
37 (10.3 mg, 63%) as a colorless oil. The E/Z ratio of 37 could not be
determined by NMR due to overlapping peaks. 37: colorless oil; 1H
Palladium 10% on carbon (0.6 mg) was added to a solution of 39
(6.0 mg, 0.012 mmol) in EtOH (0.5 mL) and the resulting solution
was stirred at room temperature under a hydrogen atmosphere
(1 atm) for 9 h. The mixture was filtered through a pad of celite and
concentrated under reduced pressure to give a mixture of 39 and
partially deprotected product as a colorless oil, which was dissolved
in anhydrous EtOH (1.6 mL). To the mixture was added palladium
10% on carbon (1.8 mg). After stirring at room temperature under a
hydrogen atmosphere (1 atm) for 1.5 h, the resulting mixture was
filtered through a pad of celite and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (eluent: Et2Oehexane ¼ 5:1 and EtOAcehexane ¼ 2:3) to
NMR (500 MHz, CDCl3, major isomer)
d 8.08e8.05 (1H, m),
7.66e7.54 (3H, m), 7.35e7.23 (5H, m), 5.55 (1H, dt, J ¼ 15.5, 6.9 Hz),
5.42 (1H, dt, J ¼ 15.5, 6.9 Hz), 4.69 (1H, ddd, J ¼ 9.5, 6.3, 4.0 Hz), 4.56
(1H, td, J ¼ 6.3, 3.4 Hz), 4.48 (1H, d, J ¼ 12.0 Hz), 4.43 (1H, br q,
J ¼ 3.4 Hz), 4.38 (1H, d, J ¼ 12.0 Hz), 3.87 (1H, dd, J ¼ 10.9, 4.0 Hz),
3.69 (1H, dd, J ¼ 10.9, 2.9 Hz), 2.67e2.60 (1H, m), 2.58e2.53 (1H,
m), 2.17 (1H, br d, J ¼ 6.3 Hz), 1.94 (2H, br q, J ¼ 6.9 Hz), 1.31e1.24
(18H, m), 0.88 (3H, t, J ¼ 6.9 Hz); 13C NMR (126 MHz, CDCl3, major
give 40 (4 mg, 83%) as a colorless oil: [
a
]
D
17 þ19.2 (c 0.20, CHCl3); IR
(neat) nmax ¼ 3410, 3364, 2921, 2851, 1657, 1421, 1365, 1149, 1106,
1085, 897, 766, 720, 635 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 4.46 (2/
isomer)
d
147.7, 137.8, 136.1, 134.6, 132.9, 132.0, 129.9, 128.3, 127.6,
3H, br d, J ¼ 8.2 Hz), 4.23 (4/3H, br s), 4.14 (1H, br q, J ¼ 6.4 Hz),
3.91e3.86 (1H, m), 3.79e3.74 (1H, m), 1.99 (1H, br d, J ¼ 6.4 Hz),
1.82e1.75 (2H, m), 1.45 (9H, s), 1.38e1.26 (24H, m), 0.88 (3H, t,
127.5, 125.1, 124.1, 73.8, 73.1, 68.8, 68.5, 66.7, 32.7, 31.9, 31.5, 29.7,
29.61, 29.60, 29.5, 29.3, 29.23, 29.18, 22.7, 14.1; HRMS (FAB) calcd
for C31H45N2O6S ([MþH]þ): 573.2998; found 573.2986.
J ¼ 6.9 Hz); 13C NMR (126 MHz, CDCl3)
d 156.8, 80.4, 71.8, 65.6, 65.3,
64.5, 31.9, 29.8, 29.67, 29.65, 29.60, 29.5, 29.3, 28.4, 27.8, 26.0, 22.7,
14.1; HRMS (FAB) calcd for C23H46NO4 ([MþH]þ): 400.3427; found
400.3423.
4.2.4. (2S,3R,4S)-2-Benzyloxymethyl-4-(tetradec-2-en-1-yl)azetidin-3-ol
(38)
Cesium carbonate (30 mg, 0.091 mmol) and PhSH (10 mL,
0.091 mmol) were added to a solution of 37 (26 mg, 0.045 mmol) in
anhydrous MeCN (2 mL) at room temperature under a nitrogen
atmosphere. After stirring at 50 ꢀC for 2 h, the resulting solution
4.2.7. (2S,3R,4S)-2-Hydroxymethyl-4-tetradecylazetidin-3-ol (3,
penaresidin straight chain analogue)
Concentrated HCl (0.5 mL) was added dropwise to a solution of
Please cite this article in press as: T. Fujiwara, et al., Divergent total synthesis of penaresidin B and its straight side chain analogue, Tetrahedron
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12
T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
40 (12 mg, 0.030 mmol) in MeOH (1 mL) at 0 ꢀC. After stirring at
room temperature for 3 h, the mixture was concentrated under
reduced pressure and then diluted with EtOAc. The resulting
mixture was treated with NaHCO3 (500 mg), dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluent:
CH2Cl2eMeOHeNH4OH ¼ 50:10:1) to give 3 (4.5 mg, 50%) as a
colorless amorphous solid. AcOH salt of 2 was prepared as a
(1H, m), 1.56e1.50 (2H, m), 1.46e1.29 (11H, m), 1.26e1.21 (2H, m),
0.92 (3H, d, J ¼ 6.9 Hz), 0.91 (3H, d, J ¼ 6.9 Hz); 13C NMR (126 MHz,
CDCl3)
d 84.7, 69.9, 68.1, 46.8, 38.0, 29.5, 29.1, 28.7, 28.4, 25.5, 24.6,
23.5, 22.0, 18.4; HRMS (EI) calcd for C14H26O ([M]þ): 210.1984;
found 210.1984.
4.2.10. (4S)-2-Methyltridec-12-en-4-ol (45)
Lindlar catalyst (32 mg) and quinoline (1.60 mL, 13.5 mmol)
were added to a solution of 44 (315 mg, 1.5 mmol) in anhydrous
CH2Cl2 (30 mL) at room temperature. The mixture was stirred for
30 min under a hydrogen atmosphere (1 atm) and then filtered
through a pad of celite. The filtrate was concentrated under
reduced pressure and then diluted in EtOAc. The resulting mixture
was washed with 10% HCl, water, and brine, dried over MgSO4,
filtered, concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluent:
EtOAcehexane ¼ 1:10) to give 45 (305 mg, 96%) as a colorless oil:
colorless amorphous solid by addition of AcOH (1 drop) to a solu-
24
tion of 3 in MeOH followed by evaporation. 3: [
a
]
e9.6 (c 0.25,
D
MeOH) (AcOH salt); IR (KBr) (AcOH salt) nmax ¼ 3381, 2919, 2849,
1566, 1464, 1411, 1384, 1123, 1042, 720, 651 cmꢁ1 1H NMR
(400 MHz, CD3OD) (AcOH salt)
;
d
4.52 (1H, br dd, J ¼ 6.9, 4.6 Hz),
4.23 (1H, br dt, J ¼ 8.2, 6.9 Hz), 4.07 (1H, br q, J ¼ 4.6 Hz), 3.84 (1H,
br dd, J ¼ 12.8, 4.6 Hz), 3.81 (1H, br dd, J ¼ 12.8, 3.7 Hz), 1.95e1.79
(2H, m), 1.91 (3H, s), 1.40e1.28 (24H, m), 0.89 (3H, t, J ¼ 6.9 Hz); 13
C
NMR (100 MHz, CD3OD)
d 70.0, 66.3, 65.5, 59.5, 33.1, 30.8, 30.6,
30.53, 30.47, 30.40, 27.6, 26.2, 23.7, 14.4; HRMS (FAB) calcd for
[
a
]
26 þ6.7 (c 1.00, CHCl3); IR (neat) nmax ¼ 3342, 3078, 2926, 2855,
D
C
18H38NO2 ([MþH]þ): 300.2903; found 300.2917.
1641, 1467, 1415, 1366, 1316, 1227, 1141, 1065, 993, 909, 841, 723,
636 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
5.81 (1H, ddt, J ¼ 16.9, 10.1,
4.2.8. (4R)-2-Methyltridec-6-yn-4-ol (43)
6.9 Hz), 4.99 (1H, dq, J ¼ 16.9, 1.8 Hz), 4.95e4.91 (1H, m), 3.70e3.64
(1H, m), 2.07e2.01 (2H, m), 1.84e1.70 (1H, m), 1.46e1.20 (15H, m),
0.92 (3H, d, J ¼ 6.9 Hz), 0.91 (3H, d, J ¼ 6.9 Hz); 13C NMR (100 MHz,
A solution of n-butyllithium in hexane (6.7 mL, 1.64 M, 11 mmol)
was added dropwise to a solution of 1-octyne (1.77 mL, 12 mmol) in
anhydrous THF (30 mL) at ꢁ78 ꢀC under a nitrogen atmosphere.
After stirring for 0.5 h, the mixture was allowed to warm to 0 ꢀC for
1 h and then cooled to ꢁ78 ꢀC. To the mixture were added dropwise
a solution of 42 [10] (1.00 g, 10 mmol) in anhydrous THF (10 mL)
and BF3$OEt2 (1.36 mL,11 mmol). The reaction mixture was allowed
to warm to ꢁ40 ꢀC for 1 h and then concentrated under reduced
pressure to one-third volume. The resulting mixture was treated
with sat. aq. NH4Cl and then extracted with Et2O. The organic layer
was washed with water and brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
CDCl3)
d 139.2, 114.1, 70.0, 46.8, 38.1, 33.8, 29.6, 29.5, 29.1, 28.9,
25.6, 24.6, 23.5, 22.1; HRMS (EI) calcd for C14H28O ([M]þ):
212.2140; found 212.2188.
4.2.11. [(4S)-2-Methyltridec-12-en-4-yl]oxymethylbenzene (46)
Sodium hydride (60% dispersion in mineral oil, 34 mg,
0.85 mmol) was added to a solution of 45 (90 mg, 0.42 mmol) in
anhydrous THF (1 mL) at 0 ꢀC under a nitrogen atmosphere. The
mixture was stirred for 30 min. Benzyl bromide (53 mL, 0.45 mmol)
and TBAI (157 mg, 0.42 mmol) were added to the mixture. After
heating under reflux with stirring for 48 h, the mixture was allowed
to cool to room temperature. To the mixture were added K2CO3
(30 mg, 0.22 mmol) and anhydrous MeOH (1 mL). The mixture was
stirred for 1 h, treated with sat. aq. NH4Cl, and then extracted with
EtOAc. The organic layer was washed with water and brine, dried
over MgSO4, filtered, concentrated under reduced pressure. The
residue was purified twice by silica gel column chromatography
(eluent: EtOAcehexane ¼ 1:20 to 1:10 and CH2Cl2ehexane ¼ 1:3)
to give 46 (102 mg, 80%) and the recovered 45 (8 mg, 9%). 46:
silica gel column chromatography (eluent: EtOAcehexane ¼ 1:20 to
24
1:10) to give 43 (2.01 g, 96%) as a colorless oil: [
a
]
D
þ2.9 (c 1.00,
CHCl3); IR (neat) nmax ¼ 3349, 2956, 2929, 2860, 1468, 1433, 1383,
1367, 1344, 1280, 1227, 1197, 1171, 1138, 1073, 1029, 989, 956, 880,
842, 723 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 3.80e3.75 (1H, m), 2.39
(1H, ddt, J ¼ 16.6, 4.6, 2.3 Hz), 2.25 (1H, ddt, J ¼ 16.6, 6.9, 2.3 Hz),
2.17 (2H, tt, J ¼ 6.9, 2.3 Hz), 1.89 (1H, br d, J ¼ 4.6 Hz), 1.82e1.74 (1H,
m), 1.53e1.44 (3H, m), 1.41e1.24 (7H, m), 0.93 (3H, d, J ¼ 6.9 Hz),
0.92 (3H, d, J ¼ 6.9 Hz), 0.89 (3H, t, J ¼ 6.9 Hz); 13C NMR (126 MHz,
CDCl3)
d
83.4, 76.1, 68.3, 45.4, 31.3, 28.9, 28.6, 28.3, 24.7, 23.3, 22.6,
colorless oil; [
a
]
24 þ13.9 (c 0.45, CHCl3); IR (neat) nmax ¼ 3065, 3031,
D
22.1, 18.7, 14.0; HRMS (EI) calcd for C14H26O ([M]þ): 210.1984; found
210.1983.
2927, 2855, 1640, 1496, 1455, 1365, 1307, 1205, 1143, 1093, 1069,
1028, 993, 909, 733, 696 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
7.36e7.24 (5H, m), 5.82 (1H, ddt, J ¼ 17.2, 10.3, 6.9 Hz), 5.00 (1H,
4.2.9. (4S)-2-Methyltridec-12-yn-4-ol (44)
dq, J ¼ 17.2, 1.7 Hz), 4.95e4.92 (1H, m), 4.52 (1H, d, J ¼ 11.5 Hz), 4.46
(1H, d, J ¼ 11.5 Hz), 3.43 (1H, ddt, J ¼ 8.0, 5.7, 5.2 Hz), 2.07e2.02 (2H,
m), 1.81e1.73 (1H, m), 1.55e1.21 (14H, m), 0.90 (3H, d, J ¼ 6.9 Hz),
Potassium hydride (30% dispersion in mineral oil, 1.60 g,
12 mmol) was washed with anhydrous Et2O (2 ꢂ 5 mL) under a
nitrogen atmosphere and the supernatant was then carefully dec-
anted off. The hydride was dried by passing nitrogen gas over its
surface while stirring and then mixed with 1,3-diaminopropane
(9.5 mL) under a nitrogen atmosphere. The mixture was stirred at
40 ꢀC for 1.5 h and then cooled to 0 ꢀC. A solution of 43 (631 mg,
3 mmol) in 1,3-diaminopropane (1 mL) was added dropwise to the
mixture. After stirring at room temperature for 21 h, the mixture
was poured into ice (100 mL) and then extracted with Et2O. The
organic layers was washed with 10% HCl, water, and brine, dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(eluent: EtOAcehexane ¼ 1:9) to give 44 (534 mg, 85%) as a color-
0.87 (3H, d, J ¼ 6.9 Hz); 13C NMR (100 MHz, CDCl3)
d 139.2, 139.1,
128.2, 127.8, 127.4, 114.1, 77.2, 70.6, 43.6, 34.1, 33.8, 29.8, 29.5, 29.1,
28.9, 25.1, 24.6, 23.3, 22.5; HRMS (EI) calcd for C21H34O ([M]þ):
302.2610; found 302.2597.
4.2.12. (2S,3R,4S)-2-Benzyloxymethyl-4-[(11S)-11-benzyloxy-13-
methyltetradec-2-en-1-yl]-1-(2-nitrobenzenesulfonyl)azetidin-3-ol
(47)
Grubbs 2nd generation catalyst (5.7 mg, 0.0067 mmol) and 46
(243 mg, 0.80 mmol) were added to a solution of 12e (56 mg,
0.13 mmol) in anhydrous CH2Cl2 (5 mL) under a nitrogen atmo-
sphere. After heating under reflux with stirring for 3.5 h, the
resulting mixture was cooled to room temperature and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (eluent: EtOAcehexane ¼ 1:15 to 1:3)
to give 47 (69 mg, 74%) as a colorless oil. The E/Z ratio of 47 could
less oil: [
a
]
23 þ6.3 (c 1.00, CHCl3); IR (neat) nmax ¼ 3375, 3312, 2930,
D
2857, 2118, 1634, 1467, 1366, 1326, 1267, 1238, 1137, 1105, 1035, 950,
887, 840, 741, 629 cmꢁ1
; d 3.69e3.64
1H NMR (500 MHz, CDCl3)
(1H, m), 2.18 (2H, td, J ¼ 7.0, 2.6 Hz),1.94 (1H, t, J ¼ 2.6 Hz),1.81e1.73
Please cite this article in press as: T. Fujiwara, et al., Divergent total synthesis of penaresidin B and its straight side chain analogue, Tetrahedron
(2018), https://doi.org/10.1016/j.tet.2018.07.023

T. Fujiwara et al. / Tetrahedron xxx (2018) 1e14
13
not be determined by NMR due to overlapping peaks. 47: colorless
oil; 1H NMR (400 MHz, CDCl3, major isomer)
8.07e8.02 (1H, m),
4.2.15. tert-Butyl (2S,3R,4S)-3-hydroxy-2-hydroxymethyl-4-[(11S)-
11-hydroxy-13-methyltetradecyl]azetidine-1-carboxylate (49)
d
7.65e7.60 (1H, m), 7.59e7.52 (2H, m), 7.35e7.22 (10H, m), 5.53 (1H,
dt, J ¼ 15.6, 6.4 Hz), 5.41 (1H, dt, J ¼ 15.6, 6.4 Hz), 4.66 (1H, ddd,
J ¼ 9.2, 6.4, 4.6 Hz), 4.54e4.50 (1H, m), 4.52 (1H, d, J ¼ 11.5 Hz), 4.46
(1H, d, J ¼ 11.9 Hz), 4.45 (1H, d, J ¼ 11.5 Hz), 4.44e4.40 (1H, m), 4.37
(1H, d, J ¼ 11.9 Hz), 3.85 (1H, dd, J ¼ 10.5, 3.7 Hz), 3.67 (1H, dd,
J ¼ 10.5, 2.8 Hz), 3.46e3.40 (1H, m), 2.66e2.51 (2H, m), 2.37 (1H, br
s), 1.96e1.91 (2H, m), 1.81e1.71 (1H, m), 1.56e1.19 (14H, m), 0.89
(3H, d, J ¼ 6.4 Hz), 0.87 (3H, d, J ¼ 6.4 Hz); 13C NMR (100 MHz,
Palladium 10% on carbon (14 mg) was added to a solution of 48
(27 mg, 0.044 mmol) in EtOH (1 mL) and the resulting solution was
stirred at room temperature under
a hydrogen atmosphere
(10 atm) for 1 h. The mixture was filtered through a filter paper and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent: EtOAcehexane ¼ 1:1) to
give 49 (19 mg, quant) as a colorless oil: [
a
]
23 þ46.8 (c 0.76, MeOH)
D
{lit [4d]. [
a
]
20 þ42.6 (c 0.23, MeOH)}, [
a
]
22 þ22.8 (c 0.76, CHCl3); IR
D
D
CDCl3, major isomer)
d
147.6, 139.0, 137.8, 136.1, 134.4, 132.9, 131.9,
(neat) nmax ¼ 3354, 2926, 2854, 1668, 1456, 1415, 1367, 1255, 1162,
129.9, 128.28, 128.26, 127.8, 127.6, 127.5, 127.4, 125.1, 124.1, 77.2,
73.7, 73.1, 70.6, 69.0, 68.6, 66.5, 43.6, 34.0, 32.6, 31.5, 29.8, 29.4, 29.2,
29.1, 25.1, 24.6, 23.3, 22.5; HRMS (FAB) calcd for C39H53N2O7S
([MþH]þ): 693.3573; found 693.3589.
1095, 1034, 855, 769, 739 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 4.54
(1/2H, br s), 4.23 (3/2H, br s), 4.16e4.10 (1H, m), 3.98 (1/10H, dd,
J ¼ 11.6, 3.7 Hz), 3.87 (9/10H, br d, J ¼ 11.6 Hz), 3.79e3.71 (1H, m),
3.70e3.64 (1H, m), 2.53 (1H, br s), 1.82e1.20 (25H, m), 1.45 (9H, s),
0.92 (3H, d, J ¼ 6.7 Hz), 0.91 (3H, d, J ¼ 6.7 Hz); 13C NMR (100 MHz,
4.2.13. (2S,3R,4S)-2-Benzyloxymethyl-4-[(11S)-11-benzyloxy-13-
methyltetradec-2-en-1-yl]azetidin-3-ol
CDCl3) d 156.8, 80.4, 71.7, 70.0, 65.7, 65.1, 64.3, 46.8, 38.0, 29.7, 29.6,
29.5, 29.4, 28.42, 28.36, 27.8, 25.9, 25.5, 24.6, 23.5, 22.1; HRMS (FAB)
Cesium carbonate (65 mg, 0.20 mmol) and PhSH (20
m
L,
calcd for C24H48NO5 ([MþH]þ): 430.3532; found 430.3538.
0.20 mmol) were added to a solution of 47 (69 mg, 0.10 mmol) in
anhydrous MeCN (4 mL) at room temperature under a nitrogen
atmosphere. After stirring at 50 ꢀC for 2 h, the resulting solution
was cooled to room temperature, treated with sat. aq. NH4Cl and
then extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (eluent: MeOHeCH2Cl2 ¼ 1:10) to give the title com-
pound (49 mg, 97%) as a pale yellow oil. The E/Z ratio of the title
compound could not be determined by NMR due to overlapping
and broadening peaks: colorless oil; 1H NMR (500 MHz, CDCl3,
4.2.16. (2S,3R,4S)-2-Hydroxymethyl-4-[(11S)-11-hydroxy-13-
methyltetradecyl]azetidin-3-ol (2, penaresidin B)
Concentrated HCl (0.3 mL) was added dropwise to a solution of
49 (15.1 mg, 0.035 mmol) in MeOH (1 mL) at 0 ꢀC and the mixture
was stirred at room temperature for 30 min. Concentrated HCl
(0.2 mL) was added again to the mixture. After stirring for 1.5 h, the
mixture was concentrated under reduced pressure and then diluted
with EtOAc. The resulting mixture was treated with NaHCO3
(500 mg), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (eluent: CH2Cl2eMeOHeNH4OH ¼ 50:10:1) to
give 2 (10.6 mg, 92%) as a colorless oil. AcOH salt of 2 was prepared
as a pale yellow oil by addition of AcOH (1 drop) to a solution of 2 in
major isomer)
d
7.35e7.24 (10H, m), 5.56 (1H, dt, J ¼ 15.5, 6.9 Hz),
5.34 (1H, dt, J ¼ 15.5, 6.9 Hz), 4.57 (1H, d, J ¼ 12.0 Hz), 4.54 (1H, d,
J ¼ 11.5 Hz), 4.50 (1H, d, J ¼ 11.5 Hz), 4.45 (1H, d, J ¼ 12.0 Hz),
4.43e4.30 (2H, m), 4.03 (1H, br q, J ¼ 4.6 Hz), 3.93 (1H, br q,
J ¼ 7.5 Hz), 3.67e3.60 (2H, m), 3.45e3.41 (1H, m), 2.59e2.54 (1H,
m), 2.46e2.40 (1H, m), 1.99e1.95 (2H, m), 1.80e1.72 (1H, m),
1.57e1.19 (14H, m), 0.89 (3H, d, J ¼ 6.9 Hz), 0.87 (3H, d, J ¼ 6.9 Hz);
MeOH followed by evaporation. 2: [a]
23 e7.1 (c 0.59, MeOH) (AcOH
D
25
salt) {lit [4c]. [
(AcOH salt) nmax ¼ 3306, 2925, 2854, 1566, 1466, 1412, 1367, 1125,
1049, 1015, 924, 839, 721, 654 cmꢁ1 1H NMR (400 MHz, CD3OD)
(AcOH salt)
a]
e6.8 (c 0.35, MeOH) (AcOH salt)}; IR (neat)
D
;
13C NMR (126 MHz, CDCl3, major isomer)
d 139.0, 137.6, 134.4,
d
4.52 (1H, br dd, J ¼ 6.9, 5.0 Hz), 4.24 (1H, br q,
128.5, 128.4, 128.3, 128.2, 127.8, 127.4, 124.4, 77.2, 73.4, 70.6, 69.5,
68.2, 65.9, 62.2, 43.6, 34.0, 32.7, 31.8, 29.8, 29.5, 29.3, 29.2, 25.2,
24.6, 23.3, 22.5; HRMS (FAB) calcd for C33H50NO3 ([MþH]þ):
508.3791; found 508.3795.
J ¼ 7.8 Hz), 4.08 (1H, br q, J ¼ 4.1 Hz), 3.85 (1H, br dd, J ¼ 12.8,
4.6 Hz), 3.82 (1H, br dd, J ¼ 12.8, 3.7 Hz), 3.61e3.55 (1H, m),
1.94e1.72 (3H, m), 1.91 (3H, s), 1.44e1.28 (19H, m), 1.18 (1H, ddd,
J ¼ 13.7, 8.7, 4.1 Hz), 0.91 (3H, d, J ¼ 6.9 Hz), 0.90 (3H, d, J ¼ 6.9 Hz);
13C NMR (100 MHz, CD3OD) (AcOH salt)
d 179.0, 70.4, 69.9, 66.4,
4.2.14. tert-Butyl (2S,3R,4S)-2-benzyloxymethyl-4-[(11S)-11-
benzyloxy-13-methyltetradec-2-en-1-yl]-3-hydroxyazetidine-1-
carboxylate (48)
65.2, 59.6, 47.9, 39.1, 30.85, 30.75, 30.69, 30.63, 30.5, 30.4, 27.7, 26.8,
26.2, 25.7, 23.9, 23.2, 22.4; HRMS (FAB) calcd for C19H40NO3
([MþH]þ): 330.3008; found 330.3012.
Di-tert-butyl dicarbonate (32 mg, 0.15 mmol) and Et3N (27
mL,
0.19 mmol) were added to solution of (2S,3R,4S)-2-
a
Acknowledgements
benzyloxymethyl-4-[(11S)-11-benzyloxy-13-methyltetradec-2-en-
1-yl]azetidin-3-ol (49 mg, 0.097 mmol) in anhydrous CH2Cl2 (5 mL)
at 0 ꢀC under a nitrogen atmosphere. After stirring for 2 h, the
resulting mixture was diluted with CH2Cl2, washed with water and
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (eluent: EtOAcehexane ¼ 1:4) to give 48 (48 mg, 82%) as a
colorless oil. The E/Z ratio of 48 could not be determined by NMR
due to overlapping and broadening peaks. 48: colorless oil; 1H NMR
This work was supported by JSPS Core-to-Core Program, B. Asia-
Africa Science Platforms.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.07.023.
(500 MHz, CDCl3, major isomer)
d 7.36e7.24 (10H, m), 5.62e5.43
References
(2H, m), 4.59 (1H, d, J ¼ 12.0 Hz), 4.55e4.52 (1H, m), 4.53 (1H, d,
J ¼ 11.5 Hz), 4.52 (1H, d, J ¼ 11.5 Hz), 4.46 (1H, d, J ¼ 12.0 Hz),
4.31e4.19 (1H, m), 4.07e3.62 (3H, m), 3.43 (1H, ddd, J ¼ 10.9, 8.0,
5.7 Hz), 2.68e2.50 (2H, m), 2.14e1.97 (3H, m), 1.81e1.73 (1H, m),
1.55e1.21 (23H, m), 0.90 (3H, d, J ¼ 6.3 Hz), 0.87 (3H, d, J ¼ 6.3 Hz);
HRMS (FAB) calcd for C38H58NO5 ([MþH]þ): 608.4315; found
608.4321.
€
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