Novel protection of 1,2-diol for trans-dihydroxycyclopentene ring construction by the C[sbnd]H insertion of alkylidene carbene: Formal total synthesis of (+)-trehazolin

Article abstract of DOI:10.1016/j.tetlet.2019.151085

The chiral vicinal diol was protected as 6-methylene-1,4-dioxepane to construct a cyclopentene ring by the C[sbnd]H insertion of alkylidene carbene. The removal of the protecting group was achieved in a few steps, affording the corresponding diol in a reasonable yield. Using these reactions, the known synthetic intermediate for (+)-trehazolin was synthesized from D-diethyl tartrate. In addition, a short route to the intermediate from a D-mannitol derivative was described.

Full text of DOI:10.1016/j.tetlet.2019.151085

Tetrahedron Letters 60 (2019) 151085
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel protection of 1,2-diol for trans-dihydroxycyclopentene ring
construction by the CAH insertion of alkylidene carbene: Formal total
synthesis of (+)-trehazolin
⇑
Susumu Ohira , Atsuhito Kuboki, Yoshimi Takimoto, Kyosuke Matsuda, Saori Itasaki, Yuki Urushibata,
Yoshiyuki Takano, Yuuki Nakamura
Department of Biochemistry, Faculty of Science, Okayama University of Science, 1-1 Ridai-cho, Kita-ku, Okayama 700-0005, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2019
Revised 27 August 2019
Accepted 27 August 2019
Available online 27 August 2019
The chiral vicinal diol was protected as 6-methylene-1,4-dioxepane to construct a cyclopentene ring by
the CAH insertion of alkylidene carbene. The removal of the protecting group was achieved in a few steps,
affording the corresponding diol in a reasonable yield. Using these reactions, the known synthetic inter-
mediate for (+)-trehazolin was synthesized from
D-diethyl tartrate. In addition, a short route to the inter-
mediate from a -mannitol derivative was described.
D
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Alkylidene carbene
CAH insertion
Glycosidase inhibitor
Protecting group
The CAH insertion of alkylidene carbene, which is one of the
direct CAH bond functionalization methods [1], is beneficial for
the construction of a cyclopentene ring. Since the report of the gen-
eration of alkylidene carbenes using lithiotrimethylsilyldia-
zomethane and ketones by our group [2], this reaction has been
used as a key reaction for natural product synthesis [2,3,4]. In a ser-
ies of studies, an antitumor agent (À)-neplanocin A containing the
cis-dihydroxycyclopentene ring was synthesized via cyclopentene
1 which was obtained by the CAH insertion of alkylidene carbene
from ketone 2 (Fig. 1) [2i,5].
On the other hand, the reaction between lithiotrimethylsilyldia-
zomethane and chiral epoxide 3 afforded cyclopentene 4, which
served as the precursor for trans-dihydroxycyclopentene derivative
5. In turn, 5 was transformed into a known intermediate 6 for the
glycosidase inhibitor (+)-trehazolin (Fig. 2) [2c,6]. This strategy
was selected to prevent the formation of a stable oxonium ylide,
which occurred when the dihydroxyl group was protected as a
non-cyclic bis ether. The formation of the oxonium ylide often
prevented smooth CAH insertion, although the equilibrium
between the carbene and the ylide was possible [2c,7].
diol [8], it was found that reaction of 1,4-dioxepane derivative 7
and lithiotrimethylsilyldiazomethane afforded cyclopentene 8a
and its epimer 8b in a combined yield of 69%. Cyclopentene 8a
could be converted into the synthetic intermediate 6. As the stere-
oselective reduction of ketone 9 was possible, cyclopentene 8a was
synthesized in much shorter way from the D-mannitol derivative
via ketone 10 and cyclopentene 11 (Fig. 2).
Ketone 7 was prepared from D-diethyl tartrate (12) (Scheme 1).
The protection of the vicinal diol of 12 as an acetonide, followed by
the reduction of esters by lithium borohydride [9] afforded diol 13.
The hydroxyl groups of 13 were protected as a bis p-methoxyben-
zyl (PMB) ether, and the acetonide was removed using acidic
methanol to yield diol 14. This reaction incompletely ended; hence,
the starting material was recovered and re-used. Compound 14
was subjected to the reaction with sodium hydride and 3-chloro-
2-chloromethyl-1-propene affording
2-methylene-1,3-propyl
ether 15. The partial deprotection of PMB ethers using one equiv-
alent of DDQ afforded mono alcohol 16. Alcohol 16 was trans-
formed to diol 17 by the oxidation of 16, reaction with
ethoxyethoxymethyllithium [10] and acidic treatment of the prod-
uct. The protection of the primary alcohol of 17 as TBS ether and
IBX oxidation of the secondary alcohol afforded ketone 7. The
alkylidene carbene generated from 7 underwent CAH insertion,
affording 8a and 8b in 36% and 33% yield, respectively [11].
The stereochemistry of 8a and 8b was determined by an NOE
experiment [12].
In this study, the direct protection of a potential trans-vicinal
diol as a cyclic ether was attempted. After unsuccessful results
were obtained with known protecting groups for the trans-vicinal
⇑
Corresponding author.
E-mail address: sohira@dbc.ous.ac.jp (S. Ohira).
https://doi.org/10.1016/j.tetlet.2019.151085
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
S. Ohira et al. / Tetrahedron Letters 60 (2019) 151085
The undesired isomer 8b was converted to ketone 9 and the
stereoselective reduction was attempted (Scheme 2). Luche reduc-
tion selectively gave the desired alcohol 18, which was converted
to 8a. It is noteworthy that lithium tri-sec-butylborohydride
showed reversed high stereoselectivity giving the other isomer 19.
The generation of the diol from 6-methylene-1,4-dioxepane
was investigated using 20 and 21 (Scheme 3). Various conditions
for the deprotection of allyl ether were not effective for these com-
pounds; however, RuHCl(CO)(PPh3)3 [13] cleanly catalyzed the iso-
merization of double bond of 20 to 22. The acidic hydrolysis of 22,
followed by b-elimination from the resulting aldehyde afforded
diol 23. Using acid-sensitive substrate 21, diol 24 was cleanly
obtained by hydroboration-oxidation and IBX oxidation, followed
by the treatment of the resulting aldehyde 25 with potassium car-
bonate in methanol (b-elimination, Michael addition of methanol
Fig. 1. Reagents and conditions: (a) TMSCLiN2, THF, 55–65%.
to the
a, b-unsaturated aldehyde, and b-elimination of the
substrate).
With the deprotection procedure to the diol in hand, the formal
synthesis of (+)-trehazolin from 8a was focused (Scheme 4). The
deprotection of the TBS ether of 8a, Sharpless asymmetric epoxida-
tion, and MOM protection of the alcohol afforded cyclopentane 26.
The generation of the trans-diol via aldehyde 27 and MOM protec-
tion afforded the known synthetic intermediate 28, which was
convertible to 6 [2c,14].
The overall yield to 16 was improved by using allylic bis(tert-
butyl carbonate) 29 with a palladium catalyst in the first step
[15]. After this mild reaction, diester 30 was converted to mono
alcohol 16 in two steps (Scheme 5).
As the reduction of 9 was highly stereoselective, an alternative
short approach to 9 starting from the commercially available
D-mannitol derivative 31 was investigated (Scheme 6). After the
protection of the diol, acetonides of 32 were removed, and three
hydroxyl groups of the tetraol 33 were protected as tris-TBS ether
34. By-products 35 and 36 were combined and treated with acidic
ethanol, regenerating 33. The IBX oxidation of secondary alcohol of
Fig. 2. Reagents and conditions: (a) TMSCLiN2, THF or DME, 49%–69%; (b) allyl
alcohol, p-TsOH, 69%.
Scheme 2. Reagents and conditions: (a) DDQ, CH2Cl2-H2O, rt, 2 h, 31%; (b) IBX,
DMSO, 50 °C, 2 h, 26%; (c) PMBCl, NaH, TBAI, DMF, 0 °C, 2 h, 53%.
Scheme 1. Reagents and conditions: (a) DMP, p-TsOH, CH2Cl2, 40 °C, 17 h, 90%; (b)
NaBH4, LiCl, THF–EtOH, rt, 14 h, 92%; (c) PMBCl, NaH, TBAI, DMF, rt, 3 h, 93%; (d)
MeOH, p-TsOH, rt, 5 h, 46% (37% of SM); (e) 3-chloro-2-chloromethyl-1-propene,
NaH, DMF, 60 °C, 3 h, 72%; (f) DDQ, CH2Cl2-H2O, rt, 2 h, 40% (50% of SM); (g) IBX,
DMSO, 50 °C, 1 h, 70%; (h) Bu3SnCH2OEE, BuLi, THF, À78 °C, 20 min, 75%; (i) MeOH,
PPTS, 0 °C, 23 h, 76%; (j) TBSCl, imidazole, DMF, rt, 0.5 h, 88%; (k) IBX, DMSO, 50 °C,
2 h, 73%; (l) TMSCHN2, BuLi, DME, À78 °C, 0.5 h to rt, 0.5 h, 36% of 8a, 33% of 8b.
Scheme 3. Reagents and conditions: (a) RuHCl(CO)(PPh3)3, THF, reflux, 24 h, 94%;
(b) AcOH-H2O, 70 °C, 48 h, 75%; (c) BH3ÁTHF, rt, 1 h; 10% NaOH, 30% H2O2, rt, 1 h,
95%; IBX, DMSO, 50 °C, 1 h, 75%; (d) K2CO3, MeOH, 50 °C, 1 h, 94%.

S. Ohira et al. / Tetrahedron Letters 60 (2019) 151085
3
transfer of the cyclic oxonium ylide [2c,5,7]. Both isomers were
separated by preparative thin-layer chromatography and
characterized [16]. Practically, a mixture of 11 and 37 was treated
with potassium fluoride in the presence of 18-crown-6-ether [17]
and silica-gel column chromatography of the products afforded
pure triol 38. Triol 38 was converted to ketone 9 by glycol fission
using lead tetra acetate, followed by the protection of the alcohol.
Ketone 9 was converted into 8a, and then into 6 (Scheme 2,
Scheme 4).
In conclusion, the vicinal diol protected as 6-methylene-1,4-
dioxepane was used to construct the cyclopentene ring which con-
tains trans-vicinal diol by the CAH insertion of alkylidene carbene.
The removal of the 3-methylene-1,3-propyl group was possible in
two ways. Since the number of cyclic protecting groups for trans-
vicinal diol is limited [8], our findings may provide another choice
of protecting group. Reversed high stereoselectivity in the reduc-
tion of carbonyl group adjacent to this protecting group is also
notable. Using these novel transformations, new formal routes to
(+)-trehazolin were established.
Scheme 4. Reagents and conditions: (a) TBAF, THF, rt, 5 h, 92%; (b) L-diethyl
tartrate, TBHP, Ti(OiPr)4, CH2Cl2, 0 °C, 19 h, 57%; (c) MOMCl, NaI, (iPr)2NEt, DME, rt,
1 h, 90%; (d) 9-BBN, THF, rt, 1 h; 6M NaOH, 30% H2O2, rt, 1 h, 56%; (e) IBX, CH3CN,
70 °C, 1 h,; (f) MeOH, K2CO3, rt, 2.5 h, 83% in two steps; (g) MOMCl, (iPr)2NEt,
CH2Cl2, rt, 2 h, 83%
Acknowledgments
We thank Professor Nozaki, H. (OUS) and Mr. Takaya, K. for
assistance with the NOE experiment.
Scheme 5. Reagents and conditions: (a) Pd2(dba)3, dppb, THF, rt, 67 h, 75%; (b) LiCl,
NaBH4, THF–EtOH, rt, 19 h, 91%; (c) PMBCl, NaH, TBAI, DMF, rt, 3 h, 60%
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Scheme 6. Reagents and conditions: (a) 3-chloro-2-chloromethyl-1-propene, NaH,
DMF, 60 °C, 2 h, 60%; (b) EtOH–1M HCl (10:1), 80 °C, 2 h; (c) TBSCl, imidazole, DMF,
rt, 1 h, 55% in two steps (>29% of 35 and 36); (d) IBX, pyridine, DMSO, 50 °C, 1 h,
97%; (e) TMSCHN2, BuLi, DME, –78 °C, 0.5 h, then rt, 0.5 h, 85% (combined); (f) KF,
18-crown-6-ether, DMF–H2O (10:1), 80 °C, 14 h, 73%; (g) Pb(OAc)4, THF, –20 °C,
1.5 h, 67%; (h) TBSCl, imidazole, DMF, rt, 2 h, 94%.
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(1,1,3,3-Tetraisopropyldisiloxanylidene) derivatives were not stable for
multistep transformations. The ketone derived from butane-2,3-diacetal-
protected tartrate18 did not afford the C–H insertion product with
lithiotrimethlsilyldiazomethane. 1,3-O-(o-xylylene) protection with simple
vicinal diols only proceeded with a non-practically low yield.
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24
[11] 8a: [
a
]
D
À20° (c 0.59 ,CHCl3); vmax(neat)/cmÀ1 1610, 1514, 1464; 1H NMR (400
34 gave the ketone 10, which was treated with lithiotrimethylsilyl-
diazomethane to afford a mixture of 11 and 37 in a ratio of 4:1.
Compound 37 was obtained as the product from silyl-group
MHz, CDCl3) d 0.05 (s, 3H), 0.06 (s, 3H), 0.9 (s, 9H), 3.0 (s, 3H), 3.96 (t, 1H, J = 6.1
Hz), 4.1 (d, 1H, J = 4.9 Hz), 4.21 (d, 1H, J = 5.4 Hz), 4.23 (q, 1H, J = 1.5 Hz),
4.27À4.29 (m, 1H), 4.31À4.35 (m, 1H), 4.42 (t, 1H, J = 12.5 Hz), 4.55 (d, 1H,

4
S. Ohira et al. / Tetrahedron Letters 60 (2019) 151085
J = 11.7 Hz), 4.67 (d, 1H, J = 11.7 Hz), 5.25 (brd, 1H, J = 2.9 Hz), 5.65 (quint, 1H,
J = 8.6 Hz), 7.29 (2H, brd, J = 8.6 Hz); 13C NMR (100 MHz, CDCl3) d 55.26, 55.33,
55.45, 55.73, 61.08, 63.58, 67.33, 71.54, 79.62, 81.54, 85.73, 95.25, 96.12, 96.42,
113.88, 129.50, 159.43.
J = 1.7 Hz), 6.7 (d, 2H, J = .5 Hz), 7.30 (2H, d, J = = .5 Hz); 13C NMR (100 MHz,
CDCl3) d À5.40, À5.29, 1.40, 25.93, 55.29, 59.73, 71.40, 73.50, 73.57, 77.21, 1.52,
24
4.72, 94.21, 113.71, 120.9, 124.29, 129.31, 130.56, 143.54, 144.9, 159.04. b: [
a
]
[15] (a) C. Damez, J.-R. Labrosse, P. Lhoste, D. Sinou, Synthesis (2001) 1456–1458;
(b) G. Wang, D. Niu, Y.-L. Qiu, L.T. Phan, Z. Chen, A. Polemeropoulos, Y.S. Or,
D
+51° (c 0.665 ,CHCl3); vmax(neat)/cmÀ1 1613, 1514, 1463; 1H NMR (400 MHz,
CDCl3) d d 0.05 (s, 3H), 0.06 (s, 3H), 0.90 (s, 9H), 3.77 (t, 1H, J = 6.0 Hz), 3.0 (s, 3H),
4.23 (d, 1H, J = 11.6 Hz), 4.25 (s, 2H), 4.26 (d, 1H, J = 12.0 Hz), 4.33 (brs, 1H), 4.41
(d, 1H, J = 12.0 Hz), 4.53 (d,1H, J = 11.6 Hz), 4.55 (d, 1H, J = = 12.0 Hz), 4.66 (d,
1H, J = 12.0 Hz), 4.99 (brd, 1H, J = 6.0 Hz), 6.6 (dd, 2H, J = 6.0 Hz, 1.6 Hz), 7.2 (dd,
2H, J = 6.0 Hz, 1.6 Hz); 13C NMR (100 MHz, CDCl3) d À5.35, À5.33, 1.39, 25.91,
55.25, 60.02, 70.90, 73.3, 73.54, 76.92, 5.35, 7.01, 113.5, 120.62, 122., 129.39,
130.7, 144.96, 149.27, 15.90.
Org. Lett. 6 (2004) 4455–4458.
13
[16] 11: [
a
]
À13° (c 0.62, CHCl3); vmax(neat)/cmÀ1 1471, 1463; 1H NMR (400
D
MHz, CDCl3) d 0.01 (s, 3H), 0.06 (s, 3H), 0.065 (s, 3H), 0.073 (s, 3H), 0.08 (s, 3H),
0.13 (s, 3H), 0.849 (s, 9H), 0.854 (s, 9H), 0.91 (s, 9H), 3.45 (d, 1H, J = 9.7 Hz),
3.66 (d, 1H, J = 9.7 Hz), 3.82 (1H, d, J = 5.8 Hz), 4.15 (t, 1H, J = 12.8 Hz), 4.16 (d,
1H, J = 12.8 Hz), 4.29 (d, 1H, J = 15.3 Hz), 4.32 (d, 1H, J = 5.8 Hz), 4.39 (d, 1H,
J = 12.4 Hz), 4.44 (d, 1H, J = 12.4 Hz), 5.20 (s, 1H), 5.22 (s, 1H), 5.64 (t, 1H, J = 1.5
Hz); 13C NMR (100 MHz, CDCl3) d À5.55, À5.46, À5.43, À2.62, À2.58, 18.06,
18.24, 18.29, 25.74, 25.85, 25.92, 59.83, 65.85, 73.40, 73.49, 83.03, 84.23,
[12] In the NOESY spectrum of 8b, a strong cross peak was observed between the
cis protons (d3.77 and 4.33) of the cyclopentene ring.
95.06, 120.22, 128.90, 142.99, 145.54. 37: [a]
14 +19° (c 0.67, CHCl3); vmax(neat)/
D
cmÀ1 1653, 1617, 1507; 1H NMR (400 MHz, CDCl3) d 0.03 (s, 3H), 0.05 (s 3H),
0.07 (s, 3H), 0.08 (s, 3H), 0.12 (s, 3H), 0.15 (s, 3H), 0.88 (s, 9H), 0.89 (s, 9H), 0.90
(s, 9H), 3.63 (dd, 1H, J = 10.4 Hz, 7.5 Hz), 3.68 (dq, 1H, J = 10.4 Hz, 1.7 Hz), 3.83
(dd, 1H, J = .0 Hz, 1.8 Hz), 3.86 (dd, 1H, J = .0 Hz, 3.7 Hz), 4.00 (d, 1H, J = 10.7 Hz),
4.19 (d, 1H, J = 7.4 Hz), 4.28 (t, 1H, J = 12.5Hz), 4.37 (d, 1H, J = .6 Hz), 4.44 (dd,
1H, J = 13.4 Hz, 3.2 Hz), 5.05 (s, 1H), 5.07 (s, 1H); 13C NMR (100 MHz, CDCl3) d
À5.55, À5.50, À5.40, À5.29, À4.59, À4.32, 17., 18.22, 18.45, 25.81, 25.93, 26.68,
58.77, 61.83, 73., 73.13, 77.14, 77.69, 79.44, 4.16, 122.75, 147.69, 157.04.
[17] Use of TBAF for the deprotection afforded an inseparable mixture of products
and reagents.
´
[13] M. Urbala, N. Kuznik, S. Krompiec, J. Rzepac, Synlett (2004) 1203–1206.
[14] 28: [
a
]
26 +6.1° (c 0.89 , CHCl3); vmax(neat)/cmÀ1 1613, 1586, 1514; 1H NMR (400
D
MHz, CDCl3) d 3.35 (3H, s), 3.36 (3H, s), 3.43 (3H, s), 3.52 (1H, s), 3.61 (1H, d,
J = 11.9 Hz), 3.81 (3H, s), 3.90 (1H, s), 4.14 (1H, s), 4.18 (1H, s), 4.24 (1H, d,
J = 11.8 Hz), 4.53 (1H, d, J = 12.5 Hz), 4.56 (1H, d, J = 7.0 Hz), 4.64 (1H, d, J = 6.4
Hz), 4.65 (1H, d, J = 12.5 Hz), 4.67 (1H, d, J = 7.0 Hz), 4.78 (2H, s), 6.89, (2H, brd,
[18] S.V. Ley, D.K. Baeschlin, D.J. Dixon, A.C. Foster, S.J. Ince, H.W.M. Priepke, D.J.
Reynolds, Chem. Rev. 101 (2001) 53–80.