Diastereoselective Flexible Synthesis of Carbocyclic C-Nucleosides

Article abstract of DOI:10.1021/acs.joc.6b02594

Carbocyclic C-nucleosides are quite rare. Our route enables flexible preparation of three classes of these nucleoside analogs from common precursors-properly substituted cyclopentanones, which can be prepared racemic (in six steps) or optically pure (in ten steps) from inexpensive norbornadiene. The methodology allows flexible manipulation of individual positions around the cyclopentane ring, namely highly diastereoselective installation of carbo- and heterocyclic substituents at position 1′, orthogonal functionalization of position 5′, and efficient inversion of stereochemistry at position 2′. Newly prepared carbocyclic C-analog of tubercidine, profiled in MCF7 (breast cancer) and HFF1 (human foreskin fibroblasts) cell cultures, is less potent than tubercidine itself, but more selectively toxic toward the tumorigenic cells.

Full text of DOI:10.1021/acs.joc.6b02594

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Article
Diastereoselective Flexible Synthesis of Carbocyclic C-nucleosides
Lukáš Maier, Prashant Khirsariya, Ond#ej Hylse, Santosh Kumar Adla, Lenka #ernová, Michal
Poljak, So#a Kraj#ovi#ová, Erik Weis, Stanislav Drápela, Karel Sou#ek, and Kamil Paruch
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02594 • Publication Date (Web): 07 Mar 2017
Downloaded from http://pubs.acs.org on March 8, 2017
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†
Diastereoselective Flexible Synthesis of Carbocyclic Cꢀnucleosides
‡
,§#
‡,§#
‡,§
‡
Lukáš Maier,
Prashant Khirsariya,
Ondřej Hylse, Santosh Kumar Adla, Lenka
‡
‡
‡
‡
ꢀ
Černová, Michal Poljak, Soňa Krajčovičová, Erik Weis, Stanislav Drápela, Karel
§
,
ꢀ
‡,§*
Souček,
and Kamil Paruch
‡Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Kamenice 5/A8 625 00 Brno,
Czech Republic
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§International Center for Clinical Research, St. Anne's University Hospital Brno, Pekařská 53, 656 91
Brno, Czech Republic
ꢀ
Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic,
Královopolská 135, 612 00 Brno, Czech Republic
†
th
Dedicated to Prof. Jaroslav Jonas of Masaryk University on the occasion of his 80 birthday
#
*
these authors contributed equally to this work
eꢀmail: paruch@chemi.muni.cz
Abstract
Carbocyclic Cꢀnucleosides are quite rare. Our route enables flexible preparation of three classes
of these nucleoside analogs from common precursors – properly substituted cyclopentanones, which
can be prepared racemic (in six steps) or optically pure (in ten steps) from inexpensive
norbornadiene. The methodology allows flexible manipulation of individual positions around the
cyclopentane ring, namely highly diastereoselective installation of carboꢀ and heterocyclic
substituents at position 1´, orthogonal functionalization of position 5´, and efficient inversion of
stereochemistry at position 2´. Newly prepared carbocyclic Cꢀanalog of tubercidine, profiled in
MCF7 (breast cancer) and HFF1 (human foreskin fibroblasts) cell cultures, is less potent than
tubercidine itself, but more selectively toxic towards the tumorigenic cells.
Introduction
For several decades, nucleoside analogs have been of high interest to medicinal chemists.
Numerous biologically active nucleosides have been identified and more than 30 of them are now
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clinically used. Classical nucleosides (structure A in Figure 1) possess the hemiaminal motif; their
chemical and metabolic stability is therefore often limited and the resulting metabolites can be a
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a,2
source of undesired side effects.
Significant effort has thus been invested into identification of
more stable analogs while preserving the biological activity. Two main strategies involve
replacement of the CꢀN bond between sugar and base by the more stable CꢀC bond (Cꢀnucleosides,
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structure B in Figure 1) and replacement of the tetrahydrofuran motif by a carbocyclic ring (e. g.,
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cyclopentane), which leads to carbocyclic Nꢀnucleosides (structure C in Figure 1).
Structure D in Figure 1 combines the stabilizing elements of structures B and C (i. e. CꢀC
connection between the (heterocyclic) base and the carbocyclic scaffold) and represents carbocyclic
Cꢀnucleosides, which are only sporadically documented in the literature. It is conceivable that, at
least in some cases, those compounds might be more robust versions of nucleoside analogs B and
C. Furthemore, installation of certain substituents (e. g. X= OH) is meaningful only in this series, as
this would lead to chemically unstable ketals and aminals in the other analog series. Compounds
with general structure D where X = H are quite rare and we are aware of only one analog of type D
containing X = OH with riboseꢀlike substitution pattern – moderately active inhibitor of human
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glycosylase NEIL1 (compound 1a in Figure 1) which we reported recently. This scarcity could be
caused by the lack of sufficiently efficient and versatile synthetic routes to these compounds that
would allow flexible variation of the substituents on the cyclopentane core. To our best knowledge,
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the reported syntheses are focused on the production of single target carbocylic Cꢀnucleosides and
do not allow easy manipulation of the substituents, which would enable the SAR mapping and
facile identification of direct analogs of nucleosides AꢀC with attractive biological activity.
Figure 1. Generic structures of natural nucleosides (A) and their analogs B, C and D. For the sake
of consistency, the numbering of substituents in D is the same as in nucleosides A, B and C.
We envisioned that a properly protected cyclopentanone 2 could be a suitable flexible precursor for
three subꢀseries of target carbocyclic Cꢀnucleosides (Scheme 1). Specifically, stereoselective
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additions of organometallic reagents were to produce compounds in series 1 and transition metalꢀ
catalyzed couplings utilizing (heretofore unknown) enol triflate of 2 were to afford unsaturated
analogs 3. Stereoselective hydrogenation of 3 was envisioned to yield subꢀseries 4. Similarly to 1,
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unsaturated compounds 3 are also meaningful in the class of carbocyclic Cꢀnucleosides, but not for
A, B or C, where the presence of double bond would lead to unstable oxonium salts and/or
enamines. Precursor 2 with the desired stereochemistry was to be prepared from inexpensive
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norbornadiene.
Scheme 1. Retrosynthetic Analysis of Carbocyclic Cꢀnucleosides 1, 3 and 4
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R5´
5
R5´
R5´
R O
R1´
OH
R1´
R2´
R1´
R2´
O
R3´
R2´
3
OR2
R3´
R3´
R O
1
2
3
4
Results and Discussion
In order to prepare analogs represented by generic structure 1 (Scheme 1), we first focused on
improvement of preparation of the acetonideꢀprotected cyclopentanone 2a, which we had
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previously used to prepare compound 1a. We modified the route reported for a closely related
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analog of 2a. Briefly, diastereoselective cis dihydroxylation of norbornadiene followed by reaction
with 2,2ꢀdimethoxypropane provided acetonideꢀprotected diol 6a, subsequent ozonolytical cleavage
and reduction afforded intermediate 7a, which was then monosilylated and converted into iodide 9a
(
Scheme 2). Finally, elimination followed by oxidative cleavage yielded the desired cyclopentanone
2a.
a
Scheme 2. Preparation of Racemic Key Cyclopentanone Intermediates
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a
Reagents and conditions: i) a) K OsO .2H O, NMO acetone:H O 4:1, 40 °C then Na S O , (55%); b) 2,2ꢀ
2
4
2
2
2
2
5
dimethoxypropane, TsOH, acetone, rt, (95%, 6a); TIPSOTf, imidazole, DMAP, DMF, 65 °C, (88%, 6b);
dimethoxydiphenylmethane, TsOH, CH Cl , rt, (85%, 6c); 1,1´ꢀcarbonyldiimidazole, PhCH , 55 °C, (80%, 6d); diꢀtertꢀ
2
2
3
butylsilyl bis(trifluoromethanesulfonate), imidazole, CH
2
Cl
2
, 0 °C to rt, (78%, 6e); BnBr, NaH, TBAI, DMF, rt, (77%,
6
f); PMBCl, NaH, TBAI, DMF, rt, (93%, 6g); TBSCl, imidazole, CH
rt, (25%, 6i); ii) a) O , CH Cl /MeOH, ꢀ78 °C then NaBH , ꢀ78 °C to rt, (50ꢀ65%, 7a, 70ꢀ80%, 7b); iii) NaH, TBDPSCl,
THF, rt, (76%, 8a) then Ph P, I , imidazole, CH Cl , 0 °C to rt, (85%, 9a) PivCl, DIPEA, DMAP, CH Cl , rt (70%, 9b)
then Ph P, I , imidazole, CH Cl , 0 °C to rt, 87%, 9b; iv) a) DBU, PhCH , 110 °C, (75%, 10a); b) O , CH Cl /MeOH, ꢀ
8 °C, then thiourea, ꢀ78 °C to rt, (92%, 2a); v) PivCl, DIPEA, DMAP, CH Cl , rt (70%, 11b); NaH, BnBr, THF, rt,
65ꢀ75%, 11c); vi) Bu P, 3ꢀNO PhSeCN, THF, rt, then H O 0 °C to rt (80%, over 2 steps, 12b, 75% over 2 steps, 12c);
2 2 2 2
Cl , rt, (76%, 6h); TBDPSCl, imidazole, CH Cl ,
3
2
2
4
3
2
2
2
2
2
3
2
2
2
3
3
2
2
7
2
2
(
3
2
2
2,
3 2 2
vii) O , CH Cl , ꢀ78 °C then thiourea, rt, (90%, 2b, 86%, 2c).
Unfortunately, we soon realized that the utility of acetonideꢀprotected cyclopentanone 2a was quite
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limited. While it did undergo highly diastereoselective additions with a variety of nucleophiles (the
other diastereomers could not be detected by TLC or NMR), the final deprotection of acetonide in
many cases proved to be extremely difficult. For instance, we were not able to convert the adduct
which we prepared by reaction of cyclopentanone 2a with (2,4ꢀbis(benzyloxy)pyrimidinꢀ5ꢀ
yl)lithium into the desired target compound, i. e. uracilꢀcontaining analog of compound 1a. Under a
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variety of standard conditions (e. g., aqueous HCl in MeOH, CH
3
3
COOH, CF COOH,
camphorsulfonic acid, PPTS, I
2
in MeOH, FeCl
3
.6H
2
O, BCl
3
, Dowex® 50WX8 100ꢀ200 mesh,
9
In(OTf)
3
) at different temperatures as well as in the presence of additives (e.g. ethylene glycol or
propanꢀ1,3ꢀdithiol in order to promote transketalization), we observed either low conversion or
decomposition. This failure can be rationalized by facile carbocation formation at position 1´ under
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acidic conditions. Indeed, in some cases we were able to isolate the products of elimination (i. e.
with a double bond between the carbon atoms at positions 1´ and 6´) in low yields.
We thus needed to identify suitable alternative protecting group(s) for the hydroxyls at 2´ and 3´
positions, which i) would be compatible with the conditions of the synthetic sequence in Scheme 2,
ii) would be easily cleaved (preferably under nonꢀacidic conditions) and iii) ideally would be
orthogonal to the group protecting the hydroxyl at position 5´.
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First, we utilized intermediate 6c and prepared the analog of cyclopentanone 2a with diphenyl ketal
1
0
in place of acetonide, which we hoped to remove hydrogenolytically . Unfortunately, the
deprotection failed under different conditions (H HCOONH different metal catalysts, e. g., PtO
2,
2
,
4,
2
Pd/C, Pd(OH) /C), in different solvents at various temperatures with or without additives (AcOH,
TFA). We mainly observed only the starting material and no traces of the desired product. Then, we
tried a variety of several cyclic and nonꢀcyclic protecting groups; e. g., carbonate, bis(tꢀbutyl)silyl,
Bn, PMB, TBS, and TBDPS. Rather surprisingly, even very early intermediates, i. e. protected diols
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bꢀ6i (Scheme 2) were not known, except for recently reported but poorly described carbonate 6d.
TBDPSꢀprotected intermediate 6i was obtained in low yield and thus was not elaborated further.
Carbonate 6d and TBSꢀprotected intermediate 6h underwent undesired transformations during the
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ozonolytical cleavage followed by reduction with NaBH . The stability of the intermediates derived
from 6e bearing cyclic siliconꢀbased protecting group was limited and purification by flash
chromatography of the corresponding alkene and ketone provided only low yields of the
compounds. On the other hand, we were able to convert intermediates protected with Bn, PMB and
TIPS groups (compounds 6f, 6g and 6b, respectively) into the desired cyclopentanones efficiently
on multigram scale. However, the stability of some of the cyclopentanones proved to be limited. For
instance, the analogs of compound 2a with benzyls or PMB in place of acetonide underwent
elimination even during the purification on neutral alumina and epimerization at position 2´ in the
presence of triethylamine in dichloromethane.
Gratifyingly, we realized that the stability of TIPSꢀprotected cyclopentanones 2b and 2c was much
better – we could purify the compounds by chromatography and store them at 25 °C for months
without noticeable decomposition. However, we had to modify the route used for 2a as the
elimination of HI from iodide 9b was extremely sluggish. Fortunately, oneꢀpot selenation of
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intermediates 11b and 11c and subsequent oxidation followed by intramolecular elimination
proceeded smoothly and provided the desired exocyclic alkenes 12b and 12c, respectively, which
enabled preparation of cyclopentanones 2b and 2c on relatively large (> 5 g) scale (Scheme 2). It is
likely that while the steric hindrance caused by the TIPS group at 2´ꢀhydroxyl makes abstraction of
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proton at position 1´ in 9b difficult during the elimination, analogous shielding provided by the
TIPS group in cyclopentanones 2b and 2c positively contributes to their stability by protecting the
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otherwise easily enolizable position 2´.
The TIPSꢀprotected cyclopentanone 2c underwent highly diastereoselective addition with lithiated
bis(benzyloxy)pyrimidine (Scheme 3) and the resulting adduct was successfully converted into the
desired target compound 1b. By the same methodology, we resynthesized the tetraol 1a (in 8 steps
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from norbornadiene, 10% overal yield; previously in 13 steps with 4% overall yield) and prepared
additional target compounds 1cꢀe bearing alkyl and (hetero)aryl moieties via sequential
deprotection of the adducts 13cꢀ13e (Scheme 3).
Scheme 3. Synthesis of Racemic Pseudouridine Analog 1b and Related Compounds 1a and 1cꢀ
b
e
b
Reagents and conditions: i) PhLi, THF, 0°C (55%, 13a); 2,4ꢀbis(benzyloxy)ꢀ5ꢀbromopyrimidine, nꢀBuLi, THF, ꢀ78 °C
then 2c, ꢀ78 °C to rt, (45%, 13b); nꢀBuMgCl, THF, 0 °C to rt (38%, 13c); BnMgCl, THF, 0 °C to rt, (79%, 13d); 4ꢀ
bromothiazole, (CH ) MgCl·LiCl (90 %, 13e); ii) Pd/C, H , EtOH, 80 °C, (93%, 14b); iii) TBAF, THF, rt, (85%, 1b);
3
2
2
iv) a) TBAF, THF, rt, (96%, 14a, 82%, 14c, 90%, 14d); Li, naphthalene, THF, rt, then TBAF, THF, rt (53%, 1e over 2
steps) b) Pd(OH) /C, H (50 bar), THF, 70 °C, (92%, 1a, 93%, 1c, 92%, 1d)c); v) a) Pd/C, H , EtOH, 80 °C, (75%, 15);
b) NaH, MeI, THF, 0 °C to rt, (67%, 16); c) TBAF, THF, rt, (42%).
2
2
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In addition, orthogonal deprotection of the benzyl group allowed us to selectively modify the
hydroxyl at position 5´: debenzylation of compound 13a followed by methylation and cleavage of
the TIPS groups provided target compound 17 (Scheme 3).
Next, we addressed the subꢀseries 3 depicted in Scheme 1. Treatment of acetonideꢀprotected
cyclopentanone 2a with LDA at ꢀ78 °C followed by addition of Nꢀphenylꢀ
bis(trifluoromethansulfonimide) provided stable enol triflate 18a in good yield (Scheme 4). In
contrast, in order to get a clean and complete conversion of TIPSꢀprotected 2b into enol triflate 18b,
we had to optimize the conditions (KHMDS added to a mixture of 2b and Comins’ reagent). The
Suzuki coupling of both 18a and 18b with phenylboronic acid proceeded smoothly and afforded
compounds 19 and 21a, respectively, in good yields (Scheme 4). We also explored the possibility to
carry out the coupling in the reversed fashion. Along this line, we were able to convert enol triflate
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18a into the corresponding boronate 20 by Pdꢀcatalyzed borylation; but, in contrast, we were not
able to perform analogous transformation on enol triflate 18b under a variety of conditions.
Scheme 4. Formation of Enol Triflates and Their Conversion into Racemic Target
c
Compounds 3aꢀh
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c
Reagents and conditions: i) LDA, THF, ꢀ78 °C then PhNTf
2
, ꢀ78 °C to rt, (80%, 18a); KHMDS, Comins’ reagent,
THF, ꢀ78 °C to rt, (97%, 18b; ii) PhB(OH)
2
, Pd(dppf)Cl
2
, K
3
PO
4
, DME, H
, Pd(dppf)Cl
, DME, H O, 80 °C, (76%, 21b); 1ꢀ
DME, O, 80 °C, (87%, 21c); 4ꢀ
PO , DME, H O, 80 °C, (81%, 21d); 4ꢀ
PO , DME, H O, 80 °C, (99%, 21e); 3ꢀ
O, 80°C, (75%, 21f); boronic acid 23, Pd(dppf)Cl , K PO
DME, H O, 80 °C, (87%, 21g); v) TBAF, THF, rt, (89%, 22a, 90%, 22b, 91%, 22c, 86%, 22d, 74%, 22e, 83%, 22f,
2
O, 80 °C, (70ꢀ80%, 19); iii) pin
2 2
B ,
Pd(Ph
(92%, 21a); 2,4ꢀdifluorophenylboronic acid, Pd(PPh
methylpyrazoleꢀ4ꢀboronic acid pinacol ester, Pd(dppf)Cl
(methoxycarbonyl)furanꢀ2ꢀboronic acid pinacol ester, Pd(dppf)Cl
methoxycarbonyl)thienylꢀ2ꢀboronic acid pinacol ester, Pd(dppf)Cl
benzothienylboronic acid, Pd(dppf)Cl , K PO , DME, H
3
P)
2
Cl
2
, Ph
3
P, KBr, KOPh, PhCH3, 50 °C (70 %, 20); iv) PhB(OH)
, LiCl, Na CO
PO
, K
2
2
, K PO , DME, H O, 80 °C,
3
4
2
3
)
4
2
3
2
2
,
K
3
4
,
H
2
2
3
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0
1
2
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8
9
0
1
2
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5
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7
8
9
0
(
2
, K
3
4
2
2
3
4
2
2
3
4
,
2
8
8%, 22g); vi) MeONa, MeOH, 65 °C, (89%, 3a, 87%, 3b, 91%, 3c, 63%, 3d, 50%, 3e, 91%, 3f, 88%, 3g); vii) PPTS,
MeOH, H O, 55 °C, (75%, 3h).
2
Once again, acetonide cleavage turned out to be problematic. We obtained best results (38% yield)
when we used PPTS to deprotect intermediate 19 to afford 3a. More forcing conditions (aq. HCl,
CH
cleavage of the TBDPS group was also observed. On the other hand, selective TIPS deprotection on
1a was successful and yielded the desired intermediate 22a in high yield (89%). Final cleavage of
3 3
COOH, CF COOH) were incompatible with the presence of the double bond and (partial)
2
the pivaloate with DIBAL or sodium methoxide proceeded uneventfully and provided the target
compound 3a. Using different boronic acids/boronates, we prepared additional target compounds
3
bꢀf with diverse substituents at position 1´. In order to prepare the new unsaturated carbocyclic
analog of tubercidine 3h (with the isosteric base that allowed linkage by the CꢀC bond), we utilized
heretofore unknown boronic acid 23, whose preparation from commercially available 7ꢀ
bromopyrrolo[1,2ꢀf][1,2,4]triazinꢀ4ꢀamine as well as the coupling were in our hands more reliable
15
than with the (known) unprotected analog. The SEM groups were removed from intermediate 3g
under mild conditions (Scheme 5).
Finally, we focused on preparation of saturated analogs represented by generic structure 4 in
Scheme 1.
d
Scheme 5. Diastereoselective Hydrogenation of Cyclopentene Intermediates
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d
Reagents and conditions: i) Crabtree’s catalyst, H , CH Cl , rt, (94%, 24a, 92%, 24b, 95%, 24d, 99%, 24e, 86%, 24f);
2
2
2
2 2 2 2 2
Pd(OH) /C, H , THF, rt, (44%, 24c); Pd(OH) /C, H , THF, rt, then PPTS, MeOH, H O, 55 °C, (44 %, 24g); ii) MeONa,
MeOH, 65 °C, (89%, 4a, 90%, 4b, 53%, 4c, 74%, 4d, 61%, 4e, 88%, 4f, 84%, 4g); iii) 7 M NH3, MeOH, 100 °C, (22%,
5% brsm, 4h, 43%, 4i).
7
Expectedly, hydrogenation of the TIPSꢀprotected intermediate 21a proceeded exclusively from the
less hindered top face of the cyclopentene scaffold and yielded only the undesired diastereomer
with the opposite configuration at the newly created stereogenic center. On the other hand, we were
able to perform hydrogenation of diol 22a with practically perfect desired diastereoselectivity in the
1
6
presence of Crabtree’s catalyst to yield pivaloate 24a. Final deprotection afforded triol 4a in high
overall yield (66 % over 5 steps from 2b). The relative configurations of the triols 4a and 4c were
unambiguously confirmed by Xꢀray crystallography (see the Supporting Information). We then
investigated the scope of the highly diastereoselective hydrogenation in preparation of target
compounds possessing various substituents at position 1.
The hydrogenation of intermediates possessing aromatic and O and S heteroaromatic moieties (22b,
22d, 22e and 22f) also proceeded with excellent diastereoselectivity (we could not detect the
undesired diastereomer in the crude reaction mixture by NMR). On the other hand, the rate and
diastereoselectivity of the hydrogenation of the substrates with Nꢀcontaining substituents
(compounds 22c and 22g) were significantly worse, which is likely caused by preferential
coordination of the catalyst to the nitrogen atoms. We tried a variety of conditions, varying pressure
(
up to 150 bar), temperature, solvents (THF, CH
2 2 3
Cl , PhCH ) and the catalyst (Ir, Rh or Ru based
catalysts); however, we did not observe any significant improvement. For the Nꢀcontaining
substrates we eventually used Pd(OH) . Although these hydrogenations gave diastereomeric
2
mixtures with the ratio of ca. 2:1, in favor of the desired epimers, the diastereomers were in all
cases separable by chromatography. Final deprotection of hydrogenated intermediates 22bꢀ22g with
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sodium methoxide proceeded uneventfully and provided the corresponding target compounds 4bꢀ
4
g. Compounds 4d and 4e were converted into amides 4h and 4i ꢀ heretofore unknown carbocyclic
1
7
analogs of furanfurin and thiophenfurin. This route also provided another heretofore unknown
carbocyclic Cꢀanalog of tubercidine (compound 4g in Scheme 6), which we than prepared optically
active and briefly tested for cytotoxicity (see below).
0
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The fact, that the orthogonality of TIPS and pivaloate protecting groups can be utilized to further
selectively manipulate the position 5´, is briefly illustrated in Scheme 6. Cleavage of the pivaloate
in 21a followed by tosylation provided tosylate 25, which proved to be a versatile intermediate for
manipulation of position 5´ via nucleophilic substitution: it underwent substitutions with ammonia
or primary amines; amine 27 was used for subsequent reactions with different electrophiles, which
ultimately provided target compounds 28aꢀc (Scheme 6). In the future, we will use the methodology
to install more elaborated nitrogenꢀcontaining substituents that are associated with biological
18
activity in classical nucleoside analogs.
e
Scheme 6. Modifications of Position 5´
e
Reagents and conditions: i) DIBALꢀH, CH
2
Cl
2
, ꢀ78 °C to rt then TsCl, TEA, DMAP, CH
in IPA, aq. NH
iv) a) AcCl, DIPEA, CH Cl , rt, (73%); b) TBAF, THF, rt, (89%, 28a); v) a) phenylisocyanate, TEA, CH Cl , rt, (93%);
2
Cl
2
rt, (88%); ii) a) 2ꢀ
methoxyethylamine, DIPEA, DMF 100 °C, (69 %); b) TBAF, THF, rt, (90%); iii) NH
3
3
, 75 °C, (87 %);
2
2
2
2
b) TBAF, THF, rt, (67%, 28b); vi) a) N,Nꢀdimethylsulfamoyl chloride, TEA, DMF, rt, (86%); b) TBAF, THF, rt, (89%,
8c).
2
We also attempted to manipulate position 2´ utilizing compound 4a, which we were able to produce
in gram quantities by the routes depicted in Schemes 4 and 5 above. Standard diꢀprotection of 5´ꢀ
19
and 3´ꢀ hydroxyls by TIPDS provided cyclic siloxane 29 (Scheme 7). Alkylation of the remaining
free hydroxyl at position 2´ followed by final deprotection yielded target compound 30, whose
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structural integrity was confirmed by Xꢀray crystallography (see the Supporting Information). Our
20
attempts to invert the stereochemistry at position 2´ by Mitsunobu reaction failed and we
recovered only unreacted 29. However, we were able to perform the inversion via diastereoselective
21
reduction of ketone 31 (Scheme 7). While with typically used NaBH
with no diastereoselectivity, the results were more satisfactory with sterically demanding agents: for
LiAlH(OꢀtBu) , the ratio of 32 to its epimer was 90:10 and for LiAlH[OꢀC(CH CH the
4
the reduction proceeded
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3
2
3 3 3
) ]
formation of 32 was exclusive (for the crystal structure of 32, see the Supporting Information).
Subsequent removal of the protecting group produced triol 33 in high overall yield.
f
Scheme 7. Manipulation of Position 2´
f
Reagents and conditions: i) TIPDSCl, Pyr, 0 °C, (88%); ii) a) nꢀBuLi, MeOTf, ꢀ78 °C, (49%); b) TBAF, THF, rt, 64 %;
CN, 80 °C, (81%); iv) LiAlH[OꢀC(CH CH , THF, 0 °C, (92%); v) TBAF, THF, rt, (73%).
iii) IBX, CH
3
2
3 3 3
) ]
Ultimately, we attempted to develop a route that would allow enantioselective synthesis of all three
22
subꢀseries 1, 3, and 4. The utility of known chiral precursors proved to be limited: monoacetate 34
was not optimal due to the presence of difficult to remove acetonide, while the synthesis of
23
24
compound 35 (especially the alkylation of cyclopentadienide ) was in our hands extremely
25
irreproducible. Similarly, attempted desymmetrization of diol 7b by enantioselective silylation or
26
by pivaloylation with chiral variant of DMAP also failed. Fortunately, upon extensive
experimentation we found a suitable chiral auxiliary that allowed preparation of nonꢀracemic 11c.
Racemic 11c was first converted into an inseparable mixture of diastereomeric camphanates (ꢀ)ꢀ36a
and (+)ꢀ36b. Subsequent hydrogenolysis afforded compounds (ꢀ)ꢀ37a and (+)ꢀ37b, which we were
2
7
able to separate by standard chromatography and reꢀbenzylate without the loss of stereochemical
integrity to obtain individual (ꢀ)ꢀ36a and (+)ꢀ36b, respectively (Scheme 8). The absolute
configuration of the crystalline camphanate (ꢀ)ꢀ37a was confirmed by Xꢀray crystallography (see
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the Supporting Information). Interestingly, attempts to prepare the camphanates (ꢀ)ꢀ37a and (+)ꢀ37b
directly from diol 7b failed and provided mixtures containing substantial amounts of poorly
separable dicamphanate. Subsequent removal of camphanate from (ꢀ)ꢀ36a provided (ꢀ)ꢀ11c, which
was converted into optically pure (ꢀ)ꢀ2c and then into (ꢀ)ꢀ2b. Optically active cyclopentanone (ꢀ)ꢀ2b
was then elaborated into two compounds with defined absolute configuration: (+)ꢀ3b and
tubercidine analog (ꢀ)ꢀ4g (Scheme 8), whose enantiomeric purity was confirmed by HPLC on chiral
stationary phase. Compared to tubercidine, (ꢀ)ꢀ4g was found to be less active against tumorigenic
MCF7 cells (IC50 values 96 nM for tubercidine and 13.3 ꢀM for (ꢀ)ꢀ4g), but the compound was
comparatively less toxic to human foreskin fibroblast HFF1 cells (21 nM for tubercidine and 10.4
ꢀM for (ꢀ)ꢀ4g). In contrast, the opposite enantiomer (+)ꢀ4g, racemic 1´ꢀepimer of 4g and the
unsaturated analog 3h were inactive (description of the assays is given in the Supporting
Information.
0
1
2
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4
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1
2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
g
Scheme 8. Enantioselective Synthesis of Tubercidine Analog (ꢀ)ꢀ4g
g
Reagents and conditions: i) a) (1S)ꢀ(ꢀ)ꢀcamphanic chloride, DIPEA, DMAP, CH
/C, H , THF, 65 °C, (67%, (ꢀ)ꢀ37a and 76%, (+)ꢀ37b); iii) a) TriBOT,
TfOH, 5Å MS, 1,4ꢀdioxane, rt, (93%, (ꢀ)ꢀ36a and 80%, (+)ꢀ36b), b) MeONa, MeOH, rt, (90%, (ꢀ)ꢀ11c and 90%, (+)ꢀ
1c); iv) Pd(OH) /C, H , THF, 65 °C then PivCl, DMAP, DIPEA, CH Cl , rt (80%, (ꢀ)ꢀ2c over two steps).
2 2
Cl , rt (97%, 1:1 diastereomeric
mixture of (ꢀ)ꢀ36a and (+)ꢀ36b); ii) Pd(OH)
2
2
1
2
2
2
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In summary, our methodology enables flexible and diastereoselective synthesis of new carbocyclic
Cꢀnucleosides with a variety of substituents at position 1´ and selective manipulations of positions
2
´ and 5´ of the cyclopentane core. Identification of suitable versatile intermediates (i. e. TIPSꢀ
protected cyclopentanones 2b and 2c) required extensive optimization of the protecting groups. We
have prepared a series of new carbocyclic Cꢀnucleosides, which included new carbocyclic analogs
of furanfurin and thiophenfurin (compounds 4h and 4i, respectively), as well as new tubercidine
analog (ꢀ)ꢀ4g. Compared to tubercidine, analog (ꢀ)ꢀ4g was found to be less potent, but more
selectively toxic to MCF7 cells (breast cancer) than to HFF1 (human foreskin fibroblasts). A
detailed account of the compounds‘ biological activity will be reported elsewhere in the near future.
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Experimental Section
General
All reagents were of reagent grade and were used without further purification. The used solvents
were anhydrous, stored over 4Å molecular sieves as received from commercial suppliers. All
reactions were carried out in ovenꢀdried glasware and under nitrogen atmosphere unless stated
otherwise. Flash chromatography was carried on silica gel (230ꢀ400 mesh). TLC plates were
visualized under UV and/or with phosphomolybdic acid, KMnO
4 2 4
, CAM or H SO in MeOH.
NMR spectra were recorded on a 500 MHz spectrometer (with operating frequencies, 500.13 MHz
1
13
19
11
for H, 125.77 MHz for C, 470.53 MHz for F and 160.46 MHz for B) and a 300 MHz
1
13
1
spectrometer (with operating frequencies 300.13 MHz for H and 75.48 MHz for C). The H, and
1
3
C NMR chemical shifts (δ in ppm) were referenced to the residual signals of solvents: CDCl3
1
13
1
13
1
[7.26 ( H) and 77.23 ( C)], CD
Cl
2 2
3
[5.32 ( H) and 53.50 ( C)], CD OD [3.35 ( H) and 49.30
1
3
1
13
1
13
19
(
C)], acetoneꢀd
6
[2.09 ( H) and 29.90, 206.7 ( C)], and DMSOꢀd
6
[2.50 ( H) and 39.51 ( C)]. F
NMR chemical shifts (δ in ppm) were referenced to the signal of trifluorotoluene (ꢀ63.72).
Structural assignment of resonances have been performed with the help of 2D NMR gradients
1
13
1
13
1
15
experiments (COSY, multiplicity edited Hꢀ C HSQC, Hꢀ C HMBC, NOESY, Hꢀ N HSQC and
1
15
Hꢀ N HMBC).
The diffraction data were collected with a partial χ geometry diffractometer equipped with a CCD
detector. Cu Kα radiation (λ= 1.54184 Å, rotating anode source, multilayer optic) was used. Data
reduction and final cell refinement were carried out using the CrysAlisPro software (CrysAlisPRO,
Agilent Technologies UK Ltd).
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6
High resolution mass spectra were measured on TOF LCꢀMS with dual electrospray/chemical
ionization mode or MALDIꢀTOF MS with mass accuracy greater than 2 ppm, applied mass range
from 25 to 20,000 Da.
–1
IR spectra (4000ꢀ400 cm ) were collected on anATR spectrometer. Solid samples were measured
neat or in KBr pellets and oily samples as films.
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Melting points were measured in capillary and are uncorrected. Optical rotations were measured in
cuvettes with the path length of 10 cm.
CD spectra were recorded at 25 °C. Data were collected in the range from 195 nm to 280 nm in a 1
cm quartz cuvette.
(1R*,2R*,3S*,4S*)ꢀBicyclo[2.2.1]heptꢀ5ꢀeneꢀ2,3ꢀdiol (5).
NMO (19.06 g, 162.8 mmol) and K
2 2
OsO4.2H O (294 mg, 0.81 mmol) were added to a solution of
norbornadiene (15.0 g, 162.8 mmol) in acetone and H O (200 + 50 mL) and the reaction mixture
2
2 2 5
was stirred at 40 °C for 14 h. After cooling to 25 °C, Na S O (1.0 g) was added and the reaction
mixture was stirred at 25 °C for another 30 min. All volatiles were removed under reduced pressure
and the black residue was purified by flash chromatography (hexane/EtOAc = 2:1) to afford 5 as a
1
white crystalline solid (11.29 g, 55%). H NMR (500 MHz, CDCl
3
): δ = 6.04 (m, 2H), 3.71 (m,
13
2
H), 2.95 (m, 2H), 2.70 m (2H), 1.89 (dm, J = 9.2 Hz, 1H), 1.63 (dm, J = 9.2 Hz, 1H) ppm.
C
NMR (126 MHz, CDCl ): δ = 136.6, 69.2, 48.2, 42.4 ppm. The spectral data were consistent with
3
7
the literature.
(exo, exo)ꢀ5,6ꢀDimethylmethylendioxyꢀbicyclo[2.2.1]heptꢀ2ꢀene (6a).
2,2ꢀdimethoxypropane (26.0 mL, 196.6 mmol) and TsOH (5 mg) were added to a solution of 5 (6.2
g, 49.2 mmol) in acetone (75 mL). The reaction mixture was stirred at 25 °C for 20 min., the
solvent was evaporated and the residue was purified on a short pad of silica gel (hexane/EtOAc =
1
20:1) to afford 6a as a colorless oil which solidified upon standing at ꢀ20 °C (7.86 g, 95 %). H
NMR (500 MHz, CDCl
3
): δ = 6.05 (m, 2H), 4.18 (d, J = 1.6 Hz, 2H), 2.76 (m, 2H), 1.97 (m, 1H),
13
1
.67 (m, 1H), 1.47 (s, 3H), 1.32 (s, 3H) ppm. C NMR (126 MHz, CDCl
3
): δ = 136.9, 113.8, 80.6,
7
45.4, 43.0, 26.3, 24.6 ppm. The spectral data were consistent with the literature.
(
1R*,4S*,5S*,6R*)ꢀ5,6ꢀbis(Triisopropylsilyloxy)bicyclo[2.2.1]heptꢀ2ꢀene (6b).
Imidazole (14.88 g, 218.73 mmol) and DMAP (870 mg, 7.14 mmol) were added to a solution of 5
6.0 g, 47.55 mmol) in anhydrous DMF (60 mL), followed by dropwise addition of TIPSOTf (29.4
(
mL, 109.38 mmol) at 25 °C. The reaction mixture was stirred at 65 °C for 5 days. The reaction
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mixture was cooled to 25 °C, quenched with H O (60 mL), and extracted with Et O (3 × 70 mL).
2
2
2 4
The organic extracts were dried over Na SO , filtered, and the solvent was evaporated. The residual
yellow oil was purified by flash chromatography (hexane) to afford 6b as a colorless oil (20.1 g, 88
1
%
). H NMR (500 MHz, CDCl
3
): δ = 6.00 (m, 2H), 3.84 (d, J = 1.7 Hz, 2H), 2.62 (m, 2H), 2.20
13
(
dm, J = 8.4 Hz, 1H), 1.60 (dm, J = 8.4 Hz, 1H), 1.12ꢀ1.07 (m, 42H) ppm. C NMR (126 MHz,
10
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12
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14
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16
17
18
19
20
21
22
23
24
25
26
27
28
29
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32
33
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36
37
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): δ = 136.9, 71.4, 49.8, 43.5, 18.5, 18.4, 13.1 ppm. IR (ν˜max) = 2927 (w), 2800 (w), 1403
3
CDCl
m), 1049 (s), 1111 (s), 702 (m), 646 (m) cm . HRMS (APCIꢀTOF) m/z: [M+H] Calcd for
C H O Si 439.3422; Found 439.3427.
–1
+
(
25
51
2
2
(3aR*,4R*,7S*,7aS*)ꢀ2,2ꢀDiphenylꢀ3a,4,7,7aꢀtetrahydroꢀ4,7ꢀ
methanobenzo[d][1,3]dioxole (6c).
Dimethoxydiphenylmethane (2.08 g, 9.15 mmol) was added to a solution of 5 (800 mg, 6.34 mmol)
in CH Cl (8 mL), followed by addition of TsOH (1 mg), and the reaction mixture was stirred at 25
2
2
°
C for 18 h. The solvent was evaporated and the residue was purified by flash chromatography
(
hexane/EtOAc = 20:1) to afford 6c (1.60 g) contaminated with residual benzophenone and
benzophenone dimethyl ketal as a white crystalline solid. An analytical sample could be obtained
by repeated flash chromatography with slow gradient elution (hexane to hexane/EtOAc = 20:1) as a
1
white crystalline solid. m.p. = 123ꢀ127 °C. H NMR (500 MHz, CDCl
3
): δ = 7.58ꢀ7.56 (m, 2H),
7
2
.51ꢀ7.49 (m, 2H), 7.37ꢀ7.34 (m, 2H), 7.31ꢀ7.26 (m, 4H), 6.05 (m, 2H), 4.13 (d, J = 1.6 Hz, 2H),
13
3
.97 (m, 2H), 2.21 (dm, J = 8.9 Hz, 1H), 1.77 (dm, J = 8.9 Hz, 1H). C NMR (126 MHz, CDCl ):
δ = 143.0, 141.7, 137.1, 128.5, 128.4, 128.3, 128.1, 126.7, 126.2, 114.4, 81.3, 45.4, 43.8 ppm. IR
(
ν˜max) = 2979 (w), 2946 (w), 2924 (w), 1489 (m), 1270 (m), 1203 (m), 1019 (s), 747 (s), 703 (s),
–1
+
6
18 2
94 (s) cm . HRMS (ESIꢀTOF) m/z: [M] Calcd for C20H O 290.1307; Found: 290.1311.
(3aR*,4R*,7S*,7aS*)ꢀ3a,4,7,7aꢀTetrahydroꢀ4,7ꢀmethanobenzo[d][1,3]dioxolꢀ2ꢀone
6d).
(
1,1´ꢀcarbonyldiimidazole (250 mg, 1.98 mmol) was added to a solution of 5 (200 mg, 1.58 mmol)
in anhydrous toluene (6 mL) and the reaction mixture was stirred at 55 °C for 16 h. The reaction
mixture was then cooled to 25 °C and the solvent was evaporated. The residue was purified by flash
chromatography (hexane/EtOAc = 5:1) to afford 6d as a white crystalline solid (191 mg, 80%). m.p.
1
=
86ꢀ88 °C. H NMR (500 MHz, CDCl
3
): δ = 6.12 (m, 2H), 4.56 (d, J = 1.4 Hz, 2H), 3.14 (m, 2H),
13
1
.90ꢀ1.82 (m, 2H) ppm. C NMR (126 MHz, CDCl ): δ = 156.5, 136.2, 78.9, 45.8, 41.2 ppm. IR
3
–1
(
ν˜max) = 3011 (w), 1777 (s), 1367 (m), 1160 (s), 1055 (s), 1014 (s), 742 (s), 697 (s) cm . HRMS
+
(
ESIꢀTOF) m/z: [M+Na] Calcd for C
8
H
8
O
3
Na 175.0371; Found: 175.0370.
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(
3aR*,4R*,7S*,7aS*)ꢀ2,2ꢀdiꢀtertꢀButylꢀ3a,4,7,7aꢀtetrahydroꢀ4,7
methanobenzo[d][1,3,2]dioxasilole (6e).
Imidazole (1.78 g, 26.16 mmol) was added to a cooled solution (0 °C, ice bath) of 5 (1.0 g, 7.93
mmol) in anhydrous DMF (10 mL) followed by dropwise addition of diꢀtertꢀbutylsilyl
bis(trifluoromethanesulfonate) (2.84 mL, 8.72 mmol). The reaction mixture was stirred while
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
allowed to warm to 25 °C for 14 h. H
2
O (60 mL) was added slowly and the mixture was extracted
SO , filtered, and the solvent was
with Et O (3 × 50 mL). The organic extracts were dried over Na
2
2
4
evaporated. The residue was purified by flash chromatography (hexane/EtOAc = 20:1) to afford 6e
1
as a colorless oil (1.42 g, 78%). H NMR (500 MHz, CDCl ): δ = 6.06 (m, 2H), 4.15 (d, J = 1.5 Hz,
3
2
H), 2.79 (m, 2H), 2.20 (dm, J = 9.2 Hz, 1H), 1.64 (dm, J = 9.2 Hz, 1H), 1.12 (s, 9H), 1.05 (s, 9H)
13
ppm. C NMR (126 MHz, CDCl
3
): δ = 137.5, 78.5, 47.2, 42.5, 28.3, 27.7, 22.9, 20.6 ppm. IR
(
(
ν˜max) = 2933 (w), 2858 (w), 1475 (m), 1171 (w), 1036 (s), 1021 (s), 853 (s), 823 (s), 704 (m), 648
–1
+
27 2
m) cm . HRMS (ESIꢀTOF) m/z: [M+H] Calcd for C15H O Si 267.1780; Found: 267.1779.
(1R*,4S*,5S*,6R*)ꢀ5,6ꢀbis(Benzyloxy)bicyclo[2.2.1]heptꢀ2ꢀene (6f).
A solution of 5 (4.88 g, 38.70 mmol) in DMF (40 mL) was added dropwise to a suspension of NaH
(60% dispersion in mineral oil, 4.64 g, 116.11 mmol) in DMF (20 mL). The reaction mixture was
stirred at 25 °C for 20 min, benzyl bromide (11.05 mL, 92.9 mmol) was slowly added, followed by
a solution of tetraꢀnꢀbutyl ammonium iodide (1.43 g, 3.87 mmol) in DMF (10 mL). The reaction
mixture was stirred at 25 °C for additional 14 h and then quenched by dropwise addition of H
mL). H O (100 mL) was added and the mixture was extracted with Et O (4 × 100 mL). The
combined organic extracts were dried over Na SO , filtered, and the solvent was evaporated. The
2
O (5
2
2
2
4
resulting yellow oil was purified by flash chromatography (hexane/EtOAc = 20:1) to afford 6f as a
1
white crystalline solid (9.08 g, 77%), m.p. = 65.9ꢀ66.1 °C. H NMR (500 MHz, CDCl
3
): δ = 7.37ꢀ
7
.26 (m, 10H), 6.01 (m, 2H), 4.69ꢀ4.63 (m, 4H), 3.53 (m, 2H), 2.85 (m, 2H), 2.20 (m, 1H), 1.67 (m,
13
1H) ppm. C NMR (126 MHz, CDCl
3
): δ = 139.2, 137.0, 128.5, 128.0, 127.6, 77.2, 72.5, 45.9, 44.2
–
ppm. IR (ν˜max) = 3063 (w), 3029 (w), 1496 (w), 1453 (m), 1343 (w), 1114 (m), 733 (s), 696 (s) cm
1
+
.
HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C21
22 2
H O Na 329.1517; Found: 329.1524.
(
1R*,4S*,5S*,6R*)ꢀ5,6ꢀbis(4ꢀMethoxybenzyloxy)bicyclo[2.2.1]heptꢀ2ꢀene (6g).
A solution of 5 (1.18 g. 9.37 mmol) in DMF (20 mL), was added dropwise to a suspension of NaH
(60% dispersion in mineral oil, 1.12 g, 28.11 mmol) in DMF (20 mL). The reaction mixture was
stirred at 25 °C for 20 min, 4ꢀmethoxybenzyl chloride (2.8 mL, 20.62 mmol) was slowly added,
followed by a solution of tetraꢀnꢀbutyl ammonium iodide (346 mg, 0.94 mmol) in DMF (10 mL).
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The reaction mixture was stirred at 25 °C for additional 14 h and then quenched by dropwise
addition of H
2
O (5 mL). H
2
O (100 mL) was added and the mixture was extracted with Et
2
O (4 ×
1
00 mL). The combined organic extracts were dried over Na
2
SO , filtered, and the solvent was
4
evaporated. The resulting yellow oil was purified by flash chromatography (hexane/EtOAc = 15:1)
1
to afford 6g as a white wax (3.2 g, 93%). H NMR (500 MHz, CDCl
3
): δ = 7.27 (d, J = 8.6 Hz, 4H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
.85 (d, J = 8.6 Hz, 4H), 5.99 (m, 2H), 4.58 (d, J = 11.7 Hz, 2H), 4.53 (d, J = 11.7 Hz, 2H), 3.80 (s,
13
6
H), 3.48 (d, J = 1.8 Hz, 2H), 2.80 (m, 2H), 2.16ꢀ2.14 (m, 1H), 1.64ꢀ1.62 (m, 1H) ppm. C NMR
): δ = 159.3, 137.0, 131.4, 129.6, 113.9, 77.0, 76.8, 72.1, 55.5, 45.9, 44.2 ppm. IR
(126 MHz, CDCl
3
–
1
(
ν˜max) = 2991 (w), 2952 (w), 1402 (m), 1257 (m), 1109 (s), 741 (s), 694, 650 (s) cm . HRMS (ESIꢀ
+
TOF) m/z: [M+Na] Calcd for C23
H
26
O
4
Na 389.1723; Found: 389.1727.
(
1R*,4S*,5S*,6R*)ꢀ5,6ꢀbis(tertꢀButyldimethylsilyloxy)bicyclo[2.2.1]heptꢀ2ꢀene (6h).
Imidazole (558 mg, 8.21 mmol) and TBSCl (544 mg, 3.61 mmol) were added to a solution of 5 (207
mg, 1.64 mmol) in CH Cl (15 mL) and the reaction mixture was stirred at 25 °C for 14 h. The
2
2
solvent was evaporated and the residue was purified by flash chromatography (hexane/EtOAc = 10:1)
1
to afford 6h as a white semiꢀsolid (440 mg, 76%). H NMR (500 MHz, CDCl
3
): δ = 6.00 (m, 2H),
3
.64 (m, 2H), 2.53 (m, 2H), 2.14 (dm, J = 8.2 Hz, 1H), 1.56 (dm, J = 8.2 Hz, 1H) 0.91 (s, 18H), 0.07
13
(
s, 6H), 0.05 (s, 6H) ppm. C NMR (126 MHz, CDCl
ꢀ4.7 ppm. IR (ν˜max) = 1481 (w), 1103 (m), 759 (s), 693 (s) cm . HRMS (ESIꢀTOF) m/z: [M+H]
Calcd for C19 Si 355.2483; Found: 355.2486.
3
): δ = 137.0, 71.0, 49.7, 43.4, 26.3, 18.6, ꢀ4.0,
–
1
+
H
39
O
2
2
(
1R*,4S*,5S*,6R*)ꢀ5,6ꢀbis(tertꢀButyldiphenylsilyloxy)bicyclo[2.2.1]heptꢀ2ꢀene (6i).
TBDPSCl (1 mL, 3.96 mmol) and imidazole (433 mg, 6.36 mmol) were added to a solution of 5
200 mg, 1.59 mmol) in CH Cl (10 mL) and the reaction mixture was stirred at 25 °C for 14 h. The
(
2
2
solvent was evaporated and the yellow residue was purified by flash chromatography
(hexane/EtOAc = 20:1) to afford 6i as a white crystalline solid (240 mg, 25 %), along with the
1
monoꢀsilylated sideꢀproduct (417 mg, 43%). m.p. = 133ꢀ136 °C. H NMR (500 MHz, CDCl
3
): δ =
7
.76ꢀ7.72 (m, 8H), 7.41ꢀ7.31 (m, 12H), 5.53 (m, 2H), 3.87 (d, J = 1.5 Hz, 2H), 2.32 (dm, J = 8.6
13
Hz, 1H), 2.24 (m, 2H), 1.38 (dm, J = 8.6 Hz, 1H), 1.10 (s, 18H) ppm. C NMR (126 MHz, CDCl ):
3
δ = 136.6, 136.3, 136.2, 135.3, 134.7, 129.7, 129.6, 127.7, 127.7, 72.3, 48.9, 43.0, 27.4, 19.6 ppm.
–1
IR (ν˜max) = 1472 (w), 1102 (m), 1086 (m), 697 (s), 499 (s), 481 (s) cm . HRMS (ESIꢀTOF) m/z:
+
[M+Na] Calcd for C H O Si Na 625.2929; Found: 625.2928.
39
46
2
2
General Procedure A for ozonolysis of protected norbornenediols
A mixture of O /O (O flow = 5L/min, ozonolysis rate ~ 12 mmol/5 min) was bubbled into a cooled
–78 °C) solution of the starting material in CH Cl :MeOH (1:3, ~ 15 mmol of the starting
3
2
2
(
2
2
material/10 mL). After completion of ozonolysis (indicated by persistent blue color of the reaction
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mixture), excess of O was removed by bubbling N into the reaction mixture. Thiourea (6 eq.) was
3
2
added in five portions and the reaction mixture was stirred at –78 °C for 1 h. NaBH
added in one portion and the reaction mixture was stirred at –78 °C for 1 h. Another portion of
NaBH (1.025 eq.) was added and the reaction mixture was stirred for additional 3ꢀ14 h while
4
(0.25 eq.) was
4
allowed to warm to 25 °C. The reaction mixture was concentrated under reduced pressure and the
residual viscous oil was partitioned between dichloromethane (100 mL/15 mmol) and brine (50
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mL). The aqueous phase was reextracted with CH
Na SO , filtered, and the solvent was evaporated. The residue was purified by flash chromatography
to afford the corresponding diol.
2 2
Cl . The organic extracts were dried over
2
4
((3aR*,4R*,6S*,6aS*)ꢀ2,2ꢀDimethyltetrahydroꢀ3aHꢀcyclopenta[d][1,3]dioxolꢀ4,6ꢀ
diyl)dimethanol (7a).
The compound was prepared by General Procedure A using 6.2 g (37.32 mmol) of 6a; flash
1
chromatography (CH
2
Cl
2
/MeOH = 20:1 to 10:1) afforded 7a as a colorless oil (5.11 g, 67%). H
NMR (500 MHz, CDCl ): δ = 4.41 (m, 2H), 3.69 (m, 4H), 2.28 (m, 2H), 2.08 (m, 1H), 1.68 (br s,
3
13
2
3
H), 1.51 (s, 3H), 1.32 (s, 3H), 1.26 (m, 1H) ppm. C NMR (126 MHz, CDCl ): δ = 112.7, 83.7,
+
6
4.5, 47.6, 30.7, 27.8, 25.3 ppm. HRMS (APCIꢀTOF) m/z: [M+H] Calcd for C H O 203.1278;
1
0
19
4
7
Found 203.1276. The spectral data were consistent with the literature.
(1R*,3S*,4S*,5R*)ꢀ4,5ꢀbis(Triisopropylsilyloxy)cyclopentaneꢀ1,3ꢀdiyl)dimethanol (7b).
The compound was prepared by General Procedure A using 10.09 g (22.80 mmol) of 6b; flash
chromatography (CH
2
2
Cl /MeOH = 20:1) afforded 7b as a white solid (10.03 g, 80%), m.p. = 107 –
1
1
4
09 °C. H NMR (500 MHz, CDCl
3
): δ = 4.05 (dd, J = 2.7, 7.4 Hz, 2H), 3.66 (dd, J = 10.6, 5.9 Hz,
H), 3.60 (dd, J = 10.6, 5.9 Hz), 2.28 (m, 2H), 2.07 (m, 1H), 1.69 (br s, ꢀOH, 2H), 1.16 (m, 1H),
1
3
1.09 (m, 42H) ppm. C NMR (126 MHz, CDCl
3
): δ = 77.7, 65.1, 45.0, 25.8, 18.5 ppm. IR (ν˜max) =
–
1
3
301 (br), 2890 (m), 2859 (m), 1432 (m), 1039 (s), 825(m), 631 (m) cm . HRMS (ESIꢀTOF) m/z:
+
[
54 4 2
M+Na] Calcd for C25H O Si Na 497.3453; Found 497.3452.
((3aS*,4S*,6R*,6aR*)ꢀ6ꢀ((tertꢀButyldiphenylsilyloxy)methyl)ꢀ2,2ꢀdimethyltetrahydroꢀ3aHꢀ
cyclopenta[d][1,3]dioxolꢀ4ꢀyl)methanol (8a).
A solution of 7a in 15 mL of anhydrous THF (1.95 g, 9.64 mmol) was added to a suspension of
NaH (464 mg, 11.60 mmol, 60 % dispersion in mineral oil) in THF (2 mL). The reaction mixture
was stirred at 25 °C for 20 min, then TBDPSCl (2.63 mL, 10.12 mmol) was added and the reaction
mixture was stirred for 14 h. The reaction mixture was quenched by addition of silica gel (500 mg)
and adsorbed on silica gel (10 g). Flash chromatography (hexane/EtOAc = 3:1) afforded 8a as a
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colorless oil (3.24 g, 76 %). H NMR (500 MHz, CDCl ): δ = 7.66ꢀ7.64 (m, 4H), 7.44ꢀ7.36 (m, 6H),
3
4
.41ꢀ4.38 (m, 1H), 4.33ꢀ4.31 (m, 1H), 3.75ꢀ3.60 (m, 4H), 2.31ꢀ2.22 (m, 4H), 2.08ꢀ2.03 (m, 1H),
13
1
3
.49 (s, 3H), 1.39 (dd, 10.9 Hz, 1H), 1.29 (s, 3H), 1.06 (s, 9H) ppm. C NMR (126 MHz, CDCl ):
δ = 135.86, 135.85, 133.9, 129.9, 127.9, 112.6, 83.9, 82.9, 65.3, 65.1, 48.1, 47.4, 30.8, 27.9, 27.1,
2
5.4, 19.6 ppm. IR (ν˜max) = 3456 (br), 2930 (w), 2857 (w), 1471 (w), 1427 (w), 1110 (s), 1060 (s),
–
1
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
36 4
01 (s), 504 (s) cm . HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C26H O SiNa 463.2257; Found
463.2275.
(
1R*, 2R*, 3S*, 4S*)ꢀ4ꢀ(Hydroxymethyl)ꢀ2, 3
bis((triisopropylsilyl)oxy)cyclopentyl)methyl pivalate (11b).
DMAP (153 mg, 1.26 mmol) and DIPEA (2.13 mL, 25.26 mmol) were added into a solution of 7b
6.00 g, 12.63 mmol) in CH Cl (30 mL). Pivaloyl chloride (1.55 mL, 12.63 mmol) was added
dropwise and the reaction mixture was stirred at 25 °C for 14 h. The reaction mixture was quenched
with water (50 mL) and extracted with CH Cl (3 × 50 mL) The organic phase was dried over
MgSO , filtered and concentrated under reduced pressure to yield the crude product, which was
purified by flash chromatography (hexane/EtOAc = 10:1) to afford 11b as white crystals (3.87 g, 71
), m.p. = 63ꢀ65 °C. NMR (500 MHz, CDCl ): δ = 4.10 (dd, J = 11.2, 6.0 Hz, 1H), 4.05 (apparent
(
2
2
2
2
.
4
%
3
d, overlapped, 1H), 3.95 (dd, J = 11.2, 6.0 Hz, 1H), 3.64 (dd, J = 10.5, 6.2 Hz, 1H), 3.56 (dd, J =
10.5, 6.2 Hz, 1H), 2.40 (m, 1H), 2.29 (m, 1H), 2.07 (m, 1H), 1.20 (s, 9H), 1.09 (m, 1H, overlapped,
1
13
13
resolved by Hꢀ C HSQC experiment), 1.09 (m, 42H) ppm. C NMR (126 MHz, CDCl
3
): δ =
signal, resolved by Hꢀ C HSQC experiment), 76.7, 65.8,
65.1, 45.0, 42.1, 39.1, 27.4, 26.0, 18.53, 18.50, 18.48, 18.44, 13.2 ppm. IR (ν˜max) = 2942 (m), 2865
1
13
1
78.8, 77.2 (overlapped with CDCl
3
–
1
(m), 1731 (m), 1713 (m), 1463 (m), 1143 (s), 881 (s), 677 (s) cm . HRMS (ESIꢀTOF) m/z:
+
[
M+Na] Calcd for C30
H
62
O
5
Si
2
Na 581.4033; Found 581.4033.
tertꢀbutyl(((3aR*,4R*,6R*,6aS*)ꢀ6ꢀ(Iodomethyl)ꢀ2,2ꢀdimethyltetrahydroꢀ
aHcyclopenta[d][1,3]dioxolꢀ4ꢀyl)methoxy)diphenylsilane (9a).
Iodine (1.96 g, 7.74 mmol) was added to a cooled (0 °C, ice bath) solution of PPh
mmol) and imidazole (1.44 g, 21.12 mmol) in CH Cl (5 mL) and the reaction mixture was stirred
at 0 °C for 20 min. A solution of 8a (3.1 g, 7.04 mmol) in CH Cl (15 mL) was added and the
reaction mixture was stirred while allowed to warm to 25 °C for 14 h. The solvent was removed
3
3
(2.33 g, 8.88
2
2
2
2
under reduced pressure and the residue was purified by flash chromatography
(
hexane/EtOAc =
1
2
0:1 to 15:1) to afford 9a as a colorless oil (3.29 g, 85%). H NMR (500 MHz, CDCl
3
): δ = 7.67ꢀ
7.64 (m, 4H), 7.45ꢀ7.37 (m, 6H), 4.45 (dd, J = 6.9, 4.9 Hz, 1H), 4.17 (dd, J = 6.9 Hz, 1H), 3.70 (d, J
=
5.6 Hz, 2H), 3.34 (dd, J = 9.9, 5.3 Hz, 1H), 3.24 (dd, J = 9.9, 6.9 Hz, 1H), 2.30 (m, 1H), 2.18 (m,
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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5
6
1
3
1
H), 2.10 (m, 1H), 1.48 (s, 3H), 1.48 (m, 1H), 1.29 (s, 3H), 1.07 (s, 9H) ppm. C NMR (126 MHz,
CDCl ): δ = 135.9, 133.83, 133.81, 129.9, 127.9, 112.8, 85.5, 83.1, 64.8, 47.5, 46.9, 35.5, 27.9,
7.2, 25.5, 19.6, 10.4 ppm. IR (ν˜max) = 2930 (m), 2857 (m), 1471 (w), 1210 (w), 1111 (m), 1069
3
2
–1
+
(m), 702 (s) cm . HRMS (MALDIꢀTOF) m/z: [M+Na] Calcd for C26
3
H35IO SiNa 573.1292;
Found: 573.1281.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
((1R*,2R*,3S*,4R*)ꢀ4ꢀ(Iodomethyl)ꢀ2,3ꢀbis((triisopropylsilyl)oxy)cyclopentyl)methyl pivalate
9b).
(
By essentially same procedure used for compound 8a, 850 mg (1.52 mmol) of 11b afforded
(
purification by flash chromatography (hexane/EtOAc = 30:1)) 9b as a pale yellow oil (880 mg,
1
8
7%). H NMR (500 MHz, CDCl
3
): δ = 4.13 (dm, J = 3.9 Hz, 1H), 4.06 (dd, J = 11.4, 6.8 Hz, 1H),
3.95 (dd, J = 11.4, 5.8 Hz, 1H), 3.89 (dd, J = 6.1, 3.3 Hz, 1H), 3.38 (dd, J = 9.6, 4.9 Hz, 1H), 3.14
dd, J = 9.4, 8.2 Hz, 1H), 2.38 (m, 1H), 2.31 (m, 1H), 2.16 (m, 1H), 1.21 (s, 9), 1.08 (m, 42H) ppm.
(
13
C NMR (126 MHz, CDCl
3
): δ = 178.7, 79.4, 76.7, 65.6, 44.9, 41.9, 39.1, 30.6, 27.5, 18.55, 18.49,
13.3, 12.6 ppm. IR (ν˜max) = 2932 (m), 2861 (m), 1492 (w), 1224 (w), 1100 (m), 1069 (m), 721 (s)
–1
+
cm . HRMS (MALDIꢀTOF) m/z: [M+Na] Calcd for C H IO Si Na 691.3045; Found: 691.3051.
30 61
4
2
((1S*,2S*,3R*,4R*)ꢀ4ꢀ((Benzyloxy)methyl)ꢀ2,3
bis((triisopropylsilyl)oxy)cyclopentyl) methanol (11c).
To a stirred suspension of NaH (590 mg, 14.76 mmol, 60% dispersion in mineral oil) in THF (10
mL) was added a solution of compound 7b (5.01 g, 10.54 mmol) in THF (15 mL). After stirring for
30 min and cooling to 0 °C, benzyl bromide (1.28 mL, 10.54 mmol) was added dropwise over the
period of 2 h and the resulting mixture was stirred for 36 h at 25 °C. The reaction was quenched by
addition of silica gel (10 g) and the solvent was evaporated. The crude mixture was then purified by
1
flash chromatography (hexane/EtOAc = 10:1) to afford 11c as a pale yellow oil (4.55 g, 77%). H
NMR (500 MHz, CDCl
2.1 Hz, 1H), 4.11 (m, 1H), 4.00 (dd, J = 6.6, 3.5 Hz, 1H), 3.67 (dd, J = 10.6, 5.8 Hz, 1H), 3.58 (dd,
J = 10.6, 5.8 Hz, 1H), 3.41 (m, 2H), 2.36ꢀ2.24 (m, 2H), 2.12ꢀ2.04 (m, 1H), 1.19 (m, 1H), 1.13ꢀ0.97
3
): δ = 7.37ꢀ7.27 (m, 5H), 4.51 (AB d, J = 12.1 Hz, 1H), 4.44 (AB d, J =
1
13
(m, 42H) ppm. C NMR (126 MHz, CDCl
3
): δ = 138.6, 128.5, 127.9, 127.7, 77.9, 77.5, 73.4, 72.4,
6
5.4, 44.9, 43.5, 43.6, 26.4, 18.52, 18.49, 18.4, 13.4, 13.2 ppm. IR (ν˜max) = 3438 (br w), 2941 (m),
–1
+
2864 (m), 1496 (m), 1067 (m), 882 (s), 677 (s) cm . HRMS (APCIꢀTOF) m/z: [M+H] Calcd for
Si 565.4103; Found 565.4099.ꢀ
C
32
H
61
O
4
2
tertꢀbutyl(((3aR*,4R*,6aS*)ꢀ2,2ꢀDimethylꢀ6ꢀmethylenetetrahydroꢀ3aHꢀ
cyclopenta[d][1,3]dioxolꢀ4ꢀyl)methoxy)diphenylsilane (10a).
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DBU (1.04 mL, 7.54 mmol) was added to a solution of 9a (1.54 g, 2.78 mmol) in toluene (10 mL)
and the reaction mixture was stirred at 90 °C for 4 h. The solvent was evaporated under reduced
pressure and the residue was purified by flash chromatography (hexane/EtOAc = 20:1) to afford
1
10a as a colorless oil (855 mg, 72%). H NMR (500 MHz, CDCl
3
): δ = 7.65ꢀ7.63 (m, 4H), 7.45ꢀ
7
.36 (m, 6H), 5.17 (m, 1H), 5.07 (m, 1H), 4.63 (d, J = 5.6 Hz, 1H), 4.50 (d, J = 5.6 Hz, 1H), 3.48
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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29
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37
38
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43
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(
m, 2H), 2.78ꢀ2.73 (m, 1H), 2.38 (m, 1H), 2.15 (m, 1H), 1.47 (s, 3H), 1.32 (s, 3H), 1.05 (s, 9H)
1
3
ppm. C NMR (126 MHz, CDCl ): δ = 149.8, 135.8, 133.77, 133.75, 129.91, 129.90, 127.9, 112.7,
3
1
10.6, 82.7, 82.0, 64.6, 45.9, 32.7, 27.1, 27.0, 24.7, 19.5 ppm. IR (ν˜max) = 2930 (m), 1732 (w),
–
1
+
1
478 (w), 1222 (w), 1127 (s), 679 (s) cm . HRMS (MALDIꢀTOF) m/z: [M+Na] Calcd for
C H O SiNa 445.2169; Found: 445.2183.
26
34
3
(1R*,2R*,3S*)ꢀ4ꢀMethyleneꢀ2,3ꢀbis(triisopropylsilyloxy)cyclopentyl)methyl pivalate (12b
2ꢀNitrophenyl selenocyanate (1.88 g, 8.28 mmol) and Bu P (3.22 mL, 12.88 mmol) were added to a
3
solution of 11b (2.58 g, 4.6 mmol) in THF (15 mL) and the reaction mixture was stirred at 25 °C for
1
4 h. Aqueous H
was stirred at 25 °C for 2 h. The crude mixture was concentrated, diluted by saturated aqueous
NaHCO (20 mL) and extracted with EtOAc (3 × 30 mL). The organic extracts were dried over
Na SO
2 2
O (30% solution, 15.5 mL) was added at 0 °C (ice bath) and the reaction mixture
3
2
4
and the brown residue was purified by flash chromatography (hexane/EtOAc = 50:1) to
1
afford 12b as a pale yellow oil (1.99 g, 80% over the two steps). H NMR (500 MHz, CDCl ): δ =
3
5
5
.12 (m, 1H), 4.92 (m, 1H), 4.40 (d, J = 2.7 Hz, 1H), 4.17 (dd, J = 11.2, 5.9 Hz, 1H), 4.00 (dd, J =
.0, 2.7 Hz, 1H), 3.97 (dd, J = 11.2, 5.9 Hz, 1H), 2.63 (apparent dd, J = 16.7, 10.2 Hz, 1H), 2.49 (m,
13
1H), 2.00 (dm, J = 16.7 Hz, 1H), 1.19 (s, 9H), 1.11ꢀ1.06 (m, 42 H) ppm. C NMR (126 MHz,
CDCl ): δ = 178.8, 149.5, 109.4, 78.0, 76.4, 65.6, 42.2, 39.1, 29.9, 27.4, 18.50, 18.47, 18.45, 18.4,
3.1 ppm. IR (ν˜max) = 2942 (m), 2865 (m), 1732 (m), 1463 (w), 1282 (w), 1139 (s), 881 (s), 678 (s)
3
1
–1
+
60 4 2
cm . HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C30H O Si Na 563.3930; Found 563.3929.
(
(1S*,2R*,3R*)ꢀ3ꢀ((Benzyloxy)methyl)ꢀ5ꢀmethylenecyclopentaneꢀ1,2ꢀdiyl)bis(oxy))bis
(triisopropylsilane) (12c).
By essentially same procedure used for compound 12b, 4.52 g (8.01 mmol) of 11c afforded
(purification by flash chromatography (hexane/EtOAc = 50:1)) 12c as a pale yellow oil (3.28 g,
1
75% over the two steps). H NMR (500 MHz, CDCl ): δ = 7.35ꢀ7.26 (m, 5H), 5.08 (m, 1H), 4.89
3
(
m, 1H), 4.52 (AB d, J = 12.0 Hz, 1H), 4.45 (AB d, J = 12.0 Hz, 1H), 4.41 (d, J = 2.8 Hz, 1H), 4.00
dd, J = 3.7 Hz, 1H), 3.47 (dd, J = 9.1, 5.4 Hz, 1H), 3.41 (dd, J = 9.1, 5.4 Hz, 1H), 2.61 (m, 1H),
(
1
3
2.39 (m, 1H), 2.11 (m, 1H), 1.08ꢀ0.91 (m, 42H) ppm. C NMR (126 MHz, CDCl ): δ = 150.6,
3
1
38.8, 128.5, 127.8, 127.7, 108.2, 77.9, 76.9, 73.4, 72.4, 43.4, 30.4, 18.49, 18.48, 18.45, 18.4, 13.1,
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
–
1
1
3.0 ppm. IR (ν˜max) = 2942 (m), 2865 (m), 1463 (m), 1110 (s), 882 (s), 679 (s) cm . HRMS
+
(APCIꢀTOF) m/z: [M+H] Calcd for C23
H
37
O
2
Si 373.2563; Found 373.2551.
General Procedure B for ozonolysis of exocyclic alkenes
A mixture of O /O (O flow = 5L/min, ozonolysis rate ~ 12 mmol/5 min) was bubbled into a cooled
–78 °C) solution of the starting material in CH Cl :MeOH (1:3, 3 mmol of starting material/25
mL). After after complete ozonolysis (indicated by persistent blue color of the reaction mixture),
excess of O was removed by bubbling N into the reaction mixture. Thiourea (2 eq.) was added and
3
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2
2
3
2
the reaction mixture was stirred for 3 h at 25 °C. The solvents were removed and the solid residue
was purified by flash chromatography to afford the desired ketone.
(3aR*,6R*,6aR*)ꢀ6ꢀ((tertꢀButyldiphenylsilyloxy)methyl)ꢀ2,2ꢀdimethyldihydroꢀ3aHꢀ
cyclopenta[d][1,3]dioxolꢀ4(5H)ꢀone (2a).
The compound was prepared by General Procedure B using 10a (3.25 g, 7.69 mmol); flash
chromatography (hexane/EtOAc = 5:1) afforded 2a as a white crystalline solid (3.0 g, 92%), m.p. =
1
9
6ꢀ97 °C. H NMR (500 MHz, CDCl ): δ = 7.62ꢀ7.59 (m, 4H), 7.47ꢀ7.38 (m, 6H), 4.63 (d, J = 5.4
3
Hz, 1H), 4.35 (d, J = 5.4 Hz, 1H), 3.80 (dd, J = 10.2, 2.8 Hz, 1H), 3.61 (dd, J = 10.2, 2.8 Hz, 1H),
2.75 (dd, J = 18.4, 9.0 Hz, 1H), 2.49 (m, 1H), 2.19 (m, 1H), 1.43 (s, 3H), 1.34 (s, 3H), 1.02 (s, 9H)
13
ppm. C NMR (126 MHz, CDCl ): δ = 213.4, 135.9, 135.8, 132.8, 132.6, 130.2, 130.2, 128.1,
3
1
11.5, 81.8, 79.3, 77.5, 77.2, 76.9, 66.1, 39.3, 37.5, 27.1, 27.0, 24.9, 19.4. IR (KBr, ν˜max) = 3486,
–1
+
2933, 1755, 1589, 1429, 1108, 705.85 cm . HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for
5
25 32 4
C H O SiNa 447.1962; Found 447.1962. The spectral data were consistent with those reported.
(1R*,2R*,3R*)ꢀ4ꢀOxoꢀ2,3ꢀbis(triisopropylsilyloxy)cyclopentyl)methyl pivalate (2b).
The compound was prepared by General Procedure B using 12b (5.74 g, 10.57 mmol); flash
1
chromatography (hexane/EtOAc = 30:1) afforded 2b as a colorless oil (5.46 g, 95%). H NMR (500
3
MHz, CDCl ): δ = 4.41 (dd, J = 3.9, 1.5 Hz, 1H), 4.37 (m, J = 3.9 Hz, 1H), 4.13 (dd, J = 11.6, 8.6
Hz, 1H), 4.05 (dd, J = 11.6, 6.2 Hz, 1H), 2.62 (m, 1H), 2.51 (dd, J = 18.9, 10.1 Hz, 1H), 1.96 (dm, J
13
=
18.9, 1H), 1.20 (s, 1H), 1.10ꢀ1.05 (m, 42H) ppm. C NMR (126 MHz, CDCl
3
): δ = 212.0, 178.5,
7
8.8, 74.3, 65.4, 39.6, 39.1, 34.3, 27.4, 18.3, 18.3, 18.3, 18.2, 12.81, 12.78 ppm. IR (ν˜max) = 2942
–1
(
m), 2866, 1763 (m), 173 (s), 1463 (m), 1132 (s), 881 (s), 676 (s) cm . HRMS (APCIꢀTOF) m/z:
+
[
M+H] Calcd for C29
H
59
O
5
Si
2
543.3896; Found 543.3892.
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(
2R*,3R*,4R*)ꢀ4ꢀ((Benzyloxy)methyl)ꢀ2,3ꢀbis((triisopropylsilyl)oxy)cyclopentanone
(2c).
The compound was prepared by General Procedure B using 12c (4.0 g, 7.31 mmol); flash
1
chromatography (hexane/EtOAc = 25:1) afforded 2c as a yellow oil (3.41 g, 85%). H NMR (500
MHz, CDCl
3
): δ = 7.35ꢀ7.25 (m, 5H), 4.61 (dd, J = 4.1, 1.6 Hz, 1H), 4.52 (AB d, J = 11.8 Hz, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
9
.46 (AB d, J = 11.8 Hz, 1H), 4.36 (d, J = 4.1 Hz, 1H), 3.61 (dd, J = 9.4, 4.0 Hz, 1H), 3.49 (dd, J =
13
.4, 5.1 Hz, 1H), 2.49ꢀ2.41 (m, 2H), 2.14ꢀ2.06 (m, 1H), 1.09ꢀ1.00 (m, 42H). C NMR (126 MHz,
): δ = 213.9, 138.0, 128.6, 128.0, 127.9, 79.5, 75.7, 73.7, 71.8, 40.9, 34.5, 18.33, 18.31,
8.27, 18.2, 12.82, 12.78. IR (ν˜max) = 2942 (m), 2865 (m), 1760 (m), 1463 (m), 1064 (s), 882 (s),
CDCl
3
1
–1
+
57 4 2
676 (s) cm . HRMS (APCIꢀTOF) m/z: [M+H] Calcd for C31H O Si 549.3790; Found 549.3783.ꢀ
(1R*,2R*,3R*,4R*)ꢀ4ꢀ((Benzyloxy)methyl)ꢀ1ꢀphenylꢀ2,3ꢀ
bis((triisopropylsilyl)oxy)cyclopentanol (13a).
Phenyllithium (1.8 M in dibutyl ether, 1.54 mL, 2.77 mmol) was added to a cooled (0 °C, ice bath)
solution of 2c (1.01 g, 1.84 mmol) in THF (10 mL). The reaction mixture was stirred for 6 h while
allowed to warm to 25 °C. The reaction was quenched with aqueous saturated NH
extracted with EtOAc (4 × 20 mL). The combined organic extracts were washed with brine (20
mL), dried over MgSO and concentrated in vacuo. The residue was purified by flash
4
Cl (5 mL) and
4
chromatography (hexane/EtOAc = 50:1) to afford 13a as a viscous brown oil (628 mg, 55%) and
1
recovered starting material (147 mg, 15%). H NMR (500 MHz, CDCl
3
): δ = 7.51 (m, 2H), 7.39ꢀ
7
.34 (m, 4H), 7.34ꢀ7.29 (m, 1H), 7.25ꢀ7.20 (m, 2H), 7.18ꢀ7.13 (m, 1H), 4.56 (d, AB, J = 11.7 Hz,
1H), 4.53 (d, AB, J = 11.7 Hz, 1H), 4.44 (s, 1H), 4.38 (d, J = 4.3 Hz, 1H), 4.34 (d, J = 4.3 Hz, 1H),
3
1
.62 (ddm, J = 9.3, 4.1 Hz, 1H), 3.46 (ddm, J = 9.3, 4.1 Hz, 1H), 2.52ꢀ2.44 (m, 2H), 2.11 (m, J =
13
0.0 Hz, 1H), 1.19ꢀ1.09 (m, 21H), 0.89ꢀ0.79 (m, 18H), 0.62ꢀ0.54 (m, 3H). C NMR (126 MHz,
CDCl
3
): δ = 145.7, 138.3, 128.6, 128.2, 128.0, 127.7, 126.5, 126.2, 82.7, 81.5, 80.7, 73.9, 72.9,
4
4.2, 43.5, 18.51, 18.48, 18.4, 18.2, 13.11, 13.08, 1.2 ppm. IR (ν˜max) = 3511 (br w), 2915 (s), 2866
–1
+
(s), 1730 (m), 1495 (m), 1047 (m), 883 (s), 681 (s) cm . HRMS (APCIꢀTOF) m/z: [M+H] Calcd
for C37
H
60
O
3
2
Si 609.4153; Found 609.4152.
(1R*,2R*,3R*,4R*)ꢀ4ꢀ((Benzyloxy)methyl)ꢀ1ꢀ(2,4ꢀbis(benzyloxy)pyrimidinꢀ5ꢀyl)ꢀ2,3ꢀ
bis((triisopropylsilyl)oxy)cyclopentanol (13b).
nꢀBuLi (1.6 M in hexanes, 1.83 mL, 2.93 mmol) was added dropwise to a cooled (–78 °C) solution
of 2,4ꢀbis(benzyloxy)ꢀ5ꢀbromopyrimidine (1.09 g, 2.93 mmol) in THF (4 mL) and the reaction
mixture was stirred at –78 °C for 1 h. A solution of ketone 2c (1.08 g, 1.97 mmol) in THF (4 mL)
was added dropwise and the reaction mixture was stirred at –78 °C for 1 h. The mixture was
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allowed to warm to 25 °C, quenched with saturated aqueous NH Cl (10 mL) and extracted with
4
2 4
EtOAc (3 × 20 mL). The combined organic extracts were dried over Na SO , filtered and
concentrated in a vacuum. The residue was purified by flash chromatography (hexane/EtOAc =
1
1
0:1) to afford 13b as a yellow crystalline solid (741 mg, 45%), m.p. = 75ꢀ77 °C. H NMR (500
MHz, CDCl
3
): δ = 8.62 (s, 1H), 7.42ꢀ7.38 (m, 2H), 7.29ꢀ 7.17 (m, 11H), 7.14ꢀ7.11 (m, 2H), 5.37 (s,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
2
1
1
1
1
6
2
H), 5.34 (d, J = 11.7 Hz, 1H), 5.10 (d, J = 11.7 Hz, 1H), 4.72 (s, 1H,ꢀOH), 4.45 (d, J = 4.0 Hz,
H), 4.19 (d, J = 4.0 Hz, 1H), 4.11 (d, J = 12.0 Hz, 1H), 3.97 (d, J = 12.0 Hz, 1H), 2.95ꢀ2.91 (m,
H), 2.84ꢀ2.79 (m, 1H), 2.41ꢀ2.34 (m, 1H), 2.10ꢀ1.99 (m, 2H), 1.01ꢀ0.95 (m, 21H), 0.87ꢀ0.72 (m,
1
3
3
8H), 0.68ꢀ0.60 (m, 3H) ppm. C NMR (126 MHz, CDCl ): δ = 166.5, 164.1, 159.7, 138.7, 137.2,
35.8, 129.8, 128.9, 128.6, 128.4, 128.2, 128.1, 127.6, 127.5, 117.0, 79.9, 79.1, 75.1, 73.1, 72.9,
9.1, 69.1, 43.4, 39.2, 18.43, 18.42, 18.3, 18.0, 13.1, 12.9 ppm. IR (ν˜max) = 3457 (br w), 2942 (m),
–1
+
865 (m), 1559 (m), 1422 (s), 825 (s), 685 (s) cm . HRMS (APCIꢀTOF) m/z: [M+H] Calcd for
Si 841.5002; Found 841.4999.
C
49
H
72
N
2
O
6
2
(1S*,2R*,3R*,4R*)ꢀ4ꢀ(Benzyloxymethyl)ꢀ1ꢀbutylꢀ2,3ꢀbis(triisopropylsilyloxy)
cyclopentanol (13c).
Butylmagnesium chloride (2M in THF, 0.20 mL, 0.41 mmol) was slowly added into a solution of
2
c (150 mg, 0.27 mmol) in THF (2 mL) at 0 °C. The reaction mixture was allowed to warm to 25
°C, stirred for 14 h, then quenched with saturated aqueous NH Cl (15 mL), and extracted with
4
4
EtOAc (3 × 15 mL). The organic extracts were dried over MgSO , filtered, and solvent was
evaporated. The residual oil was purified by flash chromatography (hexane/ EtOAc = 25:1) to
1
afford 13c as a colorless oil (620 mg, 38%). H NMR (500 MHz, CDCl
3
): δ = 7.35ꢀ7.27 (m, 5H),
4
.47 (d, AB, J = 12.1 Hz, 1H), 4.43 (d, AB, J = 12.1 Hz, 1H), 4.24 (d, J = 3.9 Hz, 1H), 3.90 (s, 1H,
OH), 3.77 (d, J = 3.9 Hz, 1H), 3.38 (dd, J = 8.7, 5.1 Hz, 1H), 3.23 (dd, J = 9.0, 6.6 Hz, 1H), 2.36
(m, 1H), 2.14 (dd, J = 14.2, 10.5 Hz, 1H), 1.77 (m, 1H), 1.49 (dd, J = 14.3, 5.2 Hz, 1H), 1.36ꢀ1.25
ꢀ
1
3
(
m, 4H), 1.24ꢀ1.16 (m, 2H), 1.12ꢀ1.05 (m, 42H), 0.9 (t, J = 6.7 Hz, 3H) ppm. C NMR (126 MHz,
CDCl ): δ = 138.5 128.5, 127.9 127.8, 80.5, 79.7, 78.6, 73.5, 72.7, 43.1, 39.5, 38.3, 26.4, 23.7, 18.6,
18.5, 14.3, 13.4, 13.1 ppm. IR (ν˜max) = 2942 (m), 2865 (s), 1463 (m), 1154 (m), 825 (s), 679 (s)
3
–1
+
cm . HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C H O Si Na 629.4392; Found 629.4391.
35
66
4
2
(1R*,2R*,3R*,4R*)ꢀ1ꢀBenzylꢀ4ꢀ(benzyloxymethyl)ꢀ2,3ꢀ
bis(triisopropylsilyloxy)cyclopentanol (13d).
The compound was prepared by essentially same procedure used for 13c, using benzylmagnesium
chloride (2M in THF, 0.21 ml, 0.41 mmol) and ketone 2c (150 mg, 0.27 mmol); flash
1
chromatography (hexane/ EtOAc = 25:1) afforded 13d as a colorless oil (63 mg, 38%). H NMR
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(
500 MHz, CDCl ): δ = 7.35ꢀ7.22 (m, 9H), 7.18 (m, 1H), 4.47 (d, AB, J = 12.1 Hz, 1H), 4.43 (d,
3
AB, J = 12.1 Hz, 1H), 4.26 (dd, J = 4.0, 1.4 Hz, 1H), 3.91 (d, J = 4.0 Hz, 1H), 3.75 (d, J = 1.0 Hz,
1
2
1
1
H, ꢀOH), 3.40 (dd, J = 9.1, 4.8 Hz, 1H), 3.23 (dd, J = 9.1, 5.8 Hz, 1H), 3.13 (d, J = 13.1 Hz, 1H),
.44 (d, J = 13.1 Hz, 1H), 2.29 (m, 1H), 1.87 (dd, J = 14.3, 10.5 Hz, 1H), 1.63 (dd, J = 14.3, 5.5 Hz,
13
H), 1.20ꢀ0ꢀ96 (m, 42H) ppm. C NMR (126 MHz, CDCl
3
): δ = 139.0, 138.5, 130.6, 128.6, 128.0,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
27.9, 127.8, 126.2, 80.5, 79.5, 79.3, 73.5, 72.4, 46.0, 43.2, 38.3, 18.6, 18.53, 18.50, 13.6, 13.1
–
1
ppm. IR (ν˜max) = 2942 (m), 2865 (m), 1463 (m), 1153 (m), 881 (s), 678 (s) cm . HRMS (ESIꢀ
+
TOF) m/z: [M+H] Calcd for C H O Si 641.4416; Found 641.4417.
38
64
4
2
(1R*,2R*,3R*,4R*)ꢀ4ꢀ((Benzyloxy)methyl)ꢀ1ꢀ(thiazolꢀ4ꢀyl)ꢀ2,3ꢀ
bis((triisopropylsilyl)oxy)cyclopentanol (13e).
Isopropylmagnesium chloride ꢀ lithium chloride complex (1.3 M in THF, 0.34 mL, 0.44 mmol) was
added dropwise into a solution of 4ꢀbromothiazole (0.04 mL, 0.41 mmol) in THF (1.5 mL). The
reaction mixture was stirred at 25 °C for 30 min, then a solution of 2c (150 mg, 0.27 mmol) in THF
(
1.5 mL) was added and the reaction mixture was stirred at 25 °C for 14 h. The solvent was
evaporated, aqueous saturated NH Cl (15 mL) was added to the residue and the mixture was
4
4
extracted with EtOAc (3 × 15 mL). The organic extracts were dried over MgSO , filtered, and the
solvent was evaporated. The residual yellow oil was purified by flash chromatography
1
(hexane/EtOAc = 25:1) to afford 13e as a yellow oil (156 mg, 90%). H NMR (500 MHz, CDCl ): δ
3
=
7.40ꢀ7.33 (m, 4H), 7.28 (m, 1H), 7.13 (s, 1H), 4.86 (s, 1H), 4.43 (d, J = 4.0 Hz, 1H), 4.55 (d, AB,
J = 11.4 Hz, 1H), 4.50 (d, AB, J = 11.4 Hz, 1H), 3.95 (d, J = 3.8 Hz, 1H), 2.53ꢀ2.48 (m, 1H,
overlapped), 2.48 (d, AB, J = 10.7 Hz, 1H, partially overlapped), 2.43 (d, AB, J = 10.7 Hz, 1H),
2
.24 (dd, J = 13.5, 4.1 Hz, 1H), 1.14ꢀ1.08 (m, 21H), 0.97ꢀ0.93 (m, 9H), 0.89ꢀ0.86 (m, 21H), 0.82ꢀ
13
0
3
.73 (m, 3H) ppm. C NMR (126 MHz, CDCl ): δ = 178.4, 138.5, 128.5, 127.9, 127.7, 124.5,
117.6, 83.9, 79.6, 79.5, 73.6, 72.4, 43.5, 42.0, 18.48, 18.45, 18.3, 18.1, 13.1 ppm. IR (ν˜max) = 2942
–1
(
s), 2865 (s), 1463 (m), 1256 (m), 1089 (s), 882 (s), 680 (s) cm . HRMS (MALDIꢀTOF) m/z:
+
[
M+H] Calcd for C34
H60NO
4
SSi
2
634.3776; Found: 634.3753.
General Procedure C for hydrogenolytic cleavage of benzyl ethers
Pd/C (10%, 10 mol %) or Pd(OH) (10%-20%, 10 mol%) was added to a solution of the starting
material in EtOH (0.1 mmol/5 mL) or THF (0.1 mmol/ 5 mL). The reaction mixture was
2
thoroughly purged with H
2
2
and heated to 80 °C under H atmosphere (1-50 bar, depending on
1
the substrate) for 2-14 h (monitored by TLC and/or by H NMR). The reaction mixture was
cooled to 25 °C, filtered through Celite and concentrated under reduced pressure. The residue
was purified by flash chromatography to afford the desired product.5ꢀ((1R*,2R*,3R*,4R*)ꢀ
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ꢀHydroxyꢀ4ꢀ(hydroxymethyl)ꢀ2,3ꢀbis(triisopropylsilyloxy)
cyclopentyl)pyrimidineꢀ2,4(1H,3H)ꢀdione (14b).
The compound was prepared by General Procedure C using compound 13b (376 mg, 0.45 mmol),
2
Pd/C (5 mg, 0.05 mmol), H (1 bar) in EtOH. The solid residues were removed by filtration through
a pad of Celite and the resulting crude product was used in the next step without further
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
purification. Analytical sample of 14b was obtained by flash chromatography (hexane/EtOAc =
1
1
:1) to afford 14b as a white crystalline solid, m.p. > 200 °C (dec). H NMR (300 MHz, DMSOꢀd
6
):
δ = 11.05 (s, 1H), 10.80 (d, J = 5.9 Hz, 1H), 7.31 (d, J = 6.0 Hz, 1H), 4.68ꢀ4.66 (m, 1H), 4.47 (s,
H), 4.32 (d, J = 3.9 Hz, 1H), 3.46ꢀ3.39 (m, 2H, partially overlapped with residual H O), 2.30ꢀ2.16
1
2
(m, 1H), 2.03 (dd, J = 14.3, 3.8 Hz, 1H), 1.87 (dd, J = 14.3, 10.3 Hz, 1H), 1.14ꢀ1.04 (m, 21H), 1.02ꢀ
13
0
6
3
.88 (m, 21H) ppm. C NMR (126 MHz, DMSOꢀd
6
): δ = 163.3, 151.1, 139.3, 113.1, 78.8, 73.8,
3.3, 45.0, 30.6, 18.97, 17.95, 17.9, 17.7, 12.3, 12.1 ppm. IR (ν˜max) = 3507 (br w), 3234 (br w),
–1
159 (br w), 2943 (m), 2866 (m), 1714 (s), 1652 (s), 1147 (m), 881 (s), 679 (s) cm . HRMS
+
(APCIꢀTOF) m/z: [M+Na] Calcd for C H N O Si Na 593.3413; Found 593.3413.
2
8
54
2
6
2
(1R*,2R*,3R*,4R*)ꢀ4ꢀ(Hydroxymethyl)ꢀ1ꢀphenylꢀ2,3ꢀbis((triisopropylsilyl)oxy) cyclopentanol
15).
The compound was prepared by General Procedure C using compound 13a 100 mg (0.16 mmol),
(
Pd/C (2 mg, 0.02 mmol) and H
2
(1 bar) in EtOH; flash chromatography (hexane/EtOAc = 20:1)
1
afforded 15 as a white crystalline solid (65 mg, 75%), m.p. = 87ꢀ89 °C. H NMR (300 MHz,
3
CDCl ): δ = 7.58ꢀ7.52 (m, 2H), 7.32ꢀ7.24 (m, 2H), 7.22ꢀ7.15 (m, 1H), 4.48 (s, 1H), 4.41 (d, AB, J =
4.1 Hz, 1H), 4.33 (d, AB, J = 4.1 Hz, 1H) 3.78 (dd, J = 10.1, 4.7 Hz, 1H), 3.68 (dd, J = 10.1, 4.7
Hz, 1H), 2.55ꢀ2.38 (m, 2H), 2.06 (ddm, J = 13.4, 3.2 Hz, 1H), 1.18ꢀ1.10 (m, 21H), 0.94ꢀ0.81 (m,
13
1
8H), 0.72ꢀ0.54 (m, 3H) ppm. C NMR (126 MHz, CDCl
3
): δ = 138.6, 128.5, 127.9, 127.8, 77.9,
77.6, 73.5, 72.4, 65.4, 44.9, 43.5, 26.4, 18.53, 18.49, 18.45, 13.4, 13.2 ppm. IR (ν˜max) = 3435 (br
–1
w), 3251 (br w), 2942 (s), 2865 (s), 1498 (m), 1151 (s), 867 (s), 680 (s) cm . HRMS (APCIꢀTOF)
+
m/z: [M+H] Calcd for C H O Si 519.3684; Found 519.3682.
3
0
55
3
2
(1R*,2R*,3R*,4R*)ꢀ4ꢀ(Methoxymethyl)ꢀ1ꢀphenylꢀ2,3ꢀbis((triisopropylsilyl)oxy)
cyclopentanol (16).
To a stirred suspension of NaH (60% dispersion in mineral oil,16 mg, 0.24 mmol) in THF (1.5 mL)
was added a solution of 15 (65 mg, 0.12 mmol) in THF (1 mL) at 25 °C. After stirring for 30 min
and cooling to 0 °C (ice bath), methyl iodide (53 µL, 0.85 mmol) was added dropwise and the
resulting mixture was stirred at 25 °C for 24 h. The reaction was quenched by addition of silica gel
(0.15 g) and the solvent was evaporated under reduced pressure. The residue was then purified by
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flash chromatography (hexane/EtOAc = 75:1 to 10:1) to afford 16 as a colorless crystalline solid
1
(
44 mg, 67%), m.p. = 61ꢀ69 °C. H NMR (500 MHz, CDCl
3
): δ = 7.57ꢀ7.54 (m, 2H), 7.30ꢀ7.26 (m,
2
H), 7.20ꢀ7.15 (m, 1H), 4.36 (d, AB, J = 4.0 Hz, 1H), 4.34 (d, AB, J = 4.0 Hz, 1H), 3.48 (dd, J =
9
.1, 4.5 Hz, 1H), 3.39 (s, 3H), 3.36 (dd, J = 9.1, 5.2 Hz, 1H), 2.52ꢀ2.41 (m, 2H, overlapped), 2.05
13
(dd, J = 13.7, 3.6 Hz, 1H), 1.16ꢀ1.11 (m, 21H), 0.95ꢀ0.81 (m, 18H), 0.67ꢀ0.57 (m, 3H) ppm.
C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (126 MHz, CDCl
3
): δ = 145.7, 127.8, 126.6, 126.2, 82.6, 81.4, 80.6, 77.4, 59.3, 44.2, 43.4,
1
8.50, 18.48, 18.42, 13.1 ppm. IR (ν˜max) = 3511 (m), 2939 (s), 2865 (s), 1461 (m), 1148 (m), 1067
–1
+
(m), 882 (s), 681 (s) cm . HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C H O Si Na 573.3765;
31
58
4
2
Found 573.3764.
General Procedure D for removal of TIPS protecting groups
TBAF (1M in THF, 1.1ꢀ1.3 eq.) was added to a stirred solution of starting material in THF (0.3
mmol/mL). The reaction mixture was stirred at 25 °C for 14ꢀ24 h. The solvent was evaporated and
the residue was purified by flash chromatography to afford the product.
5
ꢀ((1R*,2R*,3R*,4R*)ꢀ1,2,3ꢀTrihydroxyꢀ4ꢀ(hydroxymethyl)cyclopentyl)pyrimidineꢀ
2,4(1H,3H)ꢀdione (1b).
The compound was prepared by General Procedure D using compound 14b (235 mg, 0.41 mmol);
2 2 2
flash chromatography (CH Cl to CH Cl2/MeOH = 10:1 to 1:1) afforded compound 1b (90 mg, 85
%) slightly contaminated by residual TBAF. Analytically pure sample of 1b was obtained by RPꢀ
®
HPLC (Nucleodur C18 HTec, details given in Supporting Information) as a white solid, m.p. >
1
2
50 °C. H NMR (500 MHz, DMSOꢀd
6
): δ = 10.96 (bs, 1H, ꢀNH), 10.71 (bs, 1H, ꢀNH), 7.29 (s,
1H), 4.54 (s, 1H, ꢀOH), 4.42ꢀ4.50 (m, 3H, ꢀ3 x OH), 4.11 (m, 1H), 3.74 (dd, J = 10.5, 6.0 Hz, 1H),
3
.43 (m, 1H), 3.34 (m, 1H), 2.13 (m, 1H), 1.89 (dd, J = 13.3, 9.7 Hz, 1H), 1.63 (dd, J = 13.3, 8.4
13
Hz, 1H) ppm. C NMR (126 MHz, DMSOꢀd
6
): δ = 163.3, 151.3, 138.6, 114.5, 78.3, 72.9, 72.6,
63.2, 46.7, 36.3 ppm. IR (ν˜max) = 3088 (w), 3077 (w), 1704 (s), 1654 (s), 1015 (m), 849 (m), 542
–1
ꢀ
(
m) cm . HRMS (ESIꢀTOF) m/z: [MꢀH] Calcd for C10
13 2 6
H N O 257.0779; Found 257.0775.
(1R*,2R*,3R*,4R*)ꢀ4ꢀ(Benzyloxymethyl)ꢀ1ꢀphenylcyclopentaneꢀ1,2,3ꢀtriol (14a).
The compound was prepared by General Procedure D using compound 13a (256 mg, 0.41 mmol);
flash chromatography (CH
2
Cl
2
/MeOH = 20:1) afforded compound 14a as a colorless oil (123 mg,
): δ = 7.48 (m, 2H), 7.38ꢀ7.27 (m, 7H), 7.26 (m, 1H, overlapped
3
), 4.56 (d, AB, J = 12.0 Hz, 1H), 4.53 (d, AB, J = 12.0 Hz, 1H), 4.19 (d, J = 6.4 Hz,
1
9
6%). H NMR (500 MHz, CDCl
3
with CHCl
1
H), 4.06 (dd, J = 6.3, 3.7 Hz, 1H), 3.63 (dd, J = 9.1, 4.9 Hz, 1H), 3.47 (dd, J = 9.1, 6.1 Hz, 1H),
.35ꢀ2.77 (br s, 1H, ꢀOH), 2.58ꢀ2.50 (m, 1H), 2.28 (dd, J = 14.1, 8.7 Hz, 1H), 1.81 (dd, J = 14.1, 9.7
3
13
3
Hz, 1H) ppm. C NMR (126 MHz, CDCl ): δ = 144.1, 138.4, 128.7, 128.6, 127.94, 127.85, 127.5,
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1
25.5, 82.3, 77.5, 75.9, 73.5, 72.2, 45.0, 39.8 ppm. IR (ν˜max) = 2955 (s), 2849 (s), 1729 (s), 1254
–1
–
(m), 1065 (m), 702 (s) cm . HRMS (ESIꢀTOF) m/z: [MꢀH] Calcd for C19
21 4
H O 313.1445; Found
3
13.1442.
(
1R*,2R*,3R*,4R*)ꢀ4ꢀ(Hydroxymethyl)ꢀ1ꢀphenylcyclopentaneꢀ1,2,3ꢀtriol (1a).
The compound was prepared by prepared by General Procedure C using compound 14a (61 mg,
0.19 mmol), Pd(OH) /C (0.3 mg, 0.02 mmol), H (50 bar) in THF; flash chromatography (CH Cl
OH = 3:1) afforded compound 1a as a white solid (40 mg, 92 %), m.p. = 141ꢀ143
): δ = 7.49ꢀ7.44 (m, 2H), 7.33ꢀ7.27 (m, 2H), 7.22ꢀ7.17 (m, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
2
2 2 3
to CH Cl /CH
1
°C. H NMR (500 MHz, DMSOꢀd
6
4.66 (s, 1H), 4.58 (d, J = 6.1 Hz, 1H), 4.55 (m, 1H), 4.44 (d, J = 7.7 Hz, 1H), 3.82 (dd, J = 14.1, 6.8
Hz, 1H), 3.79 (m, 1H), 2.22 (m, 1H), 1.95 (dd, J = 13.5, 8.4 Hz, 1H), 1.66 (dd, J = 13.5, 10.1 Hz,
13
1
H) ppm. C NMR (126 MHz, DMSOꢀd
6
): δ = 146.3, 127.6, 126.0, 125.3, 80.7, 77.9, 72.9, 62.7,
5
46.9 ppm. The spectral data were consistent with those reported.
(1S*,2R*,3R*,4R*)ꢀ4ꢀ(Benzyloxymethyl)ꢀ1ꢀbutylcyclopentaneꢀ1,2,3ꢀtriol (14c).
The compound was prepared by General Procedure D using compound 13c (198 mg, 0.33 mmol);
flash chromatography (CH Cl /MeOH = 20:1) afforded 14c as a slightly yellow wax (78 mg, 82%).
2
2
1
H NMR (500 MHz, CDCl
3
): δ = 7.37ꢀ7.26 (m, 5H), 4.53 (d, AB, J = 12 Hz, 1H), 4.50 (d, AB, J =
1
6
1
2 Hz, 1H), 3.90 (m, 1H), 3.64 (d, J = 6.4 Hz, 1H), 3.53 (dd, J = 9.1, 5.2 Hz, 1H), 3.38 (dd, J = 9.1,
.7 Hz, 1H), 3.16 (br s, 1H, ꢀOH), 2.93 (br s, 1H, ꢀOH), 2.70 (br s, 1H, ꢀOH), 2.44ꢀ2.35 (m, 1H),
.95 (dd, J = 14.0, 8.8 Hz, 1H), 1.62ꢀ1.53 (m, 1H), 1.49ꢀ1.28 (m, 6H), 0.90 (t, J = 7.2 Hz, 3H) ppm.
1
3
C NMR (126 MHz, CDCl
3
): δ = 138.4, 128.6, 127.9, 127.8, 80.8, 76.3, 76.2, 73.4, 72.5, 44.3,
3
9.1, 36.8, 26.2, 23.4, 14.2 ppm. IR (ν˜max) = 3260 (m), 2937 (m), 1409 (w), 1096 (s), 802 (s), 698
–
1
–
–
(s) cm . HRMS (ESIꢀTOF) m/z: [MꢀH] Calcd for C H O 293.1758; Found 293.1758; [M+Cl]
1
7
26
4
Calcd for C H O Cl 329.1525; Found 329.1529.
17
26
4
(1S*,2R*,3R*,4R*)ꢀ1ꢀButylꢀ4ꢀ(hydroxymethyl)cyclopentaneꢀ1,2,3ꢀtriol (1c).
The compound was prepared by prepared by General Procedure C using compound 14c (39 mg,
0
.13 mmol) and Pd(OH) /C (2 mg, 0.01 mmol), H (50 bar) in THF; flash chromatography (CH Cl
2
2
2
2
1
2 2 3
to CH Cl /CH OH = 5:1) afforded 1c as a white wax (25 mg, 93 %). H NMR (500 MHz, DMSOꢀ
d6): δ = 4.42 (apparent t, J = 5.1 Hz, 1H), 4.34 (dd, J = 15.4, 6.3 Hz, 2H), 3.91 (s, 1H), 3.61 (dd, J =
5
.4, 11.3 Hz, 1H), 3.39ꢀ3.32 (m, 3H), 2.02 (m, 1H), 1.69 (dd, J = 8.8, 13.3 Hz, 1H), 1.49ꢀ1.41 (m,
H), 1.40ꢀ1.32 (m, 1H), 1.32ꢀ1.22 (m, 4H), 1.19 (dd, J = 9.0, 13.3 Hz, 1H), 0.86 (t, J = 7.1 Hz, 3H)
1
13
ppm. C NMR (126 MHz, DMSOꢀd ): δ = 78.7, 76.0, 73.3, 62.8, 45.9, 36.8, 25.7, 22.8, 14.0 ppm.
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IR (ν˜max) = 3424 (br w), 3235 (br w), 2955 (m), 2854 (m), 1376 (m), 1131 (s), 1020 (s), 867 (s),
–1
–
5
20 4
29 (m) cm . HRMS (ESIꢀTOF) m/z: [M+Cl] Calcd for C10H O Cl 239.1056; Found 239.1056.
(1R*,2R*,3R*,4R*)ꢀ1ꢀBenzylꢀ4ꢀ(benzyloxymethyl)cyclopentaneꢀ1,2,3ꢀtriol (14d).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The compound was prepared by General Procedure D using compound 13d (218 mg, 0.33 mmol);
1
flash chromatography (hexane/EtOAc = 20:1) afforded 14d as a white semiꢀsolid (98 mg, 90%). H
NMR (500 MHz, DMSOꢀd
6
): δ = 7.36ꢀ7.22 (m, 10H), 4.49 (d, AB, J = 12.3 Hz, 1H), 4.46 (d, AB, J
=
12.3 Hz, 1H), 3.90 (dd, J = 6.0, 4.0 Hz, 1H), 3.72 (d, J = 6.0 Hz, 1H), 3.49 (dd, J = 9.1, 5.1 Hz,
1H), 3.33 (dd, J = 9.1, 6.4 Hz, 1H), 3.03 (br s, 1H, ꢀOH), 2.92 (d, J = 13.5 Hz, 1H), 2.80 (d, J = 13.5
Hz, 1H), 2.67 (br s, 1H, ꢀOH), 2.36 (m, 1H), 1.83 (dd, J = 14.0, 8.8 Hz, 1H), 1.47 (dd, J = 14.0, 9.7
13
Hz, 1H) ppm. C NMR (126 MHz, DMSOꢀd
6
): δ = 138.4, 137.2, 130.5, 128.6, 128.5, 127.9, 127.7,
126.8, 81.1, 77.2, 77.0, 75.7, 75.6, 73.4, 72.1, 44.8, 44.4, 36.4 ppm. IR (ν˜max) = 3432 (br w), 2844
–1
(
br w), 2955 (m), 1354 (m), 1183 (m), 1090 (s), 755 (m), 695 (s) cm . HRMS (ESIꢀTOF) m/z: [Mꢀ
–
H] Calcd for C20
H
23
O
4
327.1602; Found 327.1604.
(1R*,2R*,3R*,4R*)ꢀ1ꢀBenzylꢀ4ꢀ(hydroxymethyl)cyclopentaneꢀ1,2,3ꢀtriol (1d).
The compound was prepared by prepared by General Procedure C using compound 14d (30 mg,
0
.09 mmol), Pd(OH)
2
/C (1 mg, 0.01 mmol), H
2
(50 bar) in THF; flash chromatography
1
(CH Cl /CH OH = 20:1 to 1:1) afforded 1d as a white semiꢀsolid (20 mg, 92 %). H NMR (500
2
2
3
MHz, DMSOꢀd
6
): δ = 7.27ꢀ7.21 (m, 4H), 7.19ꢀ7.15 (m, 1H), 4.43 (d, J = 6.7 Hz, 1H, ꢀOH), 4.40
(app t, J = 5.1 Hz, 1H, ꢀOH), 4.35 (d, J = 7.1 Hz, 1H), 4.10 (s, 1H, ꢀOH), 3.64 (dd, J = 11.8, 5.8 Hz,
1H), 3.38 (apparent t, J = 6.4 Hz, 1H), 3.32ꢀ3.26 (m, 2H, overlapped with H O), 2.77 (d, J = 13.1
2
Hz, 1H), 2.61 (d, J = 13.1 Hz, 1H), 2.03ꢀ1.97 (m, 1H), 1.49 (dd, J = 13.5, 8.9 Hz, 1H), 1.25 (dd,
13
1
3.5, 8.9 Hz, 1H) ppm. C NMR (126 MHz, DMSOꢀd
6
): δ = 138.4, 130.2, 127.5, 125.7, 79.3, 75.3,
72.8, 62.7, 46.0, 44.5, 36.0 ppm. IR (ν˜max) = 3528 (m), 2912 (w), 2862 (w), 1366 (w), 1018 (s),
–1
–
6
17 4
97 (s) cm . HRMS (ESIꢀTOF) m/z: [MꢀH] Calcd for C13H O 237.1132; Found 237.1132;
–
[
M+Cl] Calcd for C13
H
18
O
4
Cl 273.0899; Found 273.0898.
(1R*,2R*,3R*,4R*)ꢀ4ꢀ(Hydroxymethyl)ꢀ1ꢀ(thiazolꢀ4ꢀyl)cyclopentaneꢀ1,2,3ꢀtriol (1e).
Lithium (10 mg, 1.43 mmol) in several pieces was added into a solution of naphthalene (244 mg,
.91 mmol) in THF (9 mL). The reaction mixture was stirred at 25 °C under until the lithium was
1
completely dissolved (2ꢀ3 h). The resulting dark green solution of lithium naphthalenide was slowly
added into a solution of 13e (150 mg, 0.24 mmol) in THF (2 mL). The reaction mixture was stirred
4
at 25 °C for 1 h. The reaction mixture was quenched with saturated aqueous NH Cl (10 mL) and
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