Highly stereoselective gram scale synthesis of all the four diastereoisomers of Boc-protected 4-methylproline carboxylates

Article abstract of DOI:10.1039/c9ra06827a

A general and practical synthetic process for all the four diastereoisomers of Boc-protected 4-methylproline carboxylates has been developed with essentially complete stereoselectivity on the gram scale, which represents the most diastereoselective preparation of 4-methylproline derivatives to date. This synthesis features an Evans asymmetric alkylation to elegantly establish the challenging stereochemistry of the 4-methyl group, providing valuable insights for the diastereoselective preparation of 4-substituted prolines.

Full text of DOI:10.1039/c9ra06827a

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Highly stereoselective gram scale synthesis of all
the four diastereoisomers of Boc-protected 4-
methylproline carboxylates†
Cite this: RSC Adv., 2019, 9, 32017
cd
e
Kehuan Sun,‡ac Cheng Tao,‡bcd Bohua Long,
Xiaobin Zeng,
*
*
cd
a
*
*
Zhengzhi Wu
and Ronghua Zhang
A general and practical synthetic process for all the four diastereoisomers of Boc-protected 4-
methylproline carboxylates has been developed with essentially complete stereoselectivity on the gram
scale, which represents the most diastereoselective preparation of 4-methylproline derivatives to date.
This synthesis features an Evans asymmetric alkylation to elegantly establish the challenging
stereochemistry of the 4-methyl group, providing valuable insights for the diastereoselective preparation
of 4-substituted prolines.
Received 28th August 2019
Accepted 29th September 2019
DOI: 10.1039/c9ra06827a
rsc.li/rsc-advances
4-Methylprolines (Fig. 1) are one of the most important struc- of Boc-protected 4-methyl proline carboxylates by utilizing the
tural motifs found in numerous natural products and biologi- intramolecular radical cyclization approach.5 In 2003,
cally active compounds. For example, (2S,4S)-4-methylproline Goodman and co-workers realized the diastereoselective
(1) is the crucial component of the dimerized pentapeptides synthesis of Boc-protected 4-methyl prolines employing
nazumazoles A–C which have been found to exhibit potential a divergent asymmetric hydrogenation strategy.6 In 2010, Willis
cytotoxicity against P388 murine leukemia cells;1 the trans- and co-workers developed a chemoenzymatic route toward the
isomers (2 and 4) are valuable precursors of various natural 4-methylprolines by taking advantage of two biotransforma-
compounds, such as methylgriselimycin,2a monamycin D1,2b tions to establish the absolute conguration.7 However, most of
and cyclopeptide FR235222;3 furthermore, (2R,4R)-4-methyl- these methods suffer from the poor control of the stereo-
proline (3) has found wide application in therapeutic agents chemistry of the 4-methyl group and oen use expensive cata-
such as the N14-desacetoxytubulyisn analogue with potential lysts or toxic regents. Furthermore, the harsh conditions
applications in clinics.4 In this regard, development of a general
and highly diastereoselective route to 4-methylprolines would
greatly facilitate the synthesis of various relevant natural prod-
ucts and medicines. We wish to develop a general and practical
synthetic process of all the four diastereoisomers of 4-methyl-
prolines for our long-term efforts on the total synthesis of
nazumazoles A–C and other 4-methylproline-containing bioac-
tive compounds.
During the last few decades, several strategies have been
employed to the diastereoselective preparation of 4-methylpro-
lines. In 1991, Beaulieu and co-workers reported the synthesis
aCollege of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China
bIntegrated Chinese and Western Medicine Postdoctoral Research Station, Jinan
University, Guangzhou 510632, China
cThe First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China. E-mail:
bhlong121@163.com
dShenzhen Institute of Geriatric Medicine, Shenzhen, 518035, China
eCentral Center Lab of Longhua Branch, Department of Infectious Disease, Shenzhen
People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen
518120, Guangdong Province, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra06827a
Fig. 1 Selective relevant natural products and bioactive compounds
containing 4-methylprolines (1–4).
‡ These authors contributed equally to this work.
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coupled with expensive reagent cost would impede the appli-
cation of the current methods to multigram-scale production.
From a viewpoint of synthetic application, the Boc-protected
carboxylate form of 4-methylprolines (8, 80, ent-8 and ent-80)
were more practical and operationally simple than 4-methyl-
prolines (1–4), because the Boc-protected 4-methylproline
carboxylates can be easily puried and stored, and they also can
be further elaborated to 4-methylprolines (1–4) and other
valuable intermediates according to literature procedure.8
As part of our long-term efforts on the total synthesis of
nazumazoles A–C and other 4-methylproline-containing bioac-
tive compounds, we present herein a general and practical
synthetic process for all the four diastereoisomers of Boc-
protected 4-methylproline carboxylates with essentially
complete stereoselectivity on gram scale (Scheme 1).
We envisaged that the main synthetic challenge of 4-meth-
ylprolines is that of exercising control of the absolute congu-
ration at C4, and this vexing problem could be addressed by
employing the asymmetric alkylation approach developed by
Evans.9 With this idea in mind, we start our retrosynthetic
analysis. As the retrosynthetic analysis strategy was also suit for
other three diastereoisomers, we just take one isomer as an
example (Scheme 2).
As for the Boc-protected (2S,4S)-4-methylproline carboxylate
(8), the C2 stereocenter would be introduced via an intra-
molecular SN2 reaction of amine 9. The C4 stereocenter could be
installed by utilizing the asymmetric alkylation reaction, which
traced the origin of amine 9 to Evans' chiral auxiliary 6. The
Scheme 2 Retrosynthetic analysis.
Evans' chiral auxiliary 6 could be easily prepared from the cheap
commercial chiral glutamic acid. In such case, choosing the
different chiral glutamic acid (D-glutamic acid or L-glutamic
acid) and different chiral N-acyloxazolidinone auxiliarie ((S)-4-
benzyl-2-oxazolidinone or (R)-4-benzyl-2-oxazolidinone) would
control the conguration of the generated stereogenic center at
C4. As such, this would provide a general and facile synthetic
protocol for all the four diastereoisomers of 4-methylprolines.
Our strategy for rapid access to the Evans' chiral auxiliary 6
commenced with the chiral D-glutamic acid (5) (Scheme 3).
Compound 10 was prepared from D-glutamic acid via a known
two-step process10 in 80% yield. Then a chemoselective reduc-
tion of the ester group adjacent to the hydroxyl group was
achieved with borane-dimethyl sulde complex to afford diol 11
in 90% yield.11 Then protection of diol 11 followed by hydrolysis
of the methyl ester with lithium hydroxide gave acid 12, which
was directly coupled with chiral (S)-oxazolidinone auxiliary in
the presence of pivaloyl chloride and triethyl amine to afford
Evans' chiral auxiliary 6 (72% yield, three steps).
Scheme
1 Diastereoselective synthesis of the 4-methylproline
derivatives.
Scheme 3 Establishment of the C4 stereochemistry.
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With the Evans' chiral auxiliary 6 in hand, the crucial Therefore, the transformation was operated in a two-step
asymmetric alkylation was then explored. The methylation process. Alcohol 15 was initially subjected to oxidation with
proceeded successfully when using NaHMDS as the base fol- IBX in DMSO at 30 ꢀC, and the resulting aldehyde 16 was
lowed by treatment with MeI to give desired product 7 in 70% subsequently transformed into the corresponding methyl ester
yield. Gratifyingly, the desired product 7 was obtained as 17 by adding NIS and potassium carbonate in MeOH at room
a single stereoisomer on a 40 g scale. As such, the C4 congu- temperature17 in 90% overall yield. However, considering NIS
ration was established with essentially complete stereo- was an expensive reagent, we were not satised with the result
selectivity. As we haven't observed and isolated any isomers of 7 and were eager to nd a more cheap procedure for the prepa-
in this reaction, the 70% yield may be caused by certain ration of compound 17 to make it more accessible. Gratifyingly,
unknown non-isomeric byproducts of unwanted side-reactions, when aldehyde 16 was further oxidized with KOH/I2/MeOH
which is common in the Evan's methylation reactions.9
system,18 the desired methyl ester 17 was easily and economi-
With the access to C4 conguration realized, we next turned cally synthesized under the mild condition (95% yield, two
our attention to establishment of the requisite C2 stereocenter steps, 13 g scale).
and the completion of the diastereoselective synthesis of Boc-
protected 4-methylproline carboxylates.
Then TBS ether 17 was deprotected with CSA to afford the
corresponding alcohol 18. Tosylation of alcohol 18 was carried
As shown in Scheme 4, reductive cleavage of the Evans out with p-toluenesulfonyl chloride in the presence of base such
auxiliary by utilizing sodium borohydride generated alcohol 13 as pyridine, Et3N or DMAP, leading to less than 50% yield.
in 90% yield.12 Then the hydroxyl group in compound 13 was Fortunately, the yield was signicantly increased to 90% when
directly transformed into the azido group by treatment with DABCO (2.0 eq.) was used as the base.19
DPPA and DBU in dry toluene under reux condition in 85%
Finally, the two-step azide reduction/intramolecular SN2
isolated yield along with 10% recovered starting material. Much cyclization procedure was performed as a tandem one-pot
to our delight, when xylene was used as solvent, the azide 14 was process successfully under the hydrogenation condition. Then
forged in 92% yield.
the resulting cyclization product was directly protected as its
With the azide 14 in hand, selective cleavage of the primary Boc derivative by adding NaHCO3 and Boc2O to afford the
TBS-ether was then explored. A variety of traditional methods desired Boc-protected (2S,4S)-4-methylproline carboxylate (8) in
including CSA/MeOH,13 TsOH/MeOH,14 and conc. HCl/CHCl3 90% yield. It should be noted that, the present turned out to be
(ref. 15) were examined, and many of our efforts were fruitless, very practical, and the desired product (8) can be routinely
leading to incomplete conversion or deprotection of the two prepared on a 8.5 g scale with full stereochemical control. The
TBS-ether. In contrast, treatment of 14 with NH4F (50 eq.) in conversion of 8 into (2S,4S)-4-methylproline (1) has been
MeOH at room temperature for 6 h provided the desired previously reported.8
primary alcohol 15 in 75% yield. Unfortunately, oxidation of the
As shown in Scheme 5, we then accomplished the gram-scale
resulting hydroxyl group to carboxylic acid with NaIO4 in the synthesis of the other three diastereoisomers 80 (15 steps, 13%),
presence of catalytic amounts of RuCl3 (ref. 16) was not ach- ent-8 (15 steps, 12%), ent-80 (15 steps, 17%) by utilizing the same
ieved, leading to decomposition of the starting material. strategy described above. Because a large amount of 8 was
Scheme 4 Synthesis of the Boc-protected (2S,4S)-4-methylproline Scheme 5 Gram scale synthesis of the other three diastereoisomers
carboxylate.
of Boc-protected 4-methylproline carboxylates.
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¨
2 (a) P. Lukat, Y. Katsuyama, S. wenzel, T. binz, C. Konig,
needed for our current program on the total synthesis of
nazumazoles A–C, 8 was prepared on a 8.5 g scale (15 steps,
17%). We thought that obtaining the other three isomers in
gram scale was enough to illustrate the high synthetic practi-
cality of the present route, so we haven't attempted bigger
quantities of the other three isomers. In the key Evan's meth-
ylation reactions,9 the desired methylation products 70, ent-7,
ent-70 were obtained in yields of 66%, 73%, 73%, respectively
and without any isomeric methylation products observed,
which highlights the essentially complete selectivity of our
route. For experimental details, see ESI.†
¨
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In conclusion, a general and practical synthetic route for all the
four diastereoisomers of Boc-protected 4-methylproline
carboxylates has been developed with essentially complete
stereoselectivity on gram scale. To the best of our knowledge,
our present route represents the most diastereoselective prep-
aration of 4-methylproline derivatives to date. Other features of
the synthesis include the accessibility of simple starting mate-
rials, cheap synthetic cost, and mild reaction conditions, all of
which highlight the high synthetic practicality of the present
route. This concise strategy offers a general and facile synthetic
protocol for chiral 4-methylprolines and 4-substituted prolines.
On the basis of the current work, the investigation of the
dimerized pentapeptides nazumazoles A–C and other complex
natural products containing 4-methylprolines is ongoing in the
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Conflicts of interest
There are no conicts to declare.
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Acknowledgements
We thank the Health and Family Planning Commission of
Shenzhen Municipality (201601053), Shenzhen Science and
Technology
Program
(JCYJ20160428110124165,
JCYJ20160428110235852, JCYJ20170413161352000), NSFC
(81673837, 81574038), Guangdong Science and Technology
Program (2016A020226039, 2015B020211001), and Sanming
Project of Medicine in Shenzen (SZSM201612049) for nancial
support.
¨
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