A short asymmetric synthesis of methyl 2-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)acetate from norbornene

Article abstract of DOI:10.1016/j.tetlet.2020.152057

Methyl 2-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)acetate has been synthesized from norbornene using Hayashi's (S)-MOP Pd-catalyzed asymmetric hydrosilation. On a 1 mol scale, asymmetric hydrosilation of norbornene afforded an 84:16 exo- to endo-norborneol mixture but with exclusive 1R,4S-stereochemistry at the bridgehead carbons. The norborneol mixture was converted to an optically pure chiral bicyclic lactone via a high-yielding tandem oxidation/Baeyer-Villiger reaction. Acid-promoted ring-opening of the lactone followed by immediate silyl protection afforded the chiral cis-1,3-cyclopentane intermediate in five steps with an overall yield of 41%.

Full text of DOI:10.1016/j.tetlet.2020.152057

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A short asymmetric synthesis of methyl 2-((1S,3R)-3-((tert-butyldiphenylsil‐
yl)oxy)cyclopentyl)acetate from norbornene
Buwen Huang, Jeff Elleraas, Jason Ewanicki, Scott C. Sutton
PII:
S0040-4039(20)30503-7
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152057
TETL 152057
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 April 2020
14 May 2020
17 May 2020
Please cite this article as: Huang, B., Elleraas, J., Ewanicki, J., Sutton, S.C., A short asymmetric synthesis of
methyl 2-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)acetate from norbornene, Tetrahedron Letters
(2020), doi: https://doi.org/10.1016/j.tetlet.2020.152057
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A short asymmetric synthesis of methyl 2-
(1S,3R)-3-((tert-butyldiphenylsilyl)
Leave this area blank for abstract info.
(
oxy)cyclopentyl)acetate from norbornene.
Buwen Huang, Jeff Elleraas, Jason Ewanicki, Scott C. Sutton*
norbornene
5
steps
R SiO
3
CO Me
2
R
4
1% yield
S
99% ee

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A short asymmetric synthesis of methyl 2-((1S,3R)-3-((tert-
butyldiphenylsilyl)oxy)cyclopentyl)acetate from norbornene.
a
a
a
a
Buwen Huang , Jeff Elleraas , Jason Ewanicki , Scott C. Sutton 
a
Oncology Chemistry, Pfizer Medicine Design, 10770 Science Center Drive, San Diego, California 92121, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Methyl 2-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)acetate has been synthesized from
norbornene using Hayashi’s (S)-MOP Pd-catalyzed asymmetric hydrosilation. On a 1 mole scale,
asymmetric hydrosilation of norbornene afforded an 84:16 exo- to endo-norborneol mixture but
with exclusive 1R,4S-stereochemistry at the bridgehead carbons. The norborneol mixture was
converted to an optically pure chiral bicyclic lactone via a high-yielding tandem oxidation /
Baeyer-Villiger reaction. Acid-promoted ring-opening of the lactone followed by immediate silyl
protection afforded the chiral cis-1,3-cyclopentane intermediate in five steps with an overall yield
of 41%.
Available online
Keywords:
Norbornene
Norcamphor
Exo-norborneol
©
2019 Published by Elsevier Ltd.
Asymmetric hydroboration
Asymmetric hydrosilation
cis-3-hydroxycyclopentylacetate
—
——

Corresponding author. Tel.: +1-858-622-3279; e-mail: scott.sutton@pfizer.com

2
Tetrahedron
1
9
1
. Introduction
of norbornene. Asymmetric hydrogenation of racemic ketone,
±)-norcamphor, gives a 12:88 mixture of exo-5 (95% ee) and
(
Although planar aromatic and planar heteroaromatic systems
20
endo-5 (13% ee). Enzymatic reduction of (±)-norcamphor was
examined in conjunction with a rhodium complex but failed to
scale reproducibly. Hence, a practical direction for our initial
work was to turn toward the more established asymmetric
will always have a place in medicinal chemistry, a trend toward
three-dimensional sp hybridized structures in therapeutic agents
has emerged. Chiral 1,3-disubstituted cyclopentanes are popular
core motifs in medicinal chemistry programs at Pfizer and are
important building blocks for carbocyclic nucleosides and
nucleotides. We recently needed decagram quantities of methyl 2-
3
21
1
22-28
29-33
hydroboration
and hydrosilation
methods.
[Place Scheme 2 here]
(
(1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)acetate 4 for
Scheme 2. General norbornene route to 4.
our discovery efforts. In general, access to enantiomerically pure
cis-3-hydroxy cyclopentyl acetates has been achieved using allylic
substitution chemistry.
Using Brown’s improved method,26 we reacted norbornene
with freshly prepared (-)-Ipc BH at -25 ⁰C for 48 hours followed
2
by a multi-step treatment to enrich the optical purity and to remove
the two isopinocampheyl groups by extractive work-up (Scheme
2
-12
This approach relies on enzymatic
1
3,14
desymmetrization
of meso-diacetate 3 to afford a chiral mono-
acetate which undergoes Pd-catalyzed allylic substitution by
sodium dimethyl malonate.2,5 Decarboxylation followed by
reduction of the cyclopentene double bond and silyl protection
leads to enantiomerically pure cis-3-hydroxy cyclopentyl acetates
such as 4. While evaluating the scalability of the allylic
substitution approach, we noted several drawbacks that inspired
the work described herein. The drawbacks stem primarily from the
long sequence (8 steps) and the challenging operational demands
of the first several steps of the synthesis. In the generation of 3
from dicyclopentadiene, there are two methods predominately
used (Scheme 1).15 One method involves photooxygenation of
cyclopentadiene using Bengal rose sensitization. This reaction
usually requires a stirred-tank glass reactor irradiated with halogen
or xenon lamp and has several safety concerns on large scale due
to the possible buildup of potentially explosive endoperoxide 2 and
polymeric peroxides. A safer method for large-scale work is to
transform cyclopentadiene into cyclopentene epoxide 1 using
peracetic acid in DCM. This is followed by Pd-catalyzed Sn2’ ring
opening of the allylic epoxide with acetate.15 Unfortunately, the
epoxidation / epoxide opening sequence suffers from a low yield
3). This procedure afforded
8 in 65% yield without
chromatography and with good chemical purity. Standard
hydrogen peroxide oxidation of 8 to exo-5 resulted in 50% yield
and a disappointing 85% ee as determined by chiral supercritical
fluid chromatography (SFC). Mohar and co-workers observed
2
similarly low optical purity in the (-)-Ipc BH hydroboration on a
3
4
related norbornene derivative. Like Mohar and co-workers, we
switched to hydrosilation of norbornene to obtain higher optical
purity.
[Place Scheme 3 here]
Scheme 3. Hydroboration with (-)-Ipc BH to prepare exo-5.
2
Reagents and conditions: (i) (-)-Icp2BH, -25 ⁰C, 48 h; (ii) PhCHO, 0 ⁰C; (iii)
NaOH, MeOH; (iv) 6N HCl; (v) 1,3-propanediol, pentane, (65% for 5 steps);
2 2
(vi) NaOH, H O , 55 ⁰C, 50%.
Following Hayashi and co-workers’ Pd-catalyzed asymmetric
hydrosilation reaction, we treated norbornene with trichlorosilane,
.01 mol% allylpalladium(II) chloride dimer, and 0.04 mol% (S)-
-)-2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl [(S)-MOP]
at 0 ⁰C using the trichlorosilane / norbornene mixture as both
(56% for 2 steps). In addition, both methods require cracking
0
(
dicyclopentadiene at high temperature and storage of
cyclopentadiene at dry ice temperature to avoid re-
1
6,17
dimerization.
Overall, the allylic substitution route to 4 has
3
5
reactant and solvent (Scheme 4). The trichlorosilane product was
purified via vacuum distillation to afford 9 in 82% yield as a
multiple transition metal catalyzed reactions and one enzymatic
step. We sought to streamline the synthesis of 4 by applying the
Baeyer-Villiger reaction to (-)-norcamphor 6 followed by lactone
ring-opening. This approach takes advantage of the inherent cis-
bicyclic stereochemistry of norbornene to set the cis-5-ring
stereocenters (Scheme 2).
colorless oil. Oxidation of 9 using H
2 2
O in the presence of a large
excess of KF and KHCO afforded 5 in 84% yield. Careful analysis
3
of 5 showed the low melting solid to be an 84:16 mixture of exo to
endo isomers based on chiral SFC peak area and 2D NMR analysis
of the separated (R)-mandelic esters (vide infra). Interestingly,
Hayashi and co-workers reported 93% ee for the same reaction but
did not report observing the endo isomer. We were initially
puzzled as to the exact structure of the minor isomer. To determine
the absolute stereochemistry of exo-5 and elucidate the structure
of the minor isomer, we derivatized the alcohol mixture as
diastereomeric esters. In this regard, we noted that Whitesell and
Reynolds used diastereomeric mandelic esters to resolve a variety
of chiral alcohols. In particular, they demonstrated that exo-
norborneol mandelic ester provided a crystalline solid with a
[Place Scheme 1 here]
Scheme 1. Allylic substitution routes to 4.2-15
Reagents and conditions: (i) 160 ⁰C, distill; (iia) MeCO
Cl , 0 °C, 1.5 h, r.t., 3 h; (iiia) 5 mol% Pd(PPh , Ac O, THF, 0 °C, 30
min, 56% (for two steps); (iib) h, O , cat. Bengal rose, MeOH, –35 °C, 6 h,
r.t., 12 h, 65%; (iiib) thiourea, MeOH; then DCM, Et N, CH C(O)Cl, 97%; (iv)
Novozym-435, 95% yield, 99% ee; (v) sodium dimethyl malonate, THF, cat.
Pd(OAc) , cat. Pd(PPh , 50 ⁰C, 86%; (vii) H , 5% Rh on Al , MeOH, 12 h,
rt; (viii) TBDPSCl, DCM, imidazole, 25 °C, 16 h.
3 2 3
H, Na CO ,
CH
2
2
3
)
4
2
2
3
3
2
3
)
4
2
2 3
O
3
6
melting point of 75 ⁰C. This information enabled us to quickly
achieve a convenient separation of our gum-like alcohol mixture
and, more importantly, provide a crystalline solid suitable for X-
ray determination of absolute stereochemistry. Following the
2
. Results and discussion
We began by considering existing methods to prepare 5, 6 or 7
3
7
procedure of Weng and co-workers, the mixture exo-5 and endo-
5 was heated in toluene (80 ⁰C) in the presence of (R)-mandelic
acid and 10% salicylaldehyde as catalyst (Scheme 5).
suitable for decagram synthesis in high optical purity. Access to
via enzymatic resolution of racemic exo-norborneol has been
5
[Place Scheme 4 here]
1
8
accomplished, but with modest ee. Use of Baeyer–Villiger
monooxygenases (BVMOs) for conversion of racemic
norcamphor to the desired chiral lactone could become a very
efficient method. However, published work using BVMOs is
reported to give moderate regio and enantioselectivity in the case
Scheme 4. Asymmetric hydrosilation to prepare exo-/endo-5.

3
Reagents and conditions: (i) Cl
mol% Pd(OAc) , 64 h, distill, 82%; (ii) KF, KHCO
THF/MeOH, 84%.
3
SiH, 0 ⁰C, 0.04 mol% (S)-MOP, 0.01
refluxing MeOH to afford the ring-opened ester which was
2
3
, H , 0 - 25 ⁰C,
2
O
2
immediately protected as a silyl ether to provide 4 in 65% yield
and 99% ee after chromatography to remove an impurity derived
from lactone 7b.
The major ester from this resolution was separated via
crystallization to provide exo-10 as a single diastereomer in 26%
yield leaving behind mother liquor containing a 60:40 exo-10 to
endo-10 mixture. The absolute stereochemistry of exo-10 was
confirmed by single-crystal X-ray diffraction (Supplementary
Information) and agreed with Hayashi’s assignment. From the
mother liquor, endo-10 was isolated using chiral SFC and the
purified ester (99% ee) was confirmed to have the endo relative
stereochemistry by 2D NMR (Supplementary Information).
Hydrolysis of pure endo-10 back to endo-5 afforded pure endo-5
[Place Scheme 6 here]
Scheme 6. Synthesis of 4 from 5.
Reagents and conditions: (i) mCPBA, 5 mol% 2,4-dimethyl-2,4-pentanediol
cyclic Cr(VI) ester, DCM, 0 – 25 ⁰C, 18 h, 91%; (ii) HCl, MeOH, reflux, 5 h;
(iii) TBDPSCl, DCM, imidazole, 25 ⁰C, 16 h, 65% for 2 steps, 99% ee.
3
. Conclusion
In summary, 4 was prepared in five synthetic steps from
norbornene with an overall yield of 41% and in high optical purity.
The key step is Hayashi’s Pd-catalyzed asymmetric hydrosilation
reaction which sets three chiral centers in one reaction with
remarkable selectivity and with 84:16 exo/endo dr. Because the
endo diastereomer is inconsequential to our synthesis, we oxidized
the 5-exo/endo mixture to chiral lactone 7 using a telescoped
alcohol oxidation / Baeyer-Villiger procedure. Lactone ring
opening is followed by silyl protection to avoid potential
intramolecular cyclization back to the lactone upon storage.
Formation of the (R)-mandelic esters of exo-5 and endo-5 helped
elucidate the stereochemistry of the alcohol mixture derived from
the Pd-catalyzed asymmetric hydrosilation reaction by affording a
crystalline intermediate, exo-10. X-ray crystallography of exo-10
confirmed Hayashi’s original assignment of the absolute
stereochemistry of exo-5. Surprisingly, this is only the second
literature report for synthesis of the secondary alcohol from which
2
2
having []
D 3
−3.4 (c 0.9, CHCl ) consistent with the negative
2
2
optical rotation reported for (S)-(-)-endo-norborneol []
D
3
8
−
1.89. Taken together, these data demonstrated that (a) endo-5
has (S)-stereochemistry at the newly created alcohol chiral center,
b) that the (S)-MOP hydrosilation gives excellent selectivity with
(
respect to the enantiotopic termini of the norbornene double bond
giving exclusively (1R,4S)-stereochemistry at the bridgehead
carbons of both exo-5 and endo-5 and (c) that the (S)-MOP
hydrosilation gives imperfect selectivity with respect to the face of
the double bond. These results, supported by chiral SFC, 2D NMR,
optical rotation and X-ray evidence, represent an important
amendment to Hayashi’s original work on norbornene which
reported 93% ee for exo-5. The difference in stereochemical
purity (dr = 84:16 versus 93% ee) could be a consequence of the
larger scale (1 mole) of our current work, error in Hayashi’s chiral
1
35
shift H NMR method, or a combination of both.
4
1
[Place Scheme 5 here]
4 is derived. Because 4 is a valuable building block for a number
of applications and is not available from commercial vendors, this
work provides an expedient and inexpensive option for access to
chiral cis-1,3-disubstituted cyclopentane targets on a preparative
Scheme 5. Resolution of exo/endo diastereomers.
Reagents and conditions: (i) (R)-mandelic acid, 10 mol% salicylaldehyde,
toluene, 80 ⁰C, 4 days, 26% of exo-10 as a single diastereomer via
crystallization.
3
scale. As the trend toward chiral, sp -rich cyclic structures in
therapeutic agents increases, methods such as this become
increasingly important.
In our case, formation of the 5-exo/endo mixture is
inconsequential to our yield since the alcohol chiral centers are
subsequently removed during oxidation to the ketone. Direct
conversion of the 5-exo/endo mixture to lactone 7 was
accomplished using a tandem alcohol oxidation and Baeyer-
Villiger reaction developed by Morin-Fox and Lipton (Scheme
Acknowledgments
We gratefully acknowledge Alex Yanovsky and Curtis Moore
for providing the X-ray structure of exo-10. We appreciatively
acknowledge Pfizer management for supporting this work.
). A catalytic amount of Corey’s cyclic chromate ester40 in
3
9
6
combination with mCPBA affords a 92 : 8 mixture of lactones 7a
and 7b in 92% yield. The lactone mixture is treated with HCl in
7
8
.
.
Nicolaou, K. C.; Heretsch, P.; ElMarrouni, A.; Hale, C. R.
H.; Pulukuri, K. K.; Kudva, A. K.; Narayan, V.; Prabhu, K.
S. Angew. Chem. Int. Ed. 2014, 53, 10443-10447.
Nicolaou, K. C.; Pulukuri, K. K.; Yu, R.; Rigol, S.;
Heretsch, P.; Grove, C. I.; Hale, C. R. H.; El Marrouni, A.
Chem. Eur. J. 2016, 22, 8559-8570.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
9
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Declaration of interests
The authors declare that they have no known
☒
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐
The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests: