Synthesis of Chiral Cyclic Alcohols from Chiral Epoxides by H or N Substitution with Frontside Displacement

Article abstract of DOI:10.1021/acs.orglett.8b02822

Diverse examples are provided of enantioselective sequences for the transformation of cycloalkenes to either chiral trans-β-substituted cycloalkanols or chiral α-amino ketones.

Full text of DOI:10.1021/acs.orglett.8b02822

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Chiral Cyclic Alcohols from Chiral Epoxides by H or N
Substitution with Frontside Displacement
Roberto da Silva Gomes, Karla Mahender Reddy, and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
ABSTRACT: Diverse examples are provided of enantioselective sequences for the transformation of cycloalkenes to either
chiral trans-β-substituted cycloalkanols or chiral α-amino ketones.
Scheme 2. Diastereoselective Reduction of a Chiral Epoxide
with Retention of Configuration
e have recently reported an unusual example of epoxide
Wring-opening displacement with retention of config-
uration.1 This process was discovered in connection with work
on the enantioselective synthesis of the potentially important
antidepressant (2R,6R)-hydroxynorketamine. Specifically, it
was found that the reaction of epoxide 1 with the reagent
2
Ti(O-i-Pr)2(N3)2 in benzene gave the azido alcohol 3,
presumably via the intermediate carbocation 2 with a cis-
internal transfer of an azido unit from titanium to carbon
(Scheme 1).
Scheme 1. Epoxide Ring Opening with Retention
phenylcyclohexene oxide (ent-4) and BH3·THF in CH2Cl2 at
23 °C in 85% yield and 86% ee.
Using the same method, the chiral trans-2-substituted
cycloalkanols shown in Scheme 3 were prepared in the
indicated yield and enantiopurity. The ee values of the starting
epoxides are shown in parentheses.
The epoxides precursors of 5, 8, 9, 10, and 11 were prepared
by modified Jacobsen epoxidation1,3 of the corresponding
olefins. The epoxide precursor of 12 was synthesized by
epoxidation using Shi’s chiral dioxirane.4
The reaction of epoxide 1 with BH3·THF in CH2Cl2
requires additional discussion. Starting with epoxide of 90%
ee, the product was a 99:1 mixture of the expected trans
alcohol 13 (77% ee) and cis alcohol 14 (Scheme 4). We
believe that the reduced ee observed for the major product is
due to the competing pathway outlined in Scheme 5, in which
the racemic ketone 16 is generated from intermediate 15 by
proton loss. This interpretation finds support from the fact that
the reaction of ( )-16 with BH3·THF affords ( )-13 and
( )-14 in a ratio of 90:10 as shown in Scheme 5.
In this paper, we report further studies in this area, including
the extension to reductive cleavage with internal delivery of
hydrogen to carbon and the demonstration of internal delivery
of N3 as a useful general process for the synthesis of chiral
cyclic α-amino ketones as well as cyclic cis-vicinal amino
alcohols.
(S,S)-1-Phenylcyclohexene oxide (4)3 was selected for initial
studies of reductive epoxide cleavage. Reaction of 4 (92% ee)
with 1.5 equiv of BH3·THF in CH2Cl2 at rt for 2 h led to
complete reaction and clean formation of trans-(1S,2R)-2-
phenylcyclohexanol 5 of 86% ee in 85% yield. None of the cis-
diastereomer could be detected by TLC analysis. It seems
likely that this reaction proceeds via the carbocationic
intermediate 6 shown in Scheme 2, with internal cis-transfer
of hydrogen from boron to carbon. It is also likely that the
small loss of enantiopurity in the reduction of 4 to 5 is due to a
minor side reaction involving 1,2-hydrogen migration in 6 to
form the ketone 7, which then undergoes reduction to give ent-
5 (vide infra). ent-5 was readily prepared from (R,R)-1-
The above explanation for the diminished enantioselection
in the BH3·THF reduction of epoxide 1 to the trans alcohol 13
Received: September 4, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b02822
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The use of catechol borane for epoxide cleavage clearly is
advantageous for the other substrates which contain functional
groups that are reactive toward BH3·THF. For example, the
acetylenic epoxide 19 affords the trans alcohol 20 in only 10%
yield due to competing addition of BH3·THF to CC.
However, the reaction of epoxide 19 with catechol borane
produces the trans alcohol 20 in 82% yield and with high
position and enantioselectivity as shown in Scheme 7.
Scheme 3. Reductive Cleavage of Epoxides with Frontside
Displacement
Scheme 7. Selective Reduction of Acetylenic Epoxide Using
Catechol Borane
Scheme 4. Competing Racemization
We have also explored the synthesis of chiral cis-β-azido
alcohol from chiral epoxides as exemplified by the initial
findings summarized in Scheme 1 above. This type of process
could be very useful as a route to chiral cyclic cis-β-amino
alcohols and chiral α-amino ketones.
One example is the enantioselective synthesis of the
potential antidepressant benzo-(S)-norketamine (24), which
has been synthesized as outlined in Scheme 8. Structural
relatives of ketamine are currently of great interest for
application to treatment resistant depression and ketamine
itself has just been submitted for FDA approval.
Scheme 5. Possible Pathway for Racemization in the
Transformation of 1 to 13
Scheme 8. Simple Enantioselective Synthesis of Benzo-(S)-
norketamine
suggested that the use of catechol borane in place of BH3 for
this reduction might result in higher enantioselectivity by the
pathway shown in Scheme 6. It was anticipated that the
Scheme 6. Improvement in the Enantioselectivity of
Reduction of 1 Using Catechol Borane
The epoxide 22 underwent clean conversion as shown in
Scheme 8 to the chiral α-azido ketone 23 which by reduction
gave benzo-(S)-norketamine 24. The same sequence was
employed for the synthesis of the enantiomer of 24, benzo-
(R)- norketamine (25). The recent discovery that the relief of
depression by ketamines linked to the blocking of firing by
neurons in the lateral habenula has provided increased
incentive for the study of α-amino cyclic ketones such as 24
hydride transfer from boron to the cationic carbon of 18 would
be accelerated relative to ketone formation by 1,2 hydrogen
migration in 18. The fact that the trans alcohol 13 was
produced from 1 with much improved enantioselectivity
relative to the reaction using BH3·THF supports our
conjecture that the three oxygens attached to boron in 17
substantially increase the rate of B → C hydride transfer.
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DOI: 10.1021/acs.orglett.8b02822
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and 255 because there is now a straightforward in vivo method
for screening to find superior antidepressants.
ORCID
Roberto da Silva Gomes: 0000-0002-8075-9716
Karla Mahender Reddy: 0000-0002-9601-2967
E. J. Corey: 0000-0002-1196-7896
Notes
Three additional examples of the application of the
stereoretention O → N displacement route to chiral azido or
amino ketones are shown in Scheme 9, and the ketamine
analogues 24, 25, 28, 30, 33, and 36 are now available for
neuroscience research.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to Pfizer, Inc., and Bristol-Myers Squibb for
research grants.
■
Scheme 9. Synthesis of Other Chiral Cyclic α-Amino
Ketones
REFERENCES
■
(1) Han, Y.; Mahender Reddy, K.; Corey, E. J. Org. Lett. 2017, 19,
5224−5227.
(2) Choukroun, R.; Gervais, D. J. Chem. Soc., Dalton Trans. 1980,
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(3) Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378−
4380.
(4) Wang, Z.-X.; Shu, L.; Frohn, M.; Tu, Y.; Shi, Y. Org. Synth. 2003,
80, 9−17.
(5) Yang, Y.; Cui, Y.; Sang, K.; Dong, Y.; Ni, Z.; Ma, S.; Hu, H.
Nature 2018, 554, 317−322.
(6) (a) Babu Mereyala, H.; Frei, B. Helv. Chim. Acta 1986, 69, 415−
418. (b) Benedetti, F.; Berti, F.; Norbedo, S. Tetrahedron Lett. 1998,
39, 7971−7974. (c) Prince, M. I.; Weiss, K. J. Organomet. Chem.
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1968, 12, 37−47. (e) Aureggi, V.; Sedelmeier, G. Angew. Chem., Int.
Ed. 2007, 46, 8440−8444.
(7) To a rapidly stirred solution of 4 (100.0 mg, 0.57 mmol) in
CH2Cl2 (10 mL) at 0 °C was slowly added 1 M of BH3 in THF (0.9
mL, 0.86 mmol). The reaction mixture was warmed to rt and
vigorously stirred for 2 h, and after completion of the reaction as
judged by TLC, the reaction mixture was treated with a solution of
sodium potassium tartrate. The phases were separated, and the
aqueous phase was further extracted with CH2Cl2 (2 × 50 mL). The
combined organic extract was washed with brine (20 mL) and dried
over Na2SO4, filtered, and concentrated in vacuo. The crude residue
was purified by column chromatography (SiO2, hexanes/ethyl acetate
8:2) to afford the compound 5 (83 mg, 83% yield, 86% ee) as a white
solid, mp 65−67 °C, [α]D23 = +22.2 (c = 0.98, CHCl3), HPLC
(Chiralcel OD-H, 0.46 cm × 25 cm, hexane/iPrOH 99:1, 0.5 mL/
min, 220 nm): minor: 3.14 min; major: 3.40 min. Harada, S.;
Kuwano, S.; Yamaoka, Y.; Yamada, K.-I.; Takasu, K. Angew. Chem.
2013, 125, 10417−10420.
(8) To a suspension of NaN3 (500 mg, 7.78 mmol) in 15 mL of
CH2Cl2 was added i-Bu2AlCl (0.72 mL, 3.89 mmol) at 0 °C. The
resulting mixture was warmed to 25 °C and stirred for 12 h, after
which a 50 mL CH2Cl2 solution of 31 (400 mg, 2.59 mmol) was
added at 0 °C. After the substrate was consumed as judged by TLC,
saturated aqueous NaHCO3 (2 mL) was added, and the mixture was
filtered through a Celite pad which was washed with CH2Cl2 (2 × 50
mL). The filtrate was separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 50 mL). The combined organic phase was washed
with brine (10 mL), dried over Na2SO4, filtered, and concentrated in
vacuo to give the cis azido alcohol (372 mg, 93% yield). A solution of
the above azido alcohol in CH2Cl2 was treated with NaHCO3 (230
mg, 2.59 mmol) and Dess−Martin periodinane (1.10 g, 2.59 mmol).
After the substrate was consumed as judged by TLC, saturated
aqueous Na2SO3 (10 mL) was added, and the mixture was separated.
Then the aqueous phase was extracted with CH2Cl2 (3 × 20 mL), and
the combined organic phase was washed with brine (10 mL), dried
over Na2SO4, filtered, and concentrated in vacuo. Purification by
column chromatography (SiO2, hexanes/dichloromethane 4:1)
afforded the azido ketone 32 (218 mg, 95% yield) as a colorless oil.
To a solution of the azido ketone 32 (100 mg, 0.46 mmol) in 15 mL
of THF−H2O (4:1) was added a 1 M solution of Me3P in THF (0.46
mL, 0.46 mmol) at 0 °C. The resulting mixture was warmed to rt and
It should be mentioned that there are previous reports of the
use of alkyl aluminum azides for the epoxide → azido alcohol
conversion.6
Representative procedures for the diastereoselective epoxide
cleavages leading to chiral trans-2-substituted cycloalkanols or
chiral α-amino ketones are provided below for the convenience
of the reader.7,8
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02822.
Experimental procedures and characterization data for
novel reactions and products including copies of 1H- and
13C NMR spectra and chiral HPLC traces (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: corey@chemistry.harvard.edu.
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DOI: 10.1021/acs.orglett.8b02822
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stirred for 4 h. The mixture was washed with water, and the aqueous
layer was extracted with ethyl acetate (3 × 15 mL). The combined
organic phase was washed with brine (5 mL), dried over Na2SO4,
filtered, and concentrated in vacuo. Purification by column
chromatography (SiO2, hexanes/ethyl acetate 9:1) afforded the α-
amino ketone 33 (92 mg, 92% yield, 92% ee) as a colorless oil, [α]D23
=
−56.2 (c = 0.98, CHCl3), HPLC (Chiralcel OD-H, 0.46 cm × 25 cm,
hexane/iPrOH 99:1, 0.5 mL/min, 220 nm): minor: 5.61 min; major:
8.01 min, (ref 1).
D
DOI: 10.1021/acs.orglett.8b02822
Org. Lett. XXXX, XXX, XXX−XXX