Synthesis of enantioenriched tertiary boronic esters from secondary allylic carbamates. Application to the synthesis of C30 botryococcene

Article abstract of DOI:10.1021/ja303022d

Enantioenriched secondary allylic carbamates have been deprotonated with sBuLi and reacted with boronic esters. In contrast to other electrophiles, high α-selectivity was observed and the boronate complexes were formed with almost complete retention of stereochemistry. The boronate complexes underwent a stereospecific 1,2-migration leading to tertiary allylic boronic esters with high er (>98:2). The scope of the reaction has been explored and found to embrace a broad range of both allylic carbamates and boronic esters. The methodology has been applied to an eight-step, stereoselective synthesis of each of the diastereoisomers of C30 botryococcene.

Full text of DOI:10.1021/ja303022d

Article
pubs.acs.org/JACS
Synthesis of Enantioenriched Tertiary Boronic Esters from Secondary
Allylic Carbamates. Application to the Synthesis of C30
Botryococcene
Alexander P. Pulis and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, United Kingdom
S
* Supporting Information
ABSTRACT: Enantioenriched secondary allylic carbamates have been
deprotonated with sBuLi and reacted with boronic esters. In contrast to
other electrophiles, high α-selectivity was observed and the boronate
complexes were formed with almost complete retention of stereochemistry.
The boronate complexes underwent a stereospecific 1,2-migration leading to
tertiary allylic boronic esters with high er (>98:2). The scope of the reaction
has been explored and found to embrace a broad range of both allylic
carbamates and boronic esters. The methodology has been applied to an eight-step, stereoselective synthesis of each of the
diastereoisomers of C30 botryococcene.
Scheme 2. Reactions of Lithiated Allylic Carbamates
INTRODUCTION
■
Enantioenriched tertiary boronic esters are useful synthetic
intermediates in the creation of compounds bearing fully
substituted carbon atoms, e.g. tertiary alcohols, C-tertiary
amines, and quaternary centers.1 They have been prepared in
good to high enantioselectivity2 by β-borylation of Michael
acceptors3 and allylic carbonates4 (Scheme 1). Alternatively, we
reported the lithiation−borylation of benzylic carbamates, a
method capable of delivering tertiary boronic ester with >99:1
er (Scheme 1).5
Scheme 1. Enantioselective Routes to Tertiary Boronic
Esters
methyl chloroformate,7b MeOD (see Supporting Informa-
tion)]. Reactions with aldehydes are different and generally
lead to γ-addition products through a Zimmerman−Traxler
transition state structure.8 Despite this unpromising precedent,
we pursued our studies and now report that lithiated secondary
allylic carbamates react with boronic esters with uniquely high
α-selectivity and with very high retention of stereochemistry
(Scheme 2).
However, while such methodology shows broad substrate
scope in terms of both the boronic ester (primary/secondary
alkyl, aryl, heteroaryl) and the carbamate, it is nevertheless
limited to benzylic carbamates. The aryl group is essential as it
acidifies the benzylic position, thereby enabling deprotonation;
carbamates derived from secondary dialkyl alcohols are not
sufficiently acidic and so cannot be employed.6 In order to
extend this useful methodology to all-alkyl substrates, we
considered the possibility of employing secondary allylic
carbamates, e.g. 1a, as Hoppe had shown that they could be
readily deprotonated and trapped by electrophiles (Scheme 2).7
However, the regioselectivity of trapping was a major concern,
as Hoppe had found that mixtures of α and γ products were
invariably formed with most electrophiles [e.g., Me3SnCl,7a
RESULTS AND DISCUSSION
■
As a starting point for our studies, we chose carbamate 1a
bearing Me groups at both α and γ positions in order to
determine the inherent regioselectivity of the system,
Received: March 30, 2012
Published: April 23, 2012
© 2012 American Chemical Society
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unencumbered by steric bias. The carbamate was conveniently
prepared on a large scale by enzymatic resolution9 of the allylic
alcohol10 followed by carbamoylation. Lithiation of 1a with
sBuLi in the presence of TMEDA in Et2O for 15 min at −78 °C
followed by addition of nBuB(pin) (2a), with subsequent
warming to ambient temperature, led to the tertiary boronic
ester 3aa in 91% yield11 or to alcohol 4aa after direct oxidation
in 75% yield and 98:2 er (Table 1, entry 1). None of the γ-
addition products 5aa/6a were detected.12
Table 1. Scope and Limitations of Lithiation−Borylation−
Oxidation of Secondary Allylic Carbamates
Reaction of Li-1a with triethyl borane was also explored but
led to a complex mixture of products, perhaps arising from α-
and γ-addition products and with variable levels of stereo-
control. In addition, the allyl boranes derived from α-addition
would be prone to 1,3-borotropic shifts. As a result of these
observations we focused on reactions with boronic esters.
The lithiation−borylation reaction was extended to a diverse
range of boronic esters including primary alkyl (entry 2),
secondary alkyl (entry 3), allyl (entry 4), phenyl (entry 5), and
vinyl (entry 6), leading to the tertiary alcohols in very high er in
all cases. In the cases of the allyl and Ph boronic esters, a small
amount of the γ-addition product was observed (<10%).13
Using the hindered secondary alkyl boronic ester we observed
slight erosion in er under standard conditions (95:5 er
observed). In previous work with benzylic carbamates we also
found that a similar erosion in er was observed with hindered
boronic esters,5b which was ascribed to reversibility in
formation of the boronate complex followed by subsequent
racemization of the configurationally unstable lithiated
carbamate at elevated temperature (>−70 °C)14 and readdition.
In such cases, reversibility was minimized and racemization was
arrested by the addition of MgBr2/MeOH. Application of these
conditions to the hindered secondary alkyl boronic ester
restored the very high levels of er observed with other
substrates (entry 3).15
The unusually high regioselectivity observed in the
borylation reaction was investigated by varying the steric
hindrance at both the α- and γ-positions. As expected, changing
the methyl substituent for iPr at the γ-position (1b) reinforced
the high regioselectivity for borylation at the α-position (entries
6, 7). However, as we increased the steric demand at the α-
position, γ-addition products began to be observed. While the
ethyl substituted carbamate 1c behaved in the same way as the
methyl substituted carbamate (entry 8), when the steric bulk of
the α-substituent was increased to iBu (1d) {resulting in a
substantial difference between the two ends [iBu (R2) vs Me
(R)]} a more equal distribution of products was obtained
(entry 9). Alkyl substitution at the β-position was tolerated and
again led to high regio- and stereoselectivity in the lithiation−
borylation reaction (entry 10), although best results were
obtained using the MgBr2/MeOH additive. The related
cyclohexenyl lithiated carbamate 1f gave a lower er due to its
lower configurational stability.16 The Z-allylic carbamate 1g
gave mostly the γ-addition product (with a high er) together
with E-allylic alcohol 4ab.17 As reported by Hoppe, and as
observed by us, γ,γ-disubstituted allyl carbamate 1h could not
be deprotonated cleanly.7c
a
Determined on parent allylic alcohol prior to carbamoylation.
b
Reactions performed on 1 mmol scale; isolated yield; er determined
c
by chiral GC or HPLC. None detected by 1H NMR or GCMS of the
crude reaction mixture. 1 M MgBr2 in MeOH used. Without MgBr2/
MeOH, gave 95:5 er. 76:24 er. 50:50 er. Without MgBr2/MeOH,
d
e
f
g
h
i
gave 90:10 er. 2 h migration time to avoid 1,3-borotropic shift of 3bf.
j
k
Without MgBr2/MeOH, gave 96:4 er. Without MgBr2/MeOH, gave
l
m
n
89:11 er. Lithiation time = 15 min. Lithiation time = 60 min. 95:5
er. 30% lithiation/dueteration after 5 h, −78 °C, side products
dominate. cHex = cyclohexyl.
o
Having developed the methodology we sought to apply it in
the synthesis of C30 botryococcene, an unusual triterpenoid
natural product from the microalgae Botryococcus braunii.18
Botryococcene biosynthesis is thought to resemble that of
squalene, originating from a common intermediate, presqualene
diphosphate (PSPP).19 Reductive rearrangement of the cyclo-
propane present in PSPP leads to either squalane or
We believe that the origins of both the high α-regioselectivity
and high enantioselectivity (with retention) are intimately
related. Precoordination of the oxygen of the boronic ester to
the metal of the lithiated carbamate will deliver the boron
reagent on the same side and at the same site as the metal
(Scheme 2).
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Scheme 3. Synthesis of Botryococcene and 10-epi-Botryococcene
botryococcene. Unlike other eukaryotes, the algae B. braunii
evolved separate squalene synthases for specialized triterpene
oil production more than 500 million years ago. This organism
is of considerable contemporary attention because (i) it is
considered an ancient algal species which contributed to the
existing oil and coal shale deposits found on Earth and (ii) the
hydrocarbon oils are being considered as potential renewable
petrochemicals and biofuels.18b Such fuels are in fact currently
being tested by the US Navy.20
addition of iodine to the intermediate ate complex formed from
the addition of vinyl lithium to boronic ester 15 led to a
complex mixture. Model studies on tertiary allylic boronic ester
3aa revealed that the ate complex reacted in a fashion akin to an
allylic metal species with iodine giving an allyl iodide (Scheme
4, pathway A) rather than as an electron rich alkene attached to
Scheme 4. Attempted Zweifel Olefination
The synthesis of C30 botryococcene is especially challenging
as it is devoid of functional group handles that might be used to
assemble smaller building blocks, and because it contains distal
tertiary alkyl and quaternary stereogenic centers (at C10 and
C13). Only one asymmetric synthesis has been reported to date
which was by Maxwell who was only able to synthesize a 1:1
mixture of diastereoisomers of 7 [without control of the
difficult stereochemistry at C10 (quaternary center)]. His
synthesis was completed in eight steps from (S)-3-hydroxy-2-
methylpropionic acid methyl ester.21 We believed that the
triterpenoid could be assembled in short order and with greater
precision of stereocontrol using our lithiation−borylation
methodology.
boron (pathway B). We reasoned that a nucleophilic 2-carbon
building block was required to add to the tertiary boronic ester
which was already predisposed for 1,2-migration without
further activation and so considered the use of lithiated
oxirane. The reaction of lithiated substituted epoxides with
boronic esters has been reported, and while 1,2-migration
occurred easily,27 elimination only occurred when an anion-
stabilizing group was attached to the boronic ester.28
After some experimentation we were ultimately able to effect
a novel olefination reaction. Lithiated oxirane was generated
from the corresponding stannane29 and trapped in situ with
boronic ester 15. The ate complex formed underwent a 1,2-
migration to give β-alkoxy boronic ester 16. Elimination was
effected under mild conditions by addition of the Ghosez
reagent 1730 and heating.31 This gave C30 botryococcene in
just eight steps from geranyl chloride in >99:1 er and 94:6 dr.
The power of the methodology is further illustrated by the
synthesis of 10-epi-C30 botryococcene bearing the opposite
configuration at the difficult quaternary center. Simply using the
enantiomeric catalyst in the reduction of enone 11 and
subsequent carbamoylation gave the allylic carbamate 19 with
the same er and dr, indicative of a high level of reagent control
without interference from the substrate. The remaining steps
were completed as before. The two diastereoisomers of C30
Our synthesis began with the reaction of geranyl magnesium
chloride22 with bromomethylB(pin) which gave
homogeranylB(pin) 8 (Scheme 3). In the first key step,
asymmetric deprotonation of ethyl carbamate mediated by
(−)-sparteine,23 followed by addition of 8, furnished secondary
boronic ester 9 in 89% yield and 97:3 er (control of C13).
Homologation with dichloromethyllithium,24 followed by
oxidative workup, led to aldehyde 10, and subsequent
Horner−Wadsworth−Emmons olefination gave enone 11.
Asymmetric hydrogenation of 11 using Noyori’s ruthenium-
diphosphine catalyst 1210c gave allylic alcohol 13 with 96:4 dr
and >99:1 er. In the second key step, lithiation−borylation of
carbamate 14 with homogeranylB(pin) 8 gave tertiary boronic
ester 15 in 91% yield and 94:6 dr (control of C10), indicative of
a highly stereoselective transformation.
All that remained was Zweifel olefination25 of the tertiary
boronic ester, a reaction that we had successfully reported with
tertiary aryldialkyl and diarylalkyl boronic esters.26 However
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1
Int. Ed. Engl. 1990, 29, 296. (c) Hoppe, D. Angew. Chem., Int. Ed. Engl.
1984, 23, 932.
(8) Reactions of lithiated carbamate 1a or its titanium analogue with
botryococcene had very similar H NMR spectra, but distinct
signals were evident in their 13C NMR spectra. It is interesting
to note that all but one of the C−C bond forming steps were
mediated by a 1,2-metelate rearrangement of a boron ate
complex.
aldehydes gave the γ-addition products. (a) Hoppe, D.; Hanko, R.;
Bronneke, A.; Lichtenberg, F.; Hulsen, E. v. Chem. Ber. 1985, 118,
̈
̈
2822. (b) Hoppe, D; Zschage, O. Angew. Chem., Int. Ed. Engl. 1989, 28,
69. It should be noted that there is no information on the initial
selectivity of the transmetalation step from lithium to titanium as allyl
titaniums are known to rapidly equilibrate, with the equilibrium lying
on the side of the thermodynamically more stable product (α-
substituted titanium carbamate). See: (c) Katsatkin, A.; Nakagawa, T.;
Okamoto, S.; Sato, F. J. Am. Chem. Soc. 1995, 117, 3881. (d) Katsatkin,
A.; Sato, F. Angew. Chem., Int. Ed. Engl. 1996, 35, 2848. For reviews
CONCLUSION
■
In this paper we have described efficient methodology that
furnishes tertiary allylic boronic esters with high yields and
excellent enantioselectivity from readily available secondary
allylic alcohols. Unlike other electrophiles, the reaction of
lithiated-allylic carbamates with boronic esters is highly α-
selective. The tertiary allylic boronic esters provide access to
tertiary allylic alcohols32 and thus all-alkyl substituted
quaternary stereocenters with predictably high enantiopurity.
This method is particularly useful as it does not rely upon a
steric bias between the substituents at the stereogenic carbon.
The methodology has been exemplified in a short highly
stereoselective synthesis of C30 botryococcene which includes
a new reaction for the vinylation of boronic esters. The broad
range of functional groups that the boron atom can be
potentially converted into, and the breadth of well established
chemistry for manipulation of the double bond (from the allylic
carbamate), adds considerably to this new asymmetric
methodology.
see: Reference 7c and (e) Hoppe, D.; Kramer, T.; Schwark, J.-R.;
̈
Zschage, O. Pure Appl. Chem. 1990, 62, 1999. (f) Zschage, O.;
Schwark, J.-R.; Kramer, T.; Hoppe, D. Tetrahedron 1992, 48, 8377.
̈
(9) Kadnikova, E. N.; Thakor, V. A. Tetrahedron: Asymmetry 2008,
19, 1053.
(10) Asymmetric routes to allylic alcohols have been reported by a
variety of methods. For selected examples and reviews of: (a)
Dynamic kinetic resolution: Gais, H.-J. Catalytic Asymmetric
Synthesis of Allylic Alcohols via Dynamic Kinetic Resolution.
Asymmetric Synthesis - The Essentials; Christmann, M., Brase, S. ,
̈
Eds.; Wiley-VCH: Weinheim, 2006; pp 84−89. (b) Nucleophilic
addition to aldehydes: Kauffman, M. C.; Walsh, P. J. Arylation and
alkenylation of carbonyl and imino groups. Science of Synthesis,
Stereoselective Synthesis; De Vries, J. G., Molander, G. A., Evans, P. A.,
Eds.; Georg Thieme Verlag: Stuttgart, 2011; Vol. 2, pp 449−495. (c)
Asymmetric reduction: Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham,
T.; Kozawa, M.; Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.;
ASSOCIATED CONTENT
* Supporting Information
■
S
Noyori, R. J. Am. Chem. Soc. 1998, 120, 13529. (d)
Sharpless
Experimental procedures and analytical data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
epoxidation resolution: Johnson, R. A.; Sharpless, K. B. Catalytic
Asymmetric Epoxidation of Allylic Alcohols. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp
231−280.
(11) Tertiary pinacol boronic esters isolated in this paper (and in ref
5, as well as primary and secondary pinacol boronic ester reagents used
here) are stable at room temperature, stored under air in a closed
container for over 12 months.
(12) The γ-addition product 5 cannot be easily isolated, and so the
reaction mixture was oxidized. The γ-addition product 6 is stable to
basic conditions, and so the ratios observed after oxidation reflect the
ratios of the initial addition.
(13) The er of the minor product 6a from the reactions with 2d
(Table 1, entry 4, R3 = allyl) and 2e (entry 5, R3 = Ph) was 76:24 and
50:50 respectively. The cause of the low enantioselectivity observed is
open to speculation and could be due to one or both of the following
factors: (i) the inherent facial selectivity during the addition of the
electrophile to the lithiated species (syn-SE′ vs anti-SE′); (ii) whether
the oxidation proceeds through a polar or radical pathway. In the case
of R3 = Ph, homolytic cleavage of the C−B bond in 5 will produce two
stabilized radicals, resulting in racemization of the γ-stereocenter. For
radical oxidation of boronic esters, see: Cadot, C.; Dalko, P. I.; Cossy,
J. J. Org. Chem. 2002, 67, 7193.
AUTHOR INFORMATION
Corresponding Author
v.aggarwal@bristol.ac.uk
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.A.P. thanks the University of Bristol for a Post-Graduate
Scholarship. V.K.A. thanks the EPSRC for a Senior Research
Fellowship. We thank Inochem-Frontier Scientific for generous
donation of organoboron reagents.
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system is α to B (propargylic/benzylic or allylic) (see ref 27); or when
a CF3 is present (see ref 27b, c).
(29) (a) Eisch, J. J.; Galle, J. E. J. Organomet. Chem. 1988, 341, 293.
(b) Lohse, P.; Loner, H.; Acklin, P.; Sternfeld, F.; Pfaltz., A.
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(30) (a) Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.;
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(31) In model systems derived from 3aa, elimination could also be
mediated under the following conditions: HCl (anhydrous or
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