One-pot synthesis of 2,3,4,5,6-pentasubstituted tetrahydropyrans using lithiation-borylation, allylation and Prins cyclisation reactions

Article abstract of DOI:10.1016/j.tetlet.2012.10.091

2,3,4,5,6-Pentasubstituted tetrahydropyrans have been prepared in good yield (42-57%) with excellent dr (>95:5) and er (>95:5) using a one-pot lithiation-borylation, allylation and Prins cyclisation reaction.

Full text of DOI:10.1016/j.tetlet.2012.10.091

Tetrahedron Letters 54 (2013) 49–51
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of 2,3,4,5,6-pentasubstituted tetrahydropyrans using
lithiation–borylation, allylation and Prins cyclisation reactions
⇑
Adeem Mahmood , Jose Ramón Suárez, Stephen P. Thomas, Varinder K. Aggarwal
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
2,3,4,5,6-Pentasubstituted tetrahydropyrans have been prepared in good yield (42–57%) with excellent dr
(>95:5) and er (>95:5) using a one-pot lithiation–borylation, allylation and Prins cyclisation reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 14 August 2012
Revised 2 October 2012
Accepted 18 October 2012
Available online 26 October 2012
Keywords:
Lithiation–borylation
Allylation
Prins cyclisation
Tandem
Boronic ester
Substituted tetrahydropyrans (THPs) are ubiquitous in Nature.1
They show great diversity in structure and complexity, from the
relatively simple tri-substituted THP, (À)-diospongin A2 to the
highly complex polyketide marine metabolites clavosolide A3 and
(–)-kendomycin4 with penta-substituted THP cores (Fig. 1). One
of the most efficient strategies for their construction involves the
Prins cyclisation,5 as demonstrated by numerous research group-
s.5a,6 Indeed, the acid-catalysed Prins cyclisation of an in situ gen-
erated oxocarbenium ion has been extensively used for the
stereoselective synthesis of diversely functionalised THPs.7
Although allyltin8 and allylsilyl9 reagents have been used in this
context, to the best of our knowledge, there is only a single report
of allylboron reagents being used for the stereoselective synthesis
of racemic THPs via a tandem allylation and Prins cyclisation.10
substituted THPs (Fig. 2). The enantioselectivity would be set in
the lithiation–borylation reaction (>98:2 er) and the diastereose-
lectivity would be set in the allylation reaction (>95:5 dr), and sub-
sequent Prins cyclisation.
We recently reported the enantioselective synthesis of
a-
substituted allylic boron reagents which could be reacted with
aldehydes to give homoallylic alcohols with control of all elements
of stereochemistry (syn/anti; E/Z).11 We recognised that if these
products could be used in a subsequent Lewis acid-catalysed Prins
cyclisation we would have the ability to form highly substituted
THPs with excellent diastereoselectivity and enantioselectivity.12
We postulated that if the allylation products, 6 or 7 formed via
an initial allylation with the first equivalent of aldehyde, could be
trapped by a second aldehyde in the presence of a Lewis acid, a
Prins cyclisation should ensue (8 ? 10 or 9 ? 11) to give highly
⇑
Corresponding author. Tel.: +44 (0)117 954 6315; fax: +44 (0)117 925 1295.
E-mail address: V.Aggarwal@bristol.ac.uk (V.K. Aggarwal).
Current address: Department of Chemistry, COMSATS Institute of Information
Technology, Abbottabad 22060, Pakistan.
Figure 1. THP-containing natural products.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.091

50
A. Mahmood et al. / Tetrahedron Letters 54 (2013) 49–51
Table 1
Synthesis of 2,3,4,5,6-pentasubstituted THPs using neopentylglycol boronic estersa,b
Entry
R1
R2
R3
Yield (%)
drc
erd
1a
2a
3a
4a
5a
6a
7b
8b
9b
10b
Me
Me
Bu
Bu
H
Ph
Cy
Ph
Cy
Ph
Cy
Cy
Ph
Cy
Cy
Ph
Cy
Ph
Cy
Ph
Cy
Ph
Cy
Ph
Ph
54
51
52
57
45
49
50
48
54e
44
>95:5
>95:5
>95:5
99:1
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
96:4
—
98:2
—
98:2
—
96:4
95:5
97:3
97:3
H
Bu
Bu
Me
H
a
R2 = R3 (i) s-BuLi (1.4 equiv), (À)-sp. (1.4 equiv), Et2O (0.17 M), À78 °C, 5 h. (ii)
Compound 2 (1.7 equiv), À78 °C to rt, 2.5 h. (iii) Et2O to CH2Cl2, BF3ÁOEt2 (2 equiv),
rt, 0.5 h. (iv) R2CHO (4 equiv), À78 °C, 1 h. (v) BF3ÁOEt2 (2 equiv), À78 °C to rt, 18 h.
(vi) H2O, rt, 3 h.
b
R2 – R3 (i) s-BuLi (1.4 equiv), (À)-sp. (1.4 equiv), Et2O (0.17 M), À78 °C, 5 h. (ii)
Compound 2 (1.7 equiv), À78 °C to rt, 2.5 h. (iii) Et2O to CH2Cl2, BF3ÁOEt2 (2 equiv),
rt, 0.5 h. (iv) R2CHO (1.5 equiv), À78 °C, 1 h. (v) R3CHO (3 equiv), À78 °C, 1 h. (vi)
BF3ÁOEt2 (2 equiv), À78 °C to rt, 18 h. (vii) H2O, rt, 3 h.
c
Of the major product, ratio of major diastereomer: all other diastereomers.
Of the major product, determined by chiral-GC. Absolute stereochemistry
d
assigned in accordance with literature precedence.11
e
Of the major product, isolated as a 2:1 mixture of 2-Ph-6-c-Hex- and 2,6-di-c-
Hex-THP.
nation of ethyl carbamate 1 with s-BuLi in the presence of (À)-
sparteine followed by the addition of vinyl boronic ester 2 gave
an intermediate ate complex. To promote 1,2-metallate rearrange-
ment, and thus formation of the allylboronic ester
3
[X = (OCH2)2CMe2], a solvent exchange was carried out from Et2O
to CH2Cl2 and BF3ÁOEt2 was added. Subsequent addition of an excess
of either cyclohexylcarboxaldehyde or benzaldehyde (these were
used as representative aldehydes) and further addition of BF3ÁOEt2
followed by aqueous work-up gave the THPs in moderate yields but
very high enantioselectivity and very high diastereoselectivity. In
the one-pot process three C–C bonds, and two C–O bonds have been
formed and 5 stereogenic centres have been controlled. The use of a
variety of boronic esters was examined including Me- (entries 1 and
2), Bu- (entries 3 and 4) and H- (entries 5 and 6). In all cases excel-
lent stereocontrol was observed even with the parent unsubstitut-
ed vinylboronic ester (R1 = H, entries 5 and 6). Interestingly, no
addition of fluoride was observed at the 4-position as might be ex-
pected when using BF3 in the absence of a fluoride trap.15,16
The use of different aldehydes in the sequential allylation, Prins
cyclisation was also explored as this would lead to a fully differen-
tially substituted THP, a significantly greater challenge.5a However,
by simply adding the two aldehydes in sequence we were able to
obtain the 2,6-differentially substituted THPs in good yield and
excellent dr and er (Table 1, entries 7–10). In one case (Table 1, en-
try 9), when cyclohexylcarboxaldehyde was used as the first alde-
hyde (followed by benzaldehyde), we observed a significant
amount of the bis-cyclohexyl substituted THP. In contrast, the use
of benzaldehyde as the first aldehyde followed by cyclohexylcarb-
oxaldehyde gave the required THP with complete control over the
substitution at each THP-carbon (entry 8). Presumably, the lower
selectivity of the former reaction can be explained by the decreased
reactivity of benzaldehyde compared to cyclohexylcarboxaldehyde.
Figure 2. Proposed synthesis of highly substituted THPs via lithiation–borylation,
allylation and Prins cyclisation.
Significantly, the substituents on boron could be exploited to fa-
vour one of two transition state (TS) structures 4 and 5 in the initial
allylation reaction with the first aldehyde. Large substituents on
boron (e.g. 9-BBN) would cause a steric clash between the Me
group and the boron substituents,13 thereby favouring the allyla-
tion product arising from TS 4. This would give the (Z)-alkene
which, after Prins cyclisation, would give the 3,5-anti-THP 12 after
work-up. Use of small boron substituents [e.g. (OCH2)2CMe2] re-
duces the steric clash between the Me group and the boron substit-
uents14 and now TS 5 with the Me group in the pseudo equatorial
position would be favoured due to competing A1,3 strain in TS 4.
This would lead to the (E)-alkene which, following Prins cyclisation
and trapping by water, would give the all equatorial substituted
THP 13, with the 3,5-syn arrangement.
Furthermore, the sequential nature of our proposed THP syn-
thesis presents the possibility for a one-pot synthesis of fully dif-
ferentiated THPs via the addition of two different aldehydes. The
3- and 5-substituents arise from the carbamate 1 and boron re-
agent 2 and the 2- and 6-substituents from the aldehydes used
in the allylation and Prins reactions, respectively.
Our studies began by targeting the all equatorial substituted
THPs 13 (Table 1, entries 1–6). To favour TS 5, neopentylglycol boro-
nic esters were used along with a similar allylation protocol to that
which we had previously used with great success.11 Thus, deproto-

A. Mahmood et al. / Tetrahedron Letters 54 (2013) 49–51
51
Table 2
Synthesis of 2,3,4,5,6-pentasubstituted THPs using B-9-BBN boranesa,b
Acknowledgements
We thank the EPSRC National Mass Spectrometry Service centre
for providing high-resolution mass spectra and Inochem-Frontier
Scientific for the generous donation of organoboron reagents.
V.K.A. thanks the EPSRC for a Senior Research Fellowship and the
Royal Society for a Wolfson Research Merit Award. A.M. thanks
the Higher Education Commission of Pakistan and the University
of Bristol for a PhD studentship. J.R.S. thanks the Spanish Ministerio
de Educación y Ciencia for a postdoctoral fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.091.
Entry
R1
R2
Yield (%)
drc
erd
1a
2a
3b
Ph
Cy
Cy
Ph
Cy
Ph
48
>95:5
>95:5
>95:5
95:5
—
97:3
45
42e
References and notes
a
R1 = R2 (i) s-BuLi (1.4 equiv), (À)-sp. (1.4 equiv), Et2O (0.17 M), À78 °C, 5 h. (ii)
1. (a) Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7; (b) Norcross, R. D.; Paterson, I.
Chem. Rev. 1995, 95, 2041; (c) Wesley, J. W. Polyether Antibiotics: Naturally
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1303.
Compound 2 (1.7 equiv), À78 °C to rt, 2.5 h. (iii) Et2O to CH2Cl2, R1CHO (4 equiv),
À78 °C, 1 h. (iv) BF3ÁOEt2 (4 equiv), À78 °C to rt, 18 h. (v) H2O, rt, 3 h.
b
R1 – R2 (i) s-BuLi (1.4 equiv), (À)-sp. (1.4 equiv), Et2O (0.17 M), À78 °C, 5 h. (ii)
Compound 2 (1.7 equiv), À78 °C to rt, 2.5 h. (iii) Et2O to CH2Cl2, R1CHO (1.5 equiv),
À78 °C, 1 h. (iv) R2CHO (3 equiv), À78 °C, 1 h. (v) BF3ÁOEt2 (4 equiv), À78 °C to rt,
18 h. (vi) H2O, rt, 3 h.
c
Of the major product, ratio of major diastereomer: all other diastereomers.
Of the major product, determined by Chiral-GC. Absolute stereochemistry
d
4. (a) Funahashi, Y.; Kawamura, N.; Ishimaru, T. Japan Patent 08,231,551
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assigned in accordance with literature precedence.11
e
Of the major product, isolated as a 1:1 mixture of 2-Ph-6-c-Hex- and 2,6-di-c-
Hex-THP.
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We next turned our attention to the synthesis of the diastereo-
meric 3,5-anti-THPs 12 (Table 2). To favour TS 4, a bulky substitu-
ent at boron was required and the B-9-BBN group was selected.
Furthermore, the increased reactivity of boranes in the lithiation–
borylation reaction17 negated the need for Lewis acids to trigger
1,2-metallate rearrangement, although a solvent exchange to
CH2Cl2 was still needed to effect efficient Prins cyclisation.
Thus, deprotonation of ethyl carbamate 1 with s-BuLi in the pres-
ence of (—)-sparteine followed by addition of B-vinyl-9-BBN gave an
intermediate ate complex which underwent rapid 1,2-metallate
rearrangement at low temperatures. Solvent exchange from Et2O
to CH2Cl2 and the addition of an excess of either cyclohexylcarbox-
aldehyde or benzaldehyde, followed by further addition of BF3ÁOEt2
gave the THPs in moderate yields, but with very high enantioselec-
tivity and diastereoselectivity. Once again, excellent levels of stereo-
control were observed using both aryl- and alkyl aldehydes giving
excellent dr (entries 1 and 2) and er (entry 1) and the sequential
addition of two different aldehydes could be used to differentiate
the 2- and 6-positions with excellent dr and er (entry 3). The use
of the B-9-BBN reagents gave the highest levels of diastereoselectiv-
ity reported herein. Presumably the large 9-BBN group significantly
shifts the TS equilibrium towards 4 in the allylation reaction and the
increased reactivity of the intermediate boronic esters increases the
rate of aldehyde exchange and Prins cyclisation.
14. (a) Chen, M.; Handa, M.; Roush, W. R. J. Am. Chem. Soc. 2009, 131, 14602; (b)
Kister, J.; DeBaillie, A. C.; Lira, R.; Roush, W. R. J. Am. Chem. Soc. 2009, 131,
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Simpson, T. J.; Smith, R. W.; Willis, C. L. Chem. Commun. 2001, 835.
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In summary we have developed a one-pot synthesis of function-
alised tetrahydropyrans using a sequential lithiation–borylation,
allylation and Prins cyclisation reaction. The protocol has been
successfully applied to the highly diastereo- and enantioselective
syntheses of 2,3,4,5,6- and 2,3,4,5-substituted THPs.