Tandem Allylboration-Prins Reaction for the Rapid Construction of Substituted Tetrahydropyrans: Application to the Total Synthesis of (-)-Clavosolide A

Article abstract of DOI:10.1002/anie.201511140

Tetrahydropyrans are common motifs in natural products and have now been constructed with high stereocontrol through a three-component allylboration-Prins reaction sequence. This methodology has been applied to a concise (13 steps) and efficient (14 % ove

Full text of DOI:10.1002/anie.201511140

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International Edition: DOI: 10.1002/anie.201511140
German Edition: DOI: 10.1002/ange.201511140
Total Synthesis
Hot Paper
Tandem Allylboration–Prins Reaction for the Rapid Construction of
Substituted Tetrahydropyrans: Application to the Total Synthesis of
(À)-Clavosolide A
Alba Millµn, James R. Smith, Jack L.-Y. Chen, and Varinder K. Aggarwal*
Abstract: Tetrahydropyrans are common motifs in natural
products and have now been constructed with high stereocon-
trol through a three-component allylboration-Prins reaction
sequence. This methodology has been applied to a concise
(13 steps) and efficient (14% overall yield) synthesis of the
macrolide (À)-clavosolide A. The synthesis also features an
early stage glycosidation reaction to introduce the xylose
moiety and a lithiation-borylation reaction to attach the
cyclopropyl-containing side chain.
tetrasubstituted tetrahydropyran (THP) core alone has been
constructed in ꢀ 6 steps.[3] In some cases additional steps were
employed to construct THPs with high structural complexity
towards the end of the synthesis.
Lithiation–borylation[4] has emerged as a powerful tool for
the synthesis of chiral boronic esters including allylic boronic
esters.[5] We reasoned that this methodology, in combination
with our improved allylboration of aldehydes[6] followed
directly by a Prins cyclisation[7,8] could lead to a short, and
highly stereoselective synthesis of the THP core of (À)-
clavosolide A in just three steps. In this paper we report our
success in not only developing the three-component allylbo-
ration–Prins reaction for the rapid stereocontrolled assembly
of substituted THPs but also in developing further improve-
ments to our lithiation–borylation protocol and addressing
other issues of stereocontrol so that every step in our short
synthesis is highly stereoselective (> 95:5 dr). Furthermore,
and as previously described in earlier syntheses of (À)-
clavosolide A[3f,i,j] and B,[9] conducting the glycosidation step
early in the synthesis rather than at the end avoids the
formation of statistical mixtures of anomeric stereoisomers
(a,a; a,b; b,b), thereby improving the overall yield.
C
reating increasingly efficient syntheses of common struc-
tural motifs found in Nature is a long-running objective in
organic synthesis. For example, substituted pyrans are fre-
quently encountered in the family of polyketide natural
products.[1] Clavosolide A[2,3] is a contemporary example,
whose correct structure was established following total
syntheses by Willis,[3a] Lee[3b] and Smith[3c] (Figure 1). This
molecule has been prepared by a variety of strategies and the
Our retrosynthetic analysis is shown in Scheme 1 and
involves the initial disconnection of the macrocyclic lactone to
the hydroxy acid 2. We then envisaged incorporation of the
cyclopropyl unit through a lithiation–borylation reaction
between carbamate 3 and boronic ester 4. Whilst substrate-
controlled cyclopropanation of allylic alcohols is well estab-
lished[10] and has previously been employed in the synthesis of
(À)-clavosolide A,[3c,e–g] unfortunately it gives the undesired
diastereoisomer and therefore requires additional steps for
Figure 1. Examples of THP-containing natural products.
[*] Dr. A. Millµn, J. R. Smith, J. L.-Y. Chen, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201511140.
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Scheme 1. Retrosynthetic analysis for the synthesis of (À)-clavosoli-
de A. OCb=N,N-diisopropyl carbamate; pin=pinacol.
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correction. The carbamate bearing the THP core 3 could
instability towards silica gel purification necessitated their
potentially be assembled by a three-component allylbora-
tion–Prins reaction from boronic ester (R)-6a and aldehyde
7a.
The allylboration–Prins reaction was initially investigated
using our improved Lewis base mediated allylboration
reaction (with nBuLi and TFAA additives).
use in crude form, which resulted in considerably lower
yields.[8] The current protocol, using the more stable pinacol
boronic esters, is more practical and leads to higher yields.
The general protocol involved initial treatment of the
allylic boronic ester with nBuLi and TFAA to give inter-
mediate borinic ester II, which was reacted with the first
aldehyde to give intermediate IV. Without isolation, and
following solvent exchange to DCM, subsequent reaction
with a second aldehyde in the presence of TFA followed by
base mediated hydrolysis furnished the hydroxy THPs 8a–g.
The modified allylboration reaction occurs via the more
reactive borinic ester II, which reacts with the aldehyde
through a Zimmerman–Traxler chair transition state (TS) III.
The reduced steric hindrance around boron in the borinic
ester when compared to the pinacol ester results in greater
preference for the reaction to occur via TS IIIa, with the
methyl group situated in a pseudo-equatorial position, lead-
ing to the higher observed diastereoselectivity. The diaste-
reoselectivity of THP 8a directly reflects the E/Z selectivity
obtained in the initial allylboration of the aldehyde.[6]
In order to apply this methodology to the synthesis of (À)-
clavosolide A, we required the reaction of allylic boronic ester
(R)-6a with aldehyde 7a, followed by aldehyde 10
(Scheme 2). Boronic ester (R)-6a was obtained in two steps
from ethanol using our lithiation–borylation methodology
with (À)-sparteine, in high yield and high er. However, the
three-component allylboration–Prins reaction gave THP 11 in
low yield (due to concomitant cleavage of the silyl protecting
group) but good diastereoselectivity (88:12 dr). In search for
an alternative group to a silyl ether (TIPS and TBDPS silyl
ethers were also labile under the reaction conditions), we
considered the use of the simplest unsaturated aldehyde,
acrolein.[11] We found that the three component allylboration-
Prins reaction worked well when using acrolein, furnishing
As shown in Table 1, a control experiment was conducted
involving the allylboration (without the use of additives) of
CyCHO with allylic boronic ester 6a, followed directly by
a TFA-mediated Prins reaction with a second portion of the
same aldehyde. The reaction occurred in high yield but with
low diastereoselectivity (35:65 dr; entry 1). The diastereose-
lectivity was reversed and substantially improved when
applying our recently developed Lewis base mediated allyl-
boration reaction conditions (with nBuLi and TFAA addi-
tives) to this process (87:13 dr; entry 2). This three-compo-
nent allylboration–Prins reaction enabled boronic esters (6a/
6b) to be sequentially reacted with two different aldehydes to
give THPs 8b–g in good to high yields and good diastereo-
selectivities (entries 3–8). We have previously employed
neopentyl boronic esters in related reactions, but their
Table 1: Three-component allylboration/Prins cyclization.
Entry[a]
R1
R2
R3
8
Yield [%][b]
dr (8:9)
1[c]
2
3
4
5
6
7
8
H
H
H
H
Cy
Cy
Cy
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Cy
Cy
Cy
8a
8a
8b
8c
8d
8e
8 f
91
84
75
57
65
89
81
86
35:65
87:13
87:13
89:11
88:12
90:10
91:9
Ph(CH2)2
Cy
Ph(CH2)2
Ph(CH2)2
Cy
H
Me
Me
Me
Cy
8g
88:12
[a] General procedure: i) 6a–b (1.0 equiv), nBuLi (1.1 equiv), THF,
À788C, 15 min; ii) TFAA (1.2 equiv), À788C, 30 min; iii) R2CHO
(1.05 equiv), À788C, 2 h then RT, 16 h; iv) solvent exchange to DCM; v)
R3CHO (3 equiv), TFA:DCM (1:3), RT, 2 h; vi) K2CO3 (1.5 equiv), MeOH,
RT, 15 min. [b] Combined isolated yields of 8 and 9. [c] Control experi-
ment: i) 6a (1 equiv), CyCHO (1.05 equiv), THF, RT, 16 h; iv) solvent
exchange to DCM; v) CyCHO (3 equiv), TFA:DCM (1:3), RT, 2 h; vi)
K2CO3 (1.5 equiv), MeOH, RT, 30 min; TFAA=trifluoroacetic anhydride;
TFA=trifluoroacetic acid; THF=tetrahydrofuran; DCM=dichlorome-
thane.
Scheme 2. Synthesis of the THP core. a) Cb-Cl (1 equiv), Et3N
(1.2 equiv), 16 h, reflux; b) i) sBuLi (1.1 equiv), (À)-sp (1.2 equiv),
Et2O, À788C, 5 h; ii) vinyl boronic acid pinacol ester (1.1 equiv),
À788C, 1 h; iii) MgBr2·OEt2 (2 equiv), À788C, 10 min, then reflux,
16 h; c) i) nBuLi (1.1 equiv), THF, À788C, 15 min; ii) TFAA (1.2 equiv),
À788C, 30 min; iii) 7a or 7b (1.5 equiv), À788C (or À1008C), 2 h then
RT, 16 h; iv) solvent exchange to DCM; v) 10 (2.5 equiv,) or acrolein
(4 equiv), TFA:DCM (1:3), RT, 2 h; vi) K2CO3 (1.5 equiv), MeOH, RT,
30 min; TBS=tert-butyldimethylsilyl; OTIB=2,4,6-triisopropylben-
zoate; sp=sparteine.
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the THP 12a in high yield and good diastereoselectivity
(88:12 dr). Taking advantage of the considerably higher
reactivity of the borinic ester intermediate, we were able to
improve the diastereoselectivity (96:4 dr) by simply reducing
the temperature of the reaction to À1008C. Thus, with this
straightforward protocol we were able to convert the simple
reagents (R)-6a, 7a and acrolein into the complex THP 12a in
high yield and with high stereocontrol.
Having developed a short three-step route towards the
THP core, we considered the glycosidation next. Since the
xylose moiety was ultimately required in the target molecule,
we believed that it could also serve as a protecting group,
thereby minimising the number of additional steps. Unfortu-
nately, using the permethylated glycosyl donor analogous to
13 either a 1:1 mixture of diastereoisomers (a,b) or no
reaction was observed under a variety of reaction condi-
tions.[12] We therefore turned to exploiting neighbouring
group participation to control the desired b-selectivity.[13]
Both the perbenzoate 13[14] and corresponding peracetate[15]
were tested, but the latter suffered from competing acetyla-
tion of the hydroxy group in the pyran ring.[16] Thus, reaction
of the trichloroacetimidate 13 with pyran 12a in the presence
of TMSOTf gave the corresponding adduct in high yield and
with perfect stereocontrol. Subsequent hydrolysis of the
benzoate, followed by permethylation gave glycoside 3a in
88% yield over the three steps. Finally, hydroboration,
oxidation and protection gave the silyl ether 14a, setting the
stage for the final lithiation–borylation reaction to introduce
Scheme 3. Synthesis of (À)-clavosolide A. d) 13 (1.5 equiv), TMSOTf
(0.3 equiv), 4 Š MS, DCM, À208C to RT, 3 h; e) NaOMe (3.6 equiv),
MeOH, RT, 1 h; f) NaH (8 equiv), MeI (8 equiv), DMF, RT, 16 h; g) i)
(cHex)2BH (6 equiv), THF, 08C, 4 h; ii) H2O2, NaOH, 08C to 558C,
2 h; h) TBSCl (1.2 equiv), Et3N (1.2 equiv), DCM, RT, 16 h; i) when
R=Cb: i) sBuLi (1.1 equiv), (+)-sp (1.2 equiv), Et2O, À788C, 5 h; ii) 4
(1.2 equiv), À788C, 1 h, then reflux, 16 h; iii) NaOH (2m): H2O2
(30%) (2:1), RT, 2 h; when R=TIB: i) sBuLi (1.1 equiv), (+)-sp
(1.2 equiv), Et2O, À788C, 1 h; ii) 4 (1.2 equiv), À788C, 1 h, then reflux,
2 h; iii) NaOH (2m): H2O2 (30%) (2:1), RT, 2 h; j) 1% HCl, EtOH,
20 min, 80%; k) TEMPO (0.01 equiv), KBr (0.1 equiv), NaHCO3,
NaOCl, H2O, DCM, 08C, 5 min, 87%; l) i) 2,4,6-trichlorobenzoyl
chloride (1.1 equiv), Et3N (1.3 equiv), THF, RT, 2.5 h; ii) DMAP
(5 equiv), toluene, reflux, 16 h. OBz=benzoate; TEMPO=2,2,6,6-tetra-
methylpiperidine 1-oxyl; DMAP=4-(dimethylamino) pyridine.
the cyclopropyl moiety.[17]
[18]
À
The final C C bond construction required a late-stage
lithiation–borylation reaction and this step proved to be quite
challenging. Lithiation of the highly oxygenated carbamate
14a under our standard conditions [sBuLi (1.1 equiv),
(+)-sparteine (1.2 equiv), in Et2O at À788C, for 5 h], followed
by borylation with the known boronic ester 4 (96:4 er)[19] and
subsequent oxidation gave the desired alcohol 15a in 23–48%
yield and > 95:5 dr, together with recovered starting material
( ꢁ 40%). Longer reaction times or increased amounts of base
did not improve the yield and led to less recovered starting
material. Analysis of the crude reaction mixture showed that
competing deprotonation was occurring on the glycoside
ring,[20] perhaps because of competing complexation of the
organolithium with the highly oxygenated moiety. We there-
fore turned to the tri-isopropylbenzoyl (TIB) ester in place of
the carbamate. Although this group has been used previously
to promote 1,2-migration in difficult lithiation–borylation
reactions involving poor migrating groups,[21] we reasoned
that its greater electron withdrawing capacity (which made it
a better leaving group) might also increase the acidity of the
a-protons, promoting lithiation.[22] We therefore brought the
TIB ester 12b through the same sequence of steps to the
carbamate. This time, lithiation–borylation of the TIB ester
14b gave the desired alcohol 15a in 73% yield and > 95:5 dr
(Scheme 3).
In order to demonstrate the versatility of this method-
ology towards making alternative stereoisomers without
modifying the route, further homologations of TIB ester
14b were conducted. As shown in Scheme 4, using either of
the two chiral diamines (+)-sparteine/(À)-sparteine (L) with
Scheme 4. Synthesis of alternative diastereoisomers of alcohol 15a
using the lithiation–borylation reaction. Reaction conditions: i) sBuLi
(1.1 equiv), L (1.2 equiv), Et2O, À788C, 1 h; ii) Boronic ester 4 or ent-4
(1.2 equiv), À788C, 1 h, then reflux, 2 h; iii) NaOH (2m): H2O2 (30%)
(2:1), RT, 2 h.
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C. L. Willis, Org. Lett. 2006, 8, 3319; b) J. B. Son, S. N. Kim, N. Y.
either of the two enantiomeric boronic esters 4 (96:4 er)/ent-4
(99:1 er), enabled us to prepare each of the four diastereo-
isomers 15a–d selectively and in good yield. A small matched/
mis-matched effect was observed in the lithiation step,
presumably as a result of competing complexation with the
internal pyran oxygen, which led to lower diastereoselectivity
in the cases of 15b/15d.[23] Interestingly, both matched and
mis-matched cases were equally efficient. Furthermore, this
stereodivergent synthesis, enabling other diastereomers to be
accessed very simply without changing the route,[24] is
especially relevant and important for structures like clavoso-
lide A, whose stereochemistry had initially been incorrectly
assigned. Alcohol 15c would have led to the originally
proposed structure of clavosolide A, whilst 15a leads to the
synthesis with the correct structure.
Kim, D. H. Lee, Org. Lett. 2006, 8, 661; c) A. B. Smith III, V.
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[6] J. L.-Y. Chen, H. K. Scott, M. J. Hesse, C. L. Willis, V. K.
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[7] For recent reviews: a) I. M. Pastor, M. Yus, Curr. Org. Chem.
2007, 11, 925; b) E. A. Crane, K. A. Scheidt, Angew. Chem. Int.
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The completion of the synthesis involved acid-catalysed
deprotection of the silyl group, selective oxidation of the
primary alcohol to the carboxylic acid[25] 2 and dimerization
under Yamaguchiꢀs conditions.[26] This gave synthetic (À)-
1
clavosolide A in good yield, whose H and 13C NMR spectra
were identical to the natural product.[2]
In conclusion, we have shown that commonly occurring
substituted tetrahydropyrans can be assembled in just 3 steps
with high stereocontrol using a three-component allylbora-
tion–Prins reaction. This has been applied to a concise and
efficient synthesis of (À)-clavosolide A in just 13 steps and
14% overall yield, where all steps occurred with > 95:5
selectivity. Additional noteworthy features include 1) an early
stage diastereoselective glycosidation reaction to introduce
the xylose moiety and 2) diastereoselective lithiation–boryla-
tion reaction of a highly oxygenated hindered TIB ester,
which shows enhanced acidity over standard carbamates,
enabling improved lithiations leading to significantly higher
yields.
[8] A. Mahmood, J. R. Suµrez, S. P. Thomas, V. K. Aggarwal,
Tetrahedron Lett. 2013, 54, 49.
[9] J. B. Son, M.-h. Hwang, W. Lee, D.-H. Lee, Org. Lett. 2007, 9,
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Acknowledgements
[10] a) A. B. Charette, H. Lebel, J. Org. Chem. 1995, 60, 2966; b) H.
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A.M. thanks the Fundación Alfonso Martín Escudero for
a postdoctoral fellowship. J.R.S. thanks the Bristol Chemical
Synthesis Centre for Doctoral Training, funded by EPSRC
(EP/G036764/1), AstraZeneca and the University of Bristol,
for a PhD studentship.
[11] For examples of the use of acrolein in Prins reactions see:
a) C. S. J. Barry, S. R. Crosby, J. R. Harding, R. A. Hughes, C. D.
King, G. D. Parker, C. L. Willis, Org. Lett. 2003, 5, 2429; b) C. S.
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[12] Good-to-high b-selectivity has been obtained using benzyl ethers
derived from glucose and galactose: a) J. Yang, C. Cooper-
Vanosdell, E. A. Mensah, H. M. Nguyen, J. Org. Chem. 2008, 73,
794; b) R. R. Schmidt, M. Behrendt, A. Toepfer, Synlett 1990,
694; c) A. Marra, J.-M. Mallet, C. Amatore, P. Sinaþ, Synlett
1990, 572. Unfortunately, none of these reactions were successful
with our methyl ether derivatives of xylose. Employing the
previously described glycosidation conditions in the synthesis of
(À)-clavosolide A (references [3f] and [3i]) with the methyl
ether derivative of xylose a 1:1 mixture of diastereoisomers was
obtained. Hong and Breit reported a 79:21 and a 77:23 ratio of
anomers in a related glycosidation reaction (references [3j] and
[3k], respectively).
Keywords: allylboration · lithiation–borylation ·
natural products · Prins reaction · total synthesis
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[20] Partial deuteration of the anomeric position of 14a was observed
1
by H NMR following a lithiation–deuteration experiment with
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Received: December 1, 2015
Published online: January 14, 2016
2502
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