A bidirectional SE′ strategy for 1,5- syn and 1,5- anti stereocontrol toward the synthesis of complex polyols

Article abstract of DOI:10.1021/ol3015682

Studies report a bidirectional S_E′ strategy applicable for the stereocontrolled synthesis of nonracemic 1,5-syn and 1,5-anti diols and their derivatives. Nonracemic 1,3,2-diazaborolidine auxiliaries are incorporated by chemoselective tin-boron exchange to provide reactive allylic boranes. The convergent pathway utilizes sequential reactions with two aldehydes producing stereochemical outcomes from cyclic, closed, and open transition state preferences, respectively. Synthesis of fragment 16 of peloruside A is accomplished in four steps from readily available aldehydes 9 and 13.

Full text of DOI:10.1021/ol3015682

ORGANIC
LETTERS
0
and 1,5-anti Stereocontrol toward the
Synthesis of Complex Polyols
2012
Vol. 14, No. 15
3866–3869
A Bidirectional SE Strategy for 1,5-syn
David R. Williams,* Christopher D. Claeboe, Bo Liang, Nicolas Zorn, and
Nicholas S. C. Chow
Department of Chemistry, Indiana University, Bloomington, Indiana 47405-7102,
United States
williamd@indiana.edu
Received June 6, 2012
ABSTRACT
0
Studies report a bidirectional SE strategy applicable for the stereocontrolled synthesis of nonracemic 1,5-syn and 1,5-anti diols and their
derivatives. Nonracemic 1,3,2-diazaborolidine auxiliaries are incorporated by chemoselective tinꢀboron exchange to provide reactive allylic
boranes. The convergent pathway utilizes sequential reactions with two aldehydes producing stereochemical outcomes from cyclic, closed, and
open transition state preferences, respectively. Synthesis of fragment 16 of peloruside A is accomplished in four steps from readily available
aldehydes 9 and 13.
Bifunctional reagents possessing properties of high che-
moselectivity greatly facilitate convergent synthesis strate-
gies. Several years ago, we initiated studies of bifunctional
stannanes and 0silanes which provide for the sequential
execution of SE reactions and cross-coupling processes as
an efficient strategy for the rapid assembly of molecular
complexity.1 Efforts toward pelorusides A and B2 have led
us to expand the scope of these studies to consider bifunc-
tionallinchpin species for sequentialSE0 operations and the
stereocontrolled preparation of 1,5-syn and 1,5-anti diols.
Currently, few reagents address this challenge as a versatile
synthesis strategy affording high enantioselectivity.
distinguish the individual secondary alcohols for sub-
sequent site-specific manipulations. A goal of these studies
was to obtain nonracemic skipped polyol derivatives 3 and
4 via a mild oxidative cleavageof the central CdC followed
by stereoselective hydride reduction.
Scheme 1. General Plan for the Synthesis of Nonracemic Polyol
Derivatives
Conceptually, a trimethylenemethane dianion equiva-
lent may sequentially react with two different aldehydesfor
the construction of nonracemic 1 and 2 (Scheme 1). Our
studies introduced the additional requirement to chemically
(1) (a) Williams, D. R.; Fultz, M. W. J. Am. Chem. Soc. 2005, 127,
14550–14551. (b) Williams, D. R.; Morales-Ramos, A. I.; Williams,
ꢀ
Previous studies by Barrett et al. described an asymmetric
bidirectional double allylboration to yield C2-symmetric
3-methylenepentane-1,5-diols 1 (R1 = R2) using nonracemic
1,3-bis(diisopinocampheylboryl)-2-methylenepropanes.3
Roush et al. explored the introduction of two different aldehydes
in the double allylboration sequence of 1,3-diborylpropenes
C. M. Org. Lett. 2006, 8, 4393–4396. (c) Williams, D. R.; Shah, A. A.
Chem. Commun. 2010, 46, 4297–4299. (d) For use in total synthesis:
Williams, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765–766.
(2) (a) West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org. Chem.
2000, 65, 445–449. (b) Singh, A. J.; Xu, C.-X.; Xu, X.; West, L. M.;
Wilmes, A.; Chan, A.; Hamel, E.; Miller, J. H.; Northcote, P. T.; Ghosh,
A. K. J. Org. Chem. 2010, 75, 2–10.
r
10.1021/ol3015682
Published on Web 07/19/2012
2012 American Chemical Society

Scheme 2. Synthesis of the C1ꢀC9 Fragment of Peloruside A (5)
by taking advantage of reactivity differences of the borane
moieties and by limiting the amount of the first aldehyde.4
Interestingly, Soderquist et al. prepared borabicyclo-
[3.3.2]decane-derived 1,3-diborylpropenes which undergo
1,3-borotropic shifts to react as 1,1-bimetallic allylation
species. Sequential reactions occur first with ketones, and
subsequent additions to aldehydes produce 2-vinyl-1,3-diols
of high enantiomeric purity.5
Our previous studies have utilized the mild and quanti-
tative replacement of allylic stannanes with chiral, non-
racemic boranes as an effective strategy for asymmetric
allylation.9 This technique tolerates a wide range of func-
tionality and has proven to be extremely useful in the
synthesis of complex natural products.10 While the trans-
metalation of the stannane is highly favored, allylic tri-
methylsilanes were found to be inert. This observation
established a basis for our studies of sequential allylation
processes utilizing aninitial reagent-controlled asymmetric
reaction. These efforts have been applied for a stereocon-
trolled synthesis of the C(1)ꢀC(9) fragment of peloruside
A (5) as shown in Scheme 2. Thus, facile transmetalation of
allylic stannane 611 using the bromoborane 712 provided
in situ generation of nonracemic 1,3,2-diazaborolidine 8
upon stirring at 22 °C for 16 h. The (R,R)-1,2-diamino-
1,2-diphenylethylene N,N-sulfonamide was incorporated
as an effective chiral controller.13 A rapid SE0 reaction was
observed upon cooling to ꢀ78 °C with the addition of
0
Properties of reactivity and selectivity of SE reactions
using silyl-substituted allylmetal reagents have primarily
been investigated for examples leading to 1,2-anti-β-hydroxy
allylsilanes.6 Peng and Hall described a variation of this
theme in which enantiocontrolled allylation results in
the participation of an allylic silane in an intramolecular
Prins reaction affording nonracemic 1,2,4-trisubstituted
tetrahydrofurans.7 A significant precedent was estab-
lished by Keck et al. using 2-(trimethylsilylmethyl)-
allyltri-n-butylstannane for the convergent union of
two aldehydes in an asymmetric allylation-Prins se-
quence to yield 2,6-cis-disubstituted-4-methylenetetra-
hydropyrans.8
(9) (a) Williams, D. R.; Meyer, K. G.; Shamim, K.; Patnaik, S. Can.
J. Chem. 2004, 82, 120–130. (b) Williams, D. R.; Kiryanov, A. A.; Emde,
U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 12058–12063.
(3) Barrett, A. G. M.; Braddock, D. C.; de Koning, P. D.; White,
A. J. P.; Williams, D. J. J. Org. Chem. 2000, 65, 375–380.
(4) (a) Kister, J.; Nuhant, P.; Lira, R.; Sorg., A.; Roush, W. R. Org.
Lett. 2011, 13, 1868–1871. (b) Flamme, E. M.; Roush, W. R. J. Am.
Chem. Soc. 2002, 124, 13644–13645.
(10) (a) Hennoxazole, A; Williams, D. R.; Brooks, D. A.; aBerliner,
M. A. J. Am. Chem. Soc. 1999, 121, 4924–4925. (b) Amphidinolide, K;
Williams, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765–767. (c)
Leucascandrolide, A; Williams, D. R.; Plummer, S. V.; Patnaik, S.
Tetrahedron 2011, 67, 4949–4953. See also: Williams, D. R.; Patnaik,
S.; Plummer, S. V. Org. Lett. 2003, 5, 5035–5038. (d) Phorboxazole, A;
Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; aBerliner,
M. A. Angew. Chem., Int. Ed. 2003, 42, 1258–1262.
(11) For a preparation of stannane 6: Clive, D. L. J.; Paul, C. C.;
Wang, Z. J. Org. Chem. 1997, 62, 7028–7032.
(12) For information regarding the preparation of 7: (4R,5R)-
2-Bromo-1,3-bis[(4-methylphenyl)sulfonyl]-4,5-diphenyl-1,3,2-diazabor-
olidine. e-EROS Encyclopedia of Reagents for Organic Synthesis
[Online]; John Wiley & Sons, Ltd.: Posted October 15, 2002; DOI:
10.1002/047084289X.rn00115.
ꢀ
ꢀ
(5) Gonzalez, A. Z.; Roman, J. G.; Alicea, E.; Canales, E.; Soderquist,
J. A. J. Am. Chem. Soc. 2009, 131, 1269–1273.
(6) For a leading reference: Chen, M.; Roush, W. R. Org. Lett. 2011,
13, 1992–1995.
(7) (a) Peng, F.; Hall, D. G. J. Am. Chem. Soc. 2007, 129, 3070–3071.
(b) Sivasubramaniam, U.; Hall, D. G. Heterocycles 2010, 80, 1449–1456.
(c) See also: Sarkar, T. K.; Haque, S. A.; Basak, A. Angew. Chem., Int.
Ed. 2004, 43, 1417–1419.
(8) Keck, G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4,
1189–1192.
Org. Lett., Vol. 14, No. 15, 2012
3867

(dr 89:11) was purified, and its stereochemistry was assigned
by a modified Mosher ester analysis.16 O-Methylation and
silyl ether formation gave 11 and 12, respectively, and the
second stage of the process was undertaken as a Sakuraiꢀ
Hosomi allylation. Precomplexation of R-alkoxyaldehyde
1317 with MgBr2 etherate in methylene chloride at ꢀ26 °C
was followed by addition of silane 11 leading to selec-
tive formation of homoallylic alcohol 14 (80% yield;
dr 25:1). An open, synclinal transition state features
the chelation-controlled arrangement TS-2 to afford
the major diastereomer. Reaction of the OTIPS deri-
vative 12 provides slightly reduced yields and diastereo-
selectivity resulting in 15. In each case, the stereochemistry
of the new alcohol (C3) has been established using the
Mosher ester technique.16 Expedient construction of the
C1ꢀC9 polyketide fragments 16 and 17 is completed in
excellent yield by the Johnson;Lemieux cleavage of the
central (C5) alkene.
0
Table 1. Allylsilane Formation via SE Reactions of
1,3,2-Diazaborolidine Intermediatesa
Strategically, the convergent pathway of Scheme 2 pro-
duces 1,5-anti diol0 derivatives 16 and 17 by using two
chemodivergent SE allylations. This characteristic is ad-
vantageous for planning syntheses of complex substances
by sequential reactions employing closed and open transi-
tion state preferences. The potential and the generality of
these processes have been explored. Table 1 offers a
compilation of representative results for reactions of chi-
ral, nonracemic, and achiral aldehydes with (R,R)-7 and
(S,S)-7 using the conditions developed in Scheme 2 as a
standard protocol. We have noted that allylations with
(R,R)- and (S,S)-diazaborolidines of 8 using enantiomeric
aldehydes 18 and 19 express modest levels of matched and
mismatched characteristics (entries 2 and 3), and the
stereochemistry of the newly formed alcohol is consistently
determined by the chiral controller. Alkyl branching at the
R-position of nonracemic aldehydes 20 and 21 leads to
transition states which provide for FelkinꢀAnh additions
in entries 4 and 5. Yields are typically in the range of
79ꢀ83%. β-Branching(entry8) islesseffective, andachiral
aldehydes were included to provide a measure of asym-
metric induction due to the allylborane reagent. Generally,
a Reaction conditions: Stannane 6 was reacted with bromoborane 7 in
CH2Cl2 at 22 °C for 16 h under N2. The mixture was then cooled to ꢀ78 °C
under N2, and a solution of aldehyde (1.0 equiv) containing 4-methyl-2,6-
di-tert-butylpyridine was added via syringe. Reactions were stirred at
ꢀ78 °C for 4 h and quenched by the addition of aqueous NaHCO3. b Ratios
[dr] were determined by HPLC analysis of the crude product mixture.
c Ratios of enantiomers were determined by conversion to their correspond-
ing Mosher esters followed by integration of NMR signals. d Major
products were purified by chromatography using deactivated silica gel.
nonracemic aldehyde 9 (1.0 equiv)14 and 2,6-di-tert-butyl-
4-methylpyridine (1.1 equiv)15 leading to stereoselective
production of homoallylic alcohol 10 (80%).
The outcome of the reaction is dominated by face selec-
tivity imposed by the (R,R)-auxiliary. The closed, six-
membered arrangement TS-1 leading to 10 also features
the polar Felkin model for nucleophilic addition to the
R-alkoxyaldehyde 9. Major product (R)-10 (R = H)
0
the latter cases undergo the SE reaction with ∼90% face
selectivity (entries 6 and 7). However, entries 6ꢀ8 were not
optimized in this study and led to the recovery of small
quantities of starting aldehyde using the standard proto-
col. In practice, product purifications were conducted by
flash chromatography using deactivated silica gel by the
introduction of 0.5% NEt3 in the eluent to avoid proto-
desilylation. The stereoselectivity of each reaction was
measured by HPLC analysis of the crude homoallylic
(13) (a) Corey, E. J.; Yu, C. M.; Kim, S. S. J. Am. Chem. Soc. 1989,
111, 5495–5496. (b) Williams, D. R.; Brooks, D. A.; Meyer, K. G.;
Clark, M. P. Tetrahedron Lett. 1998, 39, 7251–7254.
(14) Aldehyde 9 is readily prepared in four steps from (S)-(ꢀ)-
glycidol (Aldrich) as illustrated below:
(16) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–
519. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092–4096.
(17) Nonracemic aldehyde 13 was prepared as shown below in three
steps from dimethyl-L-tartrate. See: Williams, D. R.; Klingler, F. D.
Tetrahedron Lett. 1987, 28, 869–872.
(15) The addition of 2,6-di-tert-butyl-4-methylpyridine serves
as an effective proton scavenger and suppresses side products of
protodesilylation.
3868
Org. Lett., Vol. 14, No. 15, 2012

were directly converted into their methyl ethers (entries 1,
3, and 5) for flash chromatography immediately prior to the
second SE0 event. Methyl ethers are incorporated to accom-
modate efforts toward peloruside A (5) and to simplify our
analyses of proton NMR spectra for subsequent products of
Table 2. However, benzylic, TBS, and TIPS silyl ethers have
also been utilized at this stage with little overall effect on the
observed yields or diastereoselectivities.
a
0
Table 2. Second-Stage Bidirectional SE Reactions
Table 2 summarizes results for second stage reactions
with the stereocontrolled production of various acyclic
polyol arrangements. In these examples, we have engi-
neered high stereoselectivity for the formation of 1,5-syn-
and 1,5-anti-products via the incorporation of nonracemic
R-alkoxyaldehydes.18 SakuraiꢀHosomi reactions proceed
smoothly at ꢀ26 °C in CH2Cl2 through open transition
states via chelation-controlled additions to the less hin-
dered face of precomplexed aldehydes. Yields of 78ꢀ89%
(dr >20:1) are routinely obtained. Significantly, the pre-
existing chirality embedded within the allylsilane at the
homoallylic site does not affect the stereoselectivity or the
efficiency of the Sakurai reaction (compare entries 1 vs 3,
and 2 vs 4; Table 2). In this fashion, the resulting 1,5-syn-
and 1,5-anti-stereochemistry of the product is dictated by
the choice of the nonracemic R-alkoxyaldehyde. The gen-
erality of the process also accommodates a number of
common protecting groups (including PMB, MOM,
MEM, TBS, and related silyl ethers) which leads to a
densely hydroxylated carbon framework in which each
latent alcohol can be differentiated for further studies.
0
In summary, we have described a bidirectional SE allyla-
tion strategy for stereoselective syntheses of acyclic 1,5-syn- or
1,5-anti-polyols. A chemoselective tinꢀboron exchange has
allowed in situ production of chiral, nonracemic allylboranes
containing an allylic silane. This feature facilitates a rational
0
and efficient preparation of polyols via two orthogonal SE
processes. In this context, the boron reagent-controlled asym-
metric allylation occurs via a preferred six-membered transi-
tion state and is followed by a SakuraiꢀHosomi reaction
demonstrating the stereochemical outcome of substrate con-
trol. Our results suggest broad applications toward the
synthesis of stereochemically complex polyols.
a Reaction conditions: Aldehyde (1.1 equiv) was precomplexed with
MgBr2•OEt2 (1.5 equiv) in CH2Cl2 at ꢀ78 °C under N2. A solution of
allylsilane (1.0 equiv) was added in CH2Cl2, and the mixturewas warmed
to ꢀ26 °C with continuous stirring (12 h). b Ratios of diastereomers were
determined for crude product mixtures by proton NMR analysis at 400
MHz. c Ratios of diastereomers were determined by analytical HPLC.
d Major products were purified by flash chromatography and were fully
characterized.
Acknowledgment. The authors acknowledge financial
support for this research, in part, from the National
Institutes of Health (GM041560), National Science Foun-
dation (CHE1055441), and Indiana University.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, and selected 1H and 13C
NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
alcohols to determine diastereomeric ratios (entries 1ꢀ5) or
by direct conversion to their corresponding Mosher esters
for integration of characteristic NMR signals (entries 6ꢀ8).
In our initial studies, the purification of major products 26,
27, 28, and 31 (entries 2, 3, 4, and 7) by flash column
chromatography was followed by O-methylation or forma-
tion of TBS silyl ethers. Subsequently, the crude alcohols
(18) For the preparation of nonracemic aldehyde 33: Corey, E. J.;
Hannon, F. J.; Boaz, N. W. Tetrahedron 1989, 45, 545–555.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
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