A Silicon Tether Approach for Addition of Functionalized Radicals to Chiral α-Hydroxyhydrazones: Diastereoselective Additions of Hydroxymethyl and Vinyl Synthons

Article abstract of DOI:10.1021/jo035405r

Stereocontrolled additions of hydroxymethyl and vinyl groups to chiral α-hydroxyhydrazones can be achieved by radical cyclizations using bromomethyl or vinyl radical precursors tethered via a temporary silicon connection. Tin-mediated 5-exo radical cycliz

Full text of DOI:10.1021/jo035405r

A Silicon Teth er Ap p r oa ch for Ad d ition of F u n ction a lized
Ra d ica ls to Ch ir a l r-Hyd r oxyh yd r a zon es: Dia ster eoselective
Ad d ition s of Hyd r oxym eth yl a n d Vin yl Syn th on s
Gregory K. Friestad* and Sara E. Massari
Department of Chemistry, University of Vermont, Burlington, Vermont 05405
gregory.friestad@uvm.edu
Received September 25, 2003
Stereocontrolled additions of hydroxymethyl and vinyl groups to chiral R-hydroxyhydrazones can
be achieved by radical cyclizations using bromomethyl or vinyl radical precursors tethered via a
temporary silicon connection. Tin-mediated 5-exo radical cyclization of R-hydroxyhydrazones using
a silicon-tethered bromomethyl group, followed by oxidative removal of the tether, provides anti-
2-hydrazino 1,3-diols in good yield. Tandem thiyl radical addition-cyclization of R-hydroxyhydra-
zones using a silicon-tethered vinyl group, followed by treatment with potassium fluoride, affords
acyclic allylic anti-hydrazino alcohols in good yield. The thiyl addition-cyclization method has been
successfully extended to the use of R,â-dihydroxyhydrazones without prior protection or hydroxyl
differentiation. Diastereoselection in both reaction types increases with increasing A values of the
appended groups, consistent with prediction by the Beckwith-Houk model for stereocontrol in
5-hexenyl radical cyclizations.
In tr od u ction
tions of stepwise C-C and C-N bond constructions with
a separate asymmetric induction step such as alkene
oxidation or carbonyl reduction. It is worth noting that
alkene oxidation methods (e.g., epoxidation, dihydroxy-
lation, or aminohydroxylation) demand isomerically pure
alkenes which can in turn require nontrivial syntheses
and/or separations. In contrast, retrosynthetic C-C bond
disconnection of R-branched amines (Figure 1) suggests
inherently efficient syntheses may be available by creat-
ing both a stereogenic center and a C-C bond in a single
synthetic transformation involving addition to a CdN
bond. Application of such a C-C bond construction
strategy has been underdeveloped, largely because ad-
ditions of carbanionic reagents to aldehyde imino deriva-
tives7 (azomethines) under basic conditions often suffer
competing aza-enolization.8 These considerations make
the discovery and development of mild, efficient C-C
bond constructions for chiral R-branched amine synthesis
an area of very active inquiry.9
Chiral R-branched amines are key substructures within
bioactive naturally occurring amino alcohols such as
sphingolipids,1 hydroxylated pyrrolidines and piperidines
(“azasugars”),2 and aminosugars.3 Amino alcohols4,5 are
also components of commonly used chiral building blocks,
auxiliaries, and ligands in asymmetric synthesis4 and
have been proposed as key binding motifs for design of
biomimetic recognition processes.6 When not available by
direct reduction of amino acids, amino alcohols are often
prepared by indirect routes involving various permuta-
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Nonpolar radical additions10 to CdN bonds11 (Figure
1) could (a) circumvent imine aza-enolization problems,
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10.1021/jo035405r CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/10/2004
J . Org. Chem. 2004, 69, 863-875
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Friestad and Massari
to aid in stereocontrol. Applications of silyl ethers as
temporary tethers, initially introduced by Nishiyama and
Stork for diastereoselective radical reactions,15 have been
extended to a variety of different stereocontrolled C-C
bond construction reactions.16 The wealth of precedents
for preparation, utilization, and subsequent manipula-
tions of the silicon tether suggested that this strategy
would be a logical first choice as the temporary linkage.
F IGURE 1. Carbon-carbon radical disconnection for synthe-
sis of chiral R-branched amines.
(b) efficiently construct crowded C-C bonds, and
(c) tolerate highly functionalized precursors. However,
stereocontrolled intermolecular alkyl radical addition to
CdN acceptors is rare.12-14 Furthermore, intermolecular
radical addition reactions are normally limited to un-
functionalized alkyl radicals; for example, synthetically
viable intermolecular addition of vinyl radicals to CdN
bonds has yet to be developed.
We envisioned a novel approach to radical addition to
CdN bonds which would address these issues through
the use of a temporary linkage to make the radical
addition more favorable from an entropic standpoint,
avoid side reactions resulting from premature radical
quenching, and enforce some conformational constraints
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864 J . Org. Chem., Vol. 69, No. 3, 2004

Diastereoselective Additions of Hydroxymethyl and Vinyl Synthons
SCHEME 1
SCHEME 2
F IGURE 2. Silicon-tethered synthetic equivalents of hy-
droxymethyl and vinyl groups and their stereocontrolled
radical addition to CdN bonds.
After removal of the tether, the net result would be an
acyclic radical adduct; thus if the cyclization step were
rendered diastereoselective, the overall process could be
considered an indirect strategy for acyclic stereocontrol.
Could the well-known high internal conformational di-
astereocontrol of 5-hexenyl radical cyclizations10b be
harnessed for this formal acyclic stereocontrol of radical
addition to CdN bonds?
of Bartlett,21 Hart,22 and Parker23 in radical cyclizations
to oxime ethers, we selected these readily available Cd
N radical acceptors for the initial study,
Our plan was to engage the preexisting stereocenter
of a chiral R-hydroxy ester17 to direct the 5-exo-trig
cyclization of an alkyl radical, tethered via a temporary
silicon connection, to an imino acceptor (Figure 2).
Subsequent removal of the tether would afford acyclic
chiral R-branched amines. Importantly, the silicon tether
would permit introduction of a variety of functionalized
fragments.18 As described in preliminary communica-
tions, we have exploited this hypothesis to achieve (a)
hydroxymethyl group addition19 through atom abstrac-
tion-cyclization of a silicon-tethered bromomethyl group,
followed by Tamao oxidation; or (b) vinyl group addition20
via a tandem thiyl addition-cyclization of a tethered
vinyl group, followed by desilylative â-elimination of
benzenethiolate. Here, we provide a full account, includ-
ing additional exploratory experiments and expanded
discussion, of this work which has led to two comple-
mentary approaches for stereocontrolled addition of
functionalized radicals to R-hydroxyhydrazones.
Silylation and DIBAL reduction of methyl lactate and
methyl mandelate according to the known method24 gave
aldehydes 1a and 1b (Scheme 1), which condensed
readily with O-benzylhydroxylamine to afford oxime
ethers 2. Desilylation gave R-hydroxyoxime ethers 3,
which upon treatment with bromomethyldimethylsilyl
chloride in the presence of triethylamine provided bro-
momethylsilyl ethers 4. These cyclization substrates were
sensitive to purification and storage, and required rapid
flash chromatography and immediate use in the next
step. All of the oxime ethers were obtained as inseparable
mixtures of E and Z isomers (E/Z ca. 3-4:1) with respect
to the CdN bond.
Cyclizations under standard tin-mediated conditions
1
led to material having H NMR spectra suggesting its
main component was oxasilacyclopentane 5. The diaste-
1
reomer ratio was estimated by H NMR as 5:1 at this
stage. However, a pure compound could not be isolated
from this mixture; efforts to extract 5 into an acidic
aqueous phase or chromatograph it on silica gel were
thwarted by decomposition. Direct Tamao oxidation (KF,
KHCO3, H2O2, MeOH/THF) of the crude cyclization
product gave a complex mixture. Because hydroxyl-
amines are prone to oxidation, it seemed prudent to
acylate the basic nitrogen before exposure to oxidant.
Acylation of 5 could be achieved with methyl chlorofor-
mate and pyridine; Tamao oxidation of this product then
gave a mixture of three oxazolidinones cis-6, trans-6, and
7 in an overall 52% yield from 4a (Scheme 2). Although
cis-6 and 7 were each separated from the mixture by
Resu lts
Hyd r oxym et h yl Ad d it ion t o Oxim e E t h er s. Our
first test of the silicon tether approach for diastereose-
lective radical addition to R-hydroxyimino compounds
involved the use of bromomethyldimethylsilyl (BDMS)
ethers. These were chosen because halogen atom ab-
straction has a wealth of precedent for generating
radicals for cyclization; the first studies could then exploit
the most standard radical cyclization conditions (Bu3SnH,
AIBN [2,2′-azobis(isobutyronitrile)], PhH, 80 °C), which
had already been shown to be successful in addition to
various CdN acceptors. Cognizant of the seminal reports
(21) Bartlett, P. A.; McLaren, K. L.; Ting, P. C. J . Am. Chem. Soc.
1988, 110, 1633-1634.
(22) (a) Hart, D. J .; Seely, F. L. J . Am. Chem. Soc. 1988, 110, 1631-
1633. (b) Hart, D. J .; Krishnamurthy, R.; Pook, L. M.; Seely, F. L.
Tetrahedron Lett. 1993, 34, 7819-7822.
(17) A variety of R-hydroxy esters are available in one or two steps
from commercially available R-hydroxy acids or R-amino acids.
(18) Tamao, K.; Maeda, K.; Yamaguchi, T.; Ito, Y. J . Am. Chem. Soc.
1989, 111, 4984-4985.
(19) Friestad, G. K. Org. Lett. 1999, 1, 1499-1501.
(20) Friestad, G. K.; Massari, S. E. Org. Lett. 2000, 2, 4237-4240.
(23) Parker, K. A.; Spero, D. M.; Van Epp, J . J . Org. Chem. 1988,
53, 4628-4630.
(24) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J . Org. Chem. 1983,
48, 5180-5182.
J . Org. Chem, Vol. 69, No. 3, 2004 865

Friestad and Massari
SCHEME 3
silica gel chromatography, trans-6 was not obtained in
pure form. After this two-stage derivatization, the anti/
syn ratio was 9:1. Two similar derivatization experiments
resulted in anti/syn ratios of 4.9:1 and 11.6:1, with low
isolated yields. Because all three experiments began with
the same crude cyclization material, the ratio of oxazo-
lidinones apparently does not reflect the actual diaste-
reomer ratio from radical cyclization.
The relative configurations of oxazolidinones cis-6 and
trans-6 were determined on the basis of simple correla-
tions of 1H NMR spectra to literature precedents. In
numerous examples, including one case with N-alkoxy
substitution, H4 and H5 of cis-4,5-disubstituted oxazo-
lidinones are reliably shifted downfield by 0.1-0.5 ppm
relative to the trans isomers.25 This chemical shift
difference was readily discerned for H4 and H5 of the 6
diastereomers. Accordingly, the isomer with downfield
resonances (δ ) 3.40, 4.57 ppm) was assigned the
structure cis-6, and the one showing upfield resonances
(δ ) 3.20, 4.45 ppm) was assigned as trans-6.
SCHEME 4
Chemical behavior established the relative configura-
tion of monosubstituted oxazolidinone 7 and corroborated
the assignments of cis- and trans-6. Different exposures
to the basic Tamao oxidation conditions gave dramati-
cally different ratios of 7 and cis-6, while the amounts of
trans-6 were similar. This suggested that the monosub-
stituted oxazolidinone 7 was configurationally related to
cis-6 and that these constitutional isomers are intercon-
verted by transesterification under the Tamao oxidation
conditions. This isomerization only occurs with one of the
disubstituted oxazolidinones, providing evidence in favor
of the indicated assignments. Torsional strain associated
with the vicinal substituents should differentiate the cis
and trans oxazolidinone isomers; in this scenario the
relief of strain by transesterification of cis-6 to the
monosubstituted isomer would appear more favorable.
In further support of this assignment, exposure of iso-
merically pure cis-6 with K2CO3/MeOH indeed produced
7.
Although these preliminary results suggested the
potential utility of the silicon tether for diastereocon-
trolled radical addition to CdN bonds, some problems
were noted. First, an attempt to apply the multistep
procedure to mandelate derivative 3b failed to give
synthetically useful yields, casting some doubt on the
versatility of the sequence. Second, the diastereoselec-
tivities of the cyclizations were obscured by the multistep
follow-up sequence leading to 6. Finally, from a more
practical standpoint, the oxime ethers were obtained as
inseparable E/Z mixtures in all cases. Other imino
derivatives were considered in an effort to avoid these
problems.
observed with oxime ethers. Hydrazone cyclization sub-
strates were prepared using standard transformations
from the R-silyloxy esters 8 (Scheme 3), as described
above for the oxime ethers. The intermediate aldehydes
obtained by DIBAL reduction were condensed with N,N-
diphenylhydrazine to afford the corresponding hydra-
zones 9, followed by desilylation to give 10. Installation
of the bromomethylsilyl radical precursor group conve-
niently provided cyclization substrates 11 in good overall
yield. Although these bromomethylsilyl ethers were
somewhat unstable, they could be briefly exposed to silica
gel in order to obtain partially purified materials suitable
for the subsequent radical cyclizations. Hydrazones 9-11
were essentially single isomers (>98:2) with respect to
the CdN bond;26 only the lactate-derived compounds
(9a -11a ) contained detectable traces (<5%) of a minor
isomer.
Cyclization of bromides 11 using standard tin hydride
conditions (1.4 equiv of Bu3SnH, 10 mol % AIBN, PhH,
0.02 M) resulted in very clean, efficient C-C bond
construction to furnish heterocycles 12 (Scheme 4, Table
1). These cyclic silanes were unstable to normal silica gel
chromatography but could be stored indefinitely in
benzene at -5 °C without significant decomposition. In
the same flask, Tamao oxidation27 for oxidative removal
of the tether28 (KF, KHCO3, H2O2) then smoothly deliv-
ered anti-2-hydrazino-1,3-diols 13 in good yields. It is
worth noting that the Tamao oxidation occurs cleanly in
the presence of an unprotected hydrazine; this contrasts
with the behavior of hydroxylamine 5 described above.
H yd r oxym et h yl Ad d it ion t o H yd r a zon es. We
turned to hydrazones in hopes of improving on the results
(25) Oh, J . S.; Park, D. Y.; Song, B. S.; Bae, J . G.; Yoon, S. W.; Kim,
Y. G. Tetrahedron Lett. 2002, 43, 7209-7212. Ncube, A.; Park, S. B.;
Chong, J . M. J . Org. Chem. 2002, 67, 3625-3636. Sugiura, M.; Hagio,
H.; Hirabayashi, R.; Kobayashi, S. J . Am. Chem. Soc. 2001, 123,
12510-12517. Merino, P.; Castillo, E.; Franco, S.; Mercha´n, F. L.;
Tejero, T. Tetrahedron 1998, 54, 12301-12322. Deng, J . G.; Hamada,
Y.; Shioiri, T. Synthesis 1998, 627-638. Williams, D. R.; Osterhout,
M. H.; Reddy, J . P. Tetrahedron Lett. 1993, 34, 3271-3274. Falb, E.;
Nudelman, A.; Hassner, A. Synth. Commun. 1993, 23, 2839-2844.
Moreno-Man˜as, M.; Padros, I. J . Heterocycl. Chem. 1993, 30, 1235-
1239. Foglia, T. A.; Swern, D. J . Org. Chem. 1968, 34, 1680-1684.
(26) Aldehyde hydrazones are generally obtained as E isomers.
Enders, D. In Asymmetric Synthesis; Morrison, J . D., Ed.; Academic
Press: New York, 1984, pp 275-339.
(27) Tamao, K.; Ishida, N.; Ito, Y.; Kumada, M. Organic Syntheses;
Wiley: New York, 1993; Collect. Vol. VIII, pp 315-321.
(28) Fleming, I. Chemtracts-Org. Chem. 1996, 9, 1-64.
866 J . Org. Chem., Vol. 69, No. 3, 2004

Diastereoselective Additions of Hydroxymethyl and Vinyl Synthons
the acetonide methyl groups in 13C NMR spectra char-
TABLE 1. Dia ster eom er Ra tios in Cycliza tion a n d
Ta m a o Oxid a tion Sequ en ce fr om
acteristic of axial and equatorial orientations; this con-
Br om om eth yld im eth ylsilyl Eth er s 11a -d (Sch em e 4)
firmed the predominance of chair conformations.30
Con figu r a tion a l In tegr ity. Mosher ester analysis
confirmed that the integrity of the preexisting stereo-
center was maintained through the sequence to diols 13b
and 13c (>96% ee). Thus, the R-hydroxy and R-silyloxy
hydrazones in these sequences are configurationally
stable under the conditions employed in this study.
However, alcohol 10d , wherein the phenyl group can
promote enolization, suffered significant racemization at
some point en route to 13d . Mosher ester analysis of 13d
showed only 33% ee. It is most likely that the racemiza-
tion occurs during silylation using triethylamine as a
base. Unfortunately, an attempt to confirm this was
unsuccessful: significant decomposition occurred during
preparation of the Mosher ester from R-hydroxyhydra-
zone 10d . Nevertheless, it can be concluded that, so long
as additional carbanion-stabilizing functionality is not
present to facilitate enolization (as in 10d ), the silicon
tether strategy for radical addition to R-hydroxyhydra-
zones preserves the configurational integrity of the
starting R-hydroxyester.
oxasilacyclopentane
2-hydrazino 1,3-diol
entry
R
product, ratio (trans/cis)a product, ratio (anti/syn)a
1
2
3
4
Me
iBu
iPr
Ph
12a , 80:20
12b, 88:12
12c, 95:5
13a , 79:21
13b, 85:15
13c, 96:4b
13d , >98:2c
12d , >98:2c
Ratios from integration of 1H NMR spectra. Ratio of isolated
a
b
diastereomers. c Minor isomer not detected.
SCHEME 5
Ta n d em Th iyl Ad d ition -Cycliza tion : Vin yl Ad -
d ition to Hyd r a zon es. Having shown that conforma-
tional constraints can be harnessed via a temporary
silicon connection to achieve formal acyclic stereocontrol
in hydroxymethyl addition, we sought a method to
introduce a functionalized two-carbon fragment. We
recognized that intermolecular addition of heteroatom
radicals to an alkene or alkyne can initiate a cyclization
event when a second radical acceptor moiety is ap-
propriately situated.31,32 This led to the hypothesis that
stannyl or thiyl radical addition to a vinyl group, tem-
porarily tethered to a chiral R-hydroxyhydrazone, would
lead to an alkyl radical which could cyclize with excellent
stereocontrol.33,34 Because chlorodimethylvinylsilane is
inexpensive and commercially available in large quanti-
ties, its derived vinylsilyl ethers appeared to be attractive
starting points to test this hypothesis.
Diastereoselectivities of the cyclizations were revealed
by independent analyses which were found to give
consistent results. Examination of cyclic silanes 12 by
1H NMR spectroscopy gave a direct measure of the
diastereomer ratios. A separate measurement was made
after Tamao oxidation; the results were very similar.
Although 13a and 13b could not be obtained in diaste-
reomerically pure form at this stage, the diastereomeric
products syn-13c and anti-13c could be separated after
Tamao oxidation; the ratio of isolated diastereomers was
nearly identical to the ratio determined spectroscopically
at the cyclic silane stage.
For further stereochemical analysis of the hydroxy-
methyl adducts, 1,3-diol acetonides 14 (Scheme 5) were
prepared by treatment with dimethoxypropane (PPTS,
CHCl3). During this preparation of 14a from 13a , small
amounts of a material tentatively identified as a 4,5-
disubstituted 1,3-dioxolane (i.e., a five-membered cyclic
O,N-acetal) were observed; this material was converted
to 14a on standing. For 13a and 13b, which were used
as diastereomeric mixtures, this procedure offered the
benefit of easy chromatographic separation of the anti
and syn diastereomers of acetonides 14a and 14b.
Hydrolysis (PPTS, MeOH) then gave access to the dia-
stereomerically pure major isomers 13a and 13b.
Relative configurations of diols 13 were readily ascer-
tained via NMR spectra of the corresponding acetonides.
Analysis of 1H NMR spectra of the major isomers 14a -d
revealed large vicinal coupling constants (J 2,3 ) 8.7-9.7
Hz) in all cases, consistent with the assignment of anti
configurations.29 The reliability of this assignment was
verified by the dramatic differences in chemical shifts of
(29) Coupling constants of acetonides have previously been used to
elucidate the relative configurations of various 2-amino-1,3-diols.
Devijver, C.; Salmoun, M.; Daloze, D.; Braekman, J . C.; De Weerdt,
W. H.; De Kluijver, M. J .; Gomez, R. J . Nat. Prod. 2000, 63, 978-980.
Mancini, I.; Guella, G.; Debitus, C.; Pietra, F. Helv. Chim. Acta 1994,
77, 51-58. Mori, K.; Uenishi, K. Liebigs Ann. Chem. 1994, 41-48.
Barrett, A. G. M.; Rys, D. J . Chem. Soc. Perkin Trans. 1 1995, 1009-
1017. Han, B. H.; Kim, J . C.; Park, M. K.; Park, J . H.; Go, H. J .; Yang,
H. D.; Suh, D.-Y.; Kang, Y.-H. Heterocycles 1995, 41, 1909-1914.
Herold, P.; Helv. Chim. Acta 1988, 71, 354-362.
(30) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9-17.
(31) Reviews: Miyata, O.; Naito, T. C. R. Acad. Sci. Paris, Chim.
2001, 4, 401-421. Naito, T. Heterocycles 1999, 50, 505-541. For
selected recent examples, see: Miyata, O.; Nakajima, E.; Naito, T.
Chem. Pharm. Bull. 2001, 49, 213-224. Miyata, O.; Muroya, K.;
Kobayashi, T.; Yamanaka, R.; Kajisa, S.; Koide, J .; Naito, T. Tetrahe-
dron 2002, 58, 4459-4479. Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito,
T. Tetrahedron 2000, 56, 6199-6207. Depature, M.; Diewok, J ..;
Grimaldi, J .; Hatem, J . Eur. J . Org. Chem. 2000, 275-280. Ryu, I.;
Ogura, S.; Minakata, S.; Komatsu, M. Tetrahedron Lett. 1999, 40,
1515-1518. Depature, M.; Siri, D.; Grimaldi, J .; Hatem, J .; Faure, R.
Tetrahedron Lett. 1999, 40, 4547-4550. Marco-Contelles, J .; Rodriguez,
M. Tetrahedron Lett. 1998, 39, 6749-6750.
(32) For cyclizations of CdN acceptors initiated by intermolecular
addition of alkyl radicals, see: Miyabe, H.; Fujii, K.; Goto, T.; Naito,
T. Org. Lett. 2000, 2, 4071-4074. Miyabe, H.; Ueda, M.; Fujii, K.;
Nishimura, A.; Naito, T. J . Org. Chem. 2003, 68, 5618-5626. Ueda,
M.; Miyabe, H.; Nishimura, A.; Miyata, O.; Takemoto, Y.; Naito, T.
Org. Lett. 2003, 5, 3835-3838.
J . Org. Chem, Vol. 69, No. 3, 2004 867

Friestad and Massari
SCHEME 6
SCHEME 7
SCHEME 8
For an initial feasibility study, we began with glycol-
aldehyde dimer, which was condensed with diphenylhy-
drazine to provide R-hydroxyhydrazone 15 (78%). Sily-
lation with chlorodimethylvinylsilane (16, Scheme 6)
provided the addition/cyclization substrate 17 (93% yield).
Treatment of 17 with thiophenol and AIBN (cyclohexane,
reflux) resulted in very clean, efficient C-C bond con-
struction to furnish cyclic silane 18 as a mixture of
diastereomers (Scheme 6). Like its analogues 5 and 12,
18 was not amenable to standard flash chromatography
on silica gel. In the same flask, 18 was smoothly
converted to allylic hydrazino alcohol 19 (racemic) by the
action of excess KF (54% yield, 2 steps). This one-pot
process (17 f 19) achieves vinyl addition to a CdN bond
under neutral conditions, without toxic and difficult-to-
remove stannane reagents.
The formation of 19 can be rationalized by a tandem
process entailing thiyl (PhS•) addition to the terminal
carbon of the alkene of 17, followed by cyclization of the
resulting R-silylalkyl radical to form an aminyl radical.
Quenching of the cyclized aminyl radical by hydrogen
atom abstraction from thiophenol would generate 18 and
a thiyl radical, propagating a radical chain. Upon treat-
ment of 18 with fluoride, â-elimination of thiolate pre-
sumably occurs from an intermediate fluorosilicate,
regenerating the alkene functionality during the desily-
lation.35 Radical addition products bearing sulfur could
not be found after the fluorodesilylation.
as a diastereomeric mixture. When this diol was exposed
to acidic transacetalization conditions (dimethoxypro-
pane, PPTS), a mixture of alkenes 19 and 21 was
formed.36 Without precautions to exclude acid and ad-
ventitious moisture, the mixed acetal 21 was rapidly
1
hydrolyzed during H NMR analysis in CDCl3 to afford
19 along with equimolar amounts of methanol and
acetone. The formation of alkenes 19 and 21 along with
loss of the tributyltin presumably occurs by a cationic
â-elimination process during acetonide formation. Al-
though the net result indicated successful C-C bond
construction, the tin-mediated process was discontinued
in favor of further pursuit of the thiyl addition-cyclization
reactions; the latter seemed more attractive because of
the opportunity to avoid the use of toxic tin reagents.
Chiral R-hydroxy acids could be envisioned as precur-
sors for chiral R-hydroxyhydrazones analogous to achiral
glycolaldehyde derivative 17. The overall sequence in-
volving the thiyl addition-cyclization reaction would
then lead to substituted vinylglycinols. These are poten-
tially useful differentially functionalized allylic amino
alcohol building blocks; the parent structure (Scheme 8,
R ) X ) H) is a chiral building block of well-documented
utility.37
A similar tandem sequence was explored using stannyl
radicals. Addition-cyclization of 17 with tributyltin
hydride and AIBN (Scheme 7) appeared to lead to the
desired addition/cyclization process as judged by 1H NMR
spectra. However, further attempted transformations
(fluorodesilylation or Tamao oxidation) of the cyclic
product gave complex mixtures and generally low yields.
In one case, Tamao oxidation in refluxing methanol-THF
occurred in 60% yield to furnish tin-containing diol 20
Toward this end, we explored the diastereoselectivity
of the tandem thiyl addition-cyclization process using
cyclization substrates 22a -d 38 (Scheme 9), easily pre-
pared from enantiomerically pure R-hydroxy hydrazones
10a -d by silylation with 16. Reductive cyclization oc-
curred upon treatment with thiophenol/AIBN, affording
(36) In this experiment, cyclic hemiaminal 25 was also formed in
low yield.
(37) For selected alternative preparations and applications, see:
Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 99-
102, and references therein. See also: Collier, P. N.; Campbell, A. D.;
Patel, I.; Raynham, T. M.; Taylor, R. J . K. J . Org. Chem. 2002, 67,
1802-1815. Overman, L. E.; Remarchuk, T. P. J . Am. Chem. Soc. 2002,
124, 12-13. Berkowitz, D. B.; Chisowa, E.; McFadden, J . M. Tetrahe-
dron 2001, 57, 6329-6343. Chandrasekhar, S.; Raza, A.; Takhi, M.
Tetrahedron: Asymmetry 2001 13, 423-428. Sabat, M.; J ohnson, C.
R. Tetrahedron Lett. 2001, 42, 1209-1212. Sabat, M.; J ohnson, C. R.
Org. Lett. 2000, 2, 1089-1092. Butler, D. C. D.; Inman, G. A.; Alper,
H. J . Org. Chem. 2000, 65, 5887-5890. Harris, M. C. J .; J ackson, M.;
Lennon, I. C.; Ramsden, J . A.; Samuel, H. Tetrahedron Lett. 2000, 41,
3187-3191. Monache, G. D.; Misiti, D.; Salvatore, P.; Zappia, G.;
Pierini, M. Tetrahedron: Asymmetry 2000, 11, 2653-2659.
(38) Hydrazones were obtained as single CdN bond isomers (>98:
2).
(33) This exploits a vinylsilane as a source of a tethered radical.
Previously, intramolecular trapping of various cyclic radicals with a
vinylsilane as a tethered radical acceptor has been reported by Matsuda
et al. For examples, see: Kodama, T.; Shuto, S.; Nomura, M.; Matsuda,
A. Chem. Eur. J . 2001, 7, 2332-2340. Shuto, S.; Yahiro, Y.; Ichikawa,
S.; Matsuda, A. J . Org. Chem. 2000, 65, 5547-5557 and references
therein.
(34) A nonradical silicon-tethered strategy using BF3‚OEt2-induced
vinylsilane addition to an acyliminium ion has been reported. Hioki,
H.; Izawa, T.; Yoshizuka, M.; Kunitake, R.; Ito, S. Tetrahedron Lett.
1995, 36, 2289-2292.
(35) For a similar fluorodesilylative â-elimination of a â-phenylse-
leno group, see: Sugimoto, I.; Shuto, S.; Matsuda, A. J . Org. Chem.
1999, 64, 7153-7157.
868 J . Org. Chem., Vol. 69, No. 3, 2004

Diastereoselective Additions of Hydroxymethyl and Vinyl Synthons
SCHEME 9
SCHEME 11
TABLE 2. Yield s a n d Selectivities of Th iyl
droxyhydrazones 15 (R ) H, from 17) or 10 (R ) alkyl or
aryl, from 22).
Ad d ition -Cycliza tion of Hyd r a zon es 22a -d (Sch em e 9)a
entry
R
product, yieldb (%)
ratio (anti/syn)c
Conversion of 19 and 23a -c to their 2,2-dimethyloxa-
zolidine (acetonide) derivatives was facile (eq 1). Using
1 equiv of PPTS and excess 2,2-dimethoxypropane, the
acetonides 25 and 26a -c were formed smoothly in
synthetically useful yields on milligram scale. Using 10
mol % PPTS, the reaction of 23c was scaled up to 0.5 g
with similar results (75% yield).
1
2
Me
iBu
iPr
iPr
Ph
23a , 77
23b, 67
23c, 61
23c, 89
23d , 49
90:10
94:6
3
98:2
4d
5
>98:2d,e
>98:2e
a
Conditions: 1.2 equiv of PhSH, 10 mol % AIBN, 0.1-0.3 mmol
of hydrazone in refluxing cyclohexane (0.1 M), 2-3 h with TLC
monitoring. If necessary (TLC), additional AIBN was added and
b
the reaction was continued until complete. Isolated yields of
diastereomeric mixtures. c Ratios from integration of 500 MHz 1H
d
NMR spectra. Reaction run on 5 g scale, yield and ratio after
isolation by crystallization. e Minor isomer not detected.
SCHEME 10
Relative configuration of anti-23c was determined by
a combination of chemical correlation experiments and
NOE difference spectra using the diastereomerically pure
acetonide 26c. Lemieux-J ohnson oxidation,41 followed by
borohydride reduction of the intermediate aldehyde, gave
a low yield of acetonide 27 (Scheme 11). Exposure to the
typical acetonide-forming conditions then converted this
to 14c, the configuration of which had already been
established (see Scheme 5). Strong NOE enhancements
were observed between the isopropyl methine and the
internal olefinic hydrogen of 26c,42 providing further
support for the assigned structure.
cyclic silane intermediates similar to 18.39 Exposure to
KF led to allylic anti-hydrazino alcohols 23a -d (Table
2). Diastereomers anti-23a and syn-23a were readily
separated by chromatography. For characterization pur-
poses, pure anti-23b was obtained by conversion to its
acetonide derivative (vide infra), chromatographic sepa-
ration, and hydrolysis.
A promising indication for multigram material through-
put was observed upon increasing the scale to ca. 5 g
(Table 2, entry 4). Crystalline, diastereomerically pure
23c was obtained in a significantly improved yield (89%
after crystallization).
Variable amounts of R-hydroxyhydrazones 10 or 15 (ca.
3-10% yield) were generally observed as byproducts after
the fluorodesilylation stage of the thiyl addition-cycliza-
tion process. As judged by 1H NMR analysis, alkenes
were absent prior to treatment with fluoride. Thus, the
recovery of this material can be attributed to hydrogen
atom abstraction to quench the R-silyl radical prior to
cyclization, leading to the product of simple addition of
thiophenol (Scheme 10).40 Fluorodesilylation of the un-
cyclized thiophenol adducts would regenerate the R-hy-
Dia ster eocon tr ol. The Beckwith-Houk model43 pre-
dicts enhancement of diastereoselectivity upon increasing
substituent steric demand in 4-substituted 5-hexenyl
radical cyclizations. The present method was conceived
in expectation that a similar transition state model would
apply. Indeed, experimental support for this is seen in
the correlation of diastereoselectivity with substituent A
values44 (Table 3). A transition state resembling chairlike
conformation A (Scheme 12), wherein the pseudoequa-
torial orientation of substituent R minimizes allylic
strain, is consistent with the observed anti diastereose-
lection. The minor syn product would be expected from
(40) The premature hydrogen abstraction process would be expected
to be suppressed by slow addition of the thiophenol.
(41) Pappo, R.; Allen, D. S.; Lemieux, R. U.; J ohnson, W. S. J . Org.
Chem. 1956, 21, 478-479.
(42) The NOE enhancement was 10% at the internal vinyl hydrogen
upon irradiation of the isopropyl methine; the inverse enhancement
was 8% at the isopropyl methine.
(43) Beckwith, A. L. J .; Schiesser, C. H. Tetrahedron 1985, 41, 3925-
3941. Spellmeyer, D. C.; Houk, K. N. J . Org. Chem. 1987, 52, 959-
974.
(44) Bushweller, C. H. In Conformational Behavior of Six-Membered
Rings; J uaristi, E., Ed.; VCH: New York, 1995.
(39) Unfortunately, 1H NMR analysis of the cyclic silane intermedi-
ate did not give a clear indication of the diastereomer ratio.
J . Org. Chem, Vol. 69, No. 3, 2004 869

Friestad and Massari
TABLE 3. Cor r ela tion of Su bstitu en t A Va lu es w ith
Dia ster eoselectivity in Hyd r oxym eth yl a n d Vin yl
Ad d ition
SCHEME 13
entry
R
A value (kcal/mol)a
dr of 13b
dr of 23c
1
2
3
4
Me
iBu
iPr
Ph
1.6
1.8 (est)
2.2
79:21
85:15
96:4
90:10
94:6
98:2
2.9
>98:2d
>98:2d
a
Free energy differences between equatorial and axial chair
b
conformers of the monosubstituted cyclohexane. Hydroxymethyl
addition; ratios determined as described in Table 1. c Vinyl addi-
d
tion; ratios determined as described in Table 2. Minor isomer
not detected.
SCHEME 12
regarded as unlikely. Indeed, only a few examples of
radical addition at the nitrogen atom of imino acceptors
have been reported, facilitated through polarity effects
or engineered through modifications to radical reactivity.
Here, in the absence of any unusual regiocontrol factors,
5-exo cyclization through the proximal silyl ether linkage
would be expected to predominate, considering the more
rapid rates relative to 6-exo cyclization. Rates of 5-exo
cyclization in related hydrazones with carbon tethers
have been determined by competition experiments to be
about 100 times faster than the corresponding 6-exo
cyclizations.46
To test the feasibility of this approach, two bis-
(vinylsilyloxy)hydrazone cyclization precursors were syn-
thesized from glyceraldehyde and crotonaldehyde. Hy-
drazone 28 (Scheme 13) was prepared by condensation
of commercially available aqueous D-glyceraldehyde with
diphenylhydrazine, followed by silylation of both hydroxyl
groups with chlorosilane 16. Another diol precursor was
obtained from E-crotonaldehyde, which was condensed
with diphenylhydrazine to furnish hydrazone 29 in 67%
yield as a ca. 9:1 mixture of olefin isomers (Scheme 13).47
Sharpless asymmetric dihydroxylation (AD)48 afforded
the resulting diol in 76% yield as a mixture of syn- and
anti-diol diastereomers; the major syn-diol 30 was formed
in 76% ee.49,50 The minor anti-diol was not unexpected
considering the small amount of Z-olefin present in the
precursor. Bis-silylation of the syn-diol with 16 furnished
cyclization substrate 31 in 77% yield (syn/anti ) 89:11).
Vinyl addition to bis-silylated substrate 28 (Scheme 14)
occurred upon treatment with thiophenol/AIBN; fluo-
rodesilylation using KF furnished hydrazino diol 32 with
disfavored chair-axial (B) and/or boat (C) conformations.45
Boat-axial conformations are considered to have negli-
gible contributions to stereocontrol in 5-hexenyl radical
cyclizations.10b
The diastereoselectivity of vinyl addition, 90:10 or
higher in all cases, is also attributable to the conforma-
tional constraints described above. The vinyl additions
occurred with consistently higher stereoselectivity in
comparison to hydroxymethyl addition. This fact may be
rationalized by considering the relative reactivities of the
two radical intermediates A and D (Scheme 12). If the
more reactive silylmethyl radicals A are assumed to have
earlier transition states than the more substituted alkyl
radicals D, this might elicit a decreased contribution from
the cyclohexane-like conformational constraints described
above and a decreased differentiation of the diastereo-
meric transition states leading to the alternative anti and
syn products.
Vin yl Ad d ition to R,â-Dih yd r oxyh yd r a zon es. We
expected that R,â-dihydroxyhydrazones, which would
support two tethered vinyl groups, could also undergo
vinyl transfer stereoselectively. In this case, either 5-exo
or 6-exo cyclization could be initiated by thiyl addition
to either of the two tethered vinylsilanes. No evidence of
6-endo cyclization was found in the experiments de-
scribed above, so 6-endo or 7-endo cyclizations may be
(46) For kinetic data, see: Sturino, C. F.; Fallis, A. G. J . Org. Chem.
1994, 59, 6514-6516.
(47) The E- and Z-isomers were inseparable at this point. Although
only the major isomer is shown in the following steps, minor diaster-
eomers were present as judged by 1H NMR spectra.
(48) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483-2547.
(49) Enantiomeric excess and absolute configuration were assessed
through 1H NMR analysis of the corresponding bis-Mosher esters (see
the Supporting Information).
(50) To our knowledge, this is the first example of asymmetric
dihydroxylation in the presence of a hydrazone.
(45) (a) Boat-axial conformations are considered to have negligible
contributions to stereocontrol in 5-hexenyl radical cyclizations.10b (b)
Cyclohexane terminology for 5-hexenyl radical transition states is the
current convention.10b
870 J . Org. Chem., Vol. 69, No. 3, 2004

Diastereoselective Additions of Hydroxymethyl and Vinyl Synthons
SCHEME 14
SCHEME 15
high selectivity (dr 91:9) as observed in the monosilylated
substrates. Cyclization substrate 31 also underwent the
addition-cyclization process to afford 33 (dr 88:12) in 63%
yield after chromatographic purification. Another dia-
stereomer was present, carried through from the syn/anti
mixture of 31 (dr 89:11) employed in this experiment.51
For this reason, the stereochemical outcome is not
entirely unambiguous in this case. However, both syn-
31 and anti-31 appeared to undergo highly diastereospe-
cific vinyl addition; only two of the four possible diaster-
eomers of 33 were found, and they were present in the
same ratio as the starting material. Also, a key point is
clearly established by the vinyl additions of Scheme 14:
The two hydroxyls of D-glyceraldehyde or dihydroxyhy-
drazone 30 do not require protection or differentiation
prior to this radical vinylation sequence. It should be
noted also that 32 and 33 are potentially useful chiral
building blocks bearing differentially functionalized ter-
mini.
Relative configurations of diols 32 and 33 were as-
signed by analogy to the hydrazino alcohols 13 and 23
described above. Mechanistic considerations support both
of these assignments (Scheme 15). First, the D-glyceral-
dehyde-derived 32 could arise through either 5-exo or
6-exo cyclization of 28, which could be initiated by thiyl
addition to either R-vinylsilyloxy or â-vinylsilyloxy groups,
respectively. Assuming the C-C bond formations (i.e.,
the cyclization steps) are irreversible, the faster 5-exo
cyclization via E should predominate and the Beckwith-
Houk model can be invoked as described above to predict
anti-32 as the major product. The 6-exo pathway from
28 via F would result in the corresponding syn-32, with
low stereoselectivity expected because of the low A value
of the silyloxy substituent. Accordingly, the highly ste-
reoselective formation of anti-32 (91:9) lends support to
the suggestion of a preferred 5-exo pathway and justifica-
tion for the application of the Beckwith-Houk model for
predicting the anti configuration. Cyclization substrate
31 also could potentially cyclize via either 5-exo or 6-exo
modes, with the 5-exo route via G predicted to be
kinetically preferred, leading to 3,4-anti-33. In this case,
however, the competition between the pathways would
be nullified by their convergence to the same configura-
tion. In the 6-exo mode, the additional methyl group of
31 (compared to 28) should enforce a preference for the
alternative chair conformer H with the smaller silyloxy
substituent axial. After cyclization and fluorodesilylation,
both pathways should lead to the same diastereomer; this
stereoconvergency model is consistent with the very high
diastereoselectivity (>98:2 with respect to the new ste-
reocenter) observed in formation of 33. In all the vinyl
additions, the stereocenter generated adjacent to the Si
atom is not preserved after fluorodesilylation, and there-
fore it is premature to draw any definitive conclusions
from this work about the stereocontrol at this center
during cyclization. However, it can be assumed that an
equatorial orientation of the radical subsituent is pre-
ferred, as shown in the transition states D-H.
Con clu sion
In conclusion, a method for stereocontrolled radical
addition to chiral hydrazones has been designed and
implemented, which, in conjunction with various estab-
lished methods for reductive cleavage of hydrazine N-N
bonds,52 constitutes a novel nonpolar complement to ionic
methods for acyclic amino alcohol synthesis. This carbon-
carbon bond construction approach to chiral R-branched
amine synthesis features the temporary silicon connec-
tion for formal acyclic stereocontrol of radical addition
to CdN bonds. The hydroxymethyl group can be added
to a range of chiral R-hydroxyhydrazones using a bro-
momethylsilyl ether as a radical precursor via tin-
mediated halogen atom abstraction. The vinyl group can
be added using a vinylsilyl ether which is activated for
radical cyclization by thiyl radical addition. In the latter
case, the method has been successfully extended to the
(52) Mellor, J . M.; Smith, N. M. J . Chem. Soc., Perkin Trans. 1 1984,
2927-2931. Burk, M. J .; Feaster, J . E. J . Am. Chem. Soc. 1992, 114,
6266-6267. Enders, D.; Reinhold, U. Angew. Chem., Int. Ed. Engl.
1995, 34, 1219-1222. Sturino, C. F.; Fallis, A. G. J . Am. Chem. Soc.
1994, 116, 7447-7448. Martin, S. F.; Hom, R. K. Tetrahedron Lett.
1999, 40, 2887-2890. Alonso, F.; Radivoy, G.; Yus, M. Tetrahedron
2000, 56, 8673-8678. Deniau, E.; Enders, D. Tetrahedron 2001, 57,
2581-2588. Dahlen, A.; Hilmersson, G. Tetrahedron Lett. 2002, 43,
7197-7200.
(51) A mixture of syn and anti diols (dr 9:1) was employed. These
inseparable isomers resulted from the 9:1 ratio of inseparable E- and
Z-olefins used in the asymmetric dihydroxylation.
J . Org. Chem, Vol. 69, No. 3, 2004 871

Friestad and Massari
65.6, 21.1. Z-Isomer: 1H NMR (500 MHz, CDCl3) δ 6.78 (d, J
) 5.0 Hz, 1H), 5.12 (s, 3H), 4.89-4.84 (m, 1H), 1.33 (d, J )
6.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 154.9, 76.4, 62.5,
20.0; some resonances were not resolved from those of the
major isomer. E/Z mixture: IR (film, ATR) 3400 (br), 2926,
1454, 1021 cm-1; MS (APCI-LCMS, H2O/MeOH) m/z (relative
intensity) 180 ([M + H]+, 100). Anal. Calcd for C10H13NO2: C,
67.02; H, 7.31; N, 7.82. Found: C, 66.45; H, 7.37; N, 7.57.
use of R,â-dihydroxyhydrazones without prior protection
or hydroxyl differentiation. Stereoselectivity in both these
processes is consistent with predictions by the Beckwith-
Houk model for 5-exo cyclizations of substituted 5-hex-
enyl radicals.
Exp er im en ta l Section 53
(S)-2-Hyd r oxy-2-p h en yleth a n a l O-Ben zyloxim e (3b). A
solution of 2b (352 mg, 0.99 mmol) and TBAF (1 M in THF,
1.2 mL, 1.2 mmol) in THF (12 mL) was stirred at ambient
temperature for 1 h. Concentration in vacuo and flash chro-
matography (5:1 hexane/EtOAc) furnished 3b (227 mg, 95%
yield, inseparable 4:1 E/Z mixture) as a colorless oil. E-
Isomer: 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J ) 5.3 Hz,
1H), 7.43-7.28 (m, 10H), 5.34 (d, J ) 5.1 Hz, 1H), 5.14 (s,
2H), 2.60 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 151.0, 139.6,
137.2, 128.7, 128.4, 128.3, 128.2, 128.0, 126.4, 76.3, 71.7.
Z-Isomer: 1H NMR (500 MHz, CDCl3) δ 6.97 (d, J ) 5.5 Hz,
1H), 5.86 (d, J ) 5.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
152.7, 140.0, 137.3, 128.6, 128.0, 76.5, 68.0; some resonances
were not resolved from those of the major isomer. E/Z
Hyd r oxym eth yl Ad d ition to Oxim e Eth er s. (S)-2-(ter t-
Bu tyld im eth ylsilyloxy)p r op a n a l O-Ben zyloxim e (2a ). A
solution of (S)-2-(tert-butyldimethylsilyloxy)propanal24 (1a ) (0.5
g, 2.6 mmol) and O-benzylhydroxylamine hydrochloride (0.48
g, 3.0 mmol) in pyridine (1 mL) was stirred at ambient
temperature for 40 h. After concentration in vacuo to remove
most of the pyridine, the mixture was partitioned between aq
NaHCO3 and CH2Cl2. Drying over Na2SO4, concentration, and
gradient flash chromatography (hexane f 10:1 hexane/EtOAc)
furnished 2a (715 mg, 92% yield, inseparable 3:1 E/Z mixture)
as a colorless oil. E-Isomer: 1H NMR (500 MHz, CDCl3) δ
7.36-7.29 (m, 6H), 5.07 (s, 2H), 4.41 (quintet, J ) 6.4 Hz, 1H),
1.30 (d, J ) 6.4 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.03 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 153.6, 137.6, 128.3, 128.2,
127.8, 75.8, 66.6, 25.8, 22.4, 18.1, -4.6, -4.9. Z-Isomer: 1H
NMR (500 MHz, CDCl3) δ 6.72 (d, J ) 5.6 Hz, 1H), 5.07 (ABq,
∆ν ) 8.5 Hz, J ) 12.4 Hz, 2H), 5.02-4.96 (m, 1H), 1.28 (d, J
) 6.6 Hz, 3H), 0.90 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 153.6, 137.9, 127.9, 76.1, 63.0, 25.8, 21.0,
18.1, -4.9, -5.0; some resonances were not resolved from those
of the major isomer. E/Z mixture: IR (film, ATR) 2955, 1471,
1254, 1089 cm-1; MS (APCI-LCMS, H2O/MeOH) m/z (relative
mixture: IR (film, ATR) 3413 (br), 3032, 1453, 1010 (s) cm-1
;
MS (APCI-LCMS, H2O/MeOH) m/z (relative intensity) 242 ([M
+ H]+, 100), 224 ([M - OH]+, 58). Anal. Calcd for C10H13NO2:
C, 74.67; H, 6.27; N, 5.81. Found: C, 74.28; H, 6.37; N, 5.72.
Oxa zolid in on es cis-6, 7, a n d tr a n s-6. A solution of
R-hydroxyoxime 3a (196 mg, 1.09 mmol) in dry CH2Cl2 (1.1
mL) at 0 °C was treated sequentially with Et3N (0.20 mL, 1.4
mmol) and bromomethyldimethylsilyl chloride (0.20 mL, 1.4
mmol). After 0.5 h at 0 °C, the mixture was diluted with ether
(2 mL) and filtered through a short plug of silica gel (elution
with ether). Rapid flash chromatography (10:1 hexane/EtOAc)
gave bromomethylsilyl ether 4a (297 mg, 83%) which was used
directly for the subsequent step. A portion of 4a (170 mg, 0.515
mmol), tributyltin hydride (0.19 mL, 0.67 mmol), and 2,2′-
azobis(isobutyronitrile) (AIBN, 20 mg, 0.12 mmol) in benzene
(18 mL) was deoxygenated (N2 via needle) for ca. 10 min and
then heated at reflux for 1.5 h. Additional AIBN (20 mg, 0.12
mmol) was added in two portions at 0.5 h intervals. The
colorless crude intermediate cyclic silane (5, dr 5:1 by 1H NMR)
was obtained as a solution in benzene. A portion of the cyclic
silane (0.023 M in benzene, 4.0 mL, 0.092 mmol) was concen-
trated to remove benzene and then treated with pyridine (11
µL, 0.14 mmol) and methyl chloroformate (11 µL, 0.14 mmol)
in CH2Cl2 (0.3 mL) at ambient temperature for ca. 12 h. The
reaction mixture was partitioned between CH2Cl2 and H2O,
dried (Na2SO4), and concentrated. The residue was dissolved
in THF/methanol (1:1, 0.5 mL) and treated with KF (15 mg,
0.26 mmol) and KHCO3 (20 mg, 0.20 mmol) at ambient
temperature for 15 min, followed by addition of H2O2 (30%,
0.1 mL, 0.88 mmol). After 8 h, the emaining H2O2 was
quenched with aqueous Na2S2O3 (20%, 0.5 mL), and the
reaction mixture was diluted with ether, dried over Na2SO4,
and concentrated. Gradient flash chromatography (hexane f
EtOAc) afforded a mixture of oxazolidinones cis-6, 7, and
trans-6 (17 mg, 52%54 from 4a ) as a colorless oil. Radial
chromatography resolved cis-6 and 7, but trans-6 could not
be obtained in pure form. Monosubstituted oxazolidinone 7
intensity) 294 ([M + H]+, 100), 162 (22). Anal. Calcd for C16H27
-
NO2Si: C, 65.48; H, 9.27; N, 4.77. Found: C, 65.18; H, 9.42;
N, 4.84.
(S)-2-(ter t-Bu tyld im eth ylsilyloxy)-2-p h en yleth a n a l O-
Ben zyloxim e (2b). A solution of (S)-2-(tert-butyldimethylsil-
yloxy)-2-phenylethanal24 (1b) (536 mg, 2.14 mmol) and O-
benzylhydroxylamine hydrochloride (0.38 g, 2.4 mmol) in
pyridine (1 mL) and toluene (1 mL) was stirred at ambient
temperature for 36 h. After concentration in vacuo to remove
most of the pyridine, the mixture was partitioned between aq
NaHCO3 and CH2Cl2. Drying over Na2SO4, concentration, and
gradient flash chromatography (hexane f 5:1 hexane/EtOAc)
furnished 2b (702 mg, 92% yield, inseparable 3:1 E/Z mixture)
as a colorless oil. E-Isomer: 1H NMR (500 MHz, CDCl3) δ
7.46-7.30 (m, 11H), 5.37 (d, J ) 7.6 Hz, 1H), 4.54 (s, 2H),
0.95 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 152.3, 140.9, 137.3, 128.4, 128.3, 128.2, 127.8, 127.6,
125.8, 75.9, 72.2, 25.8, 18.2, -4.6, -4.9. Z-Isomer: 1H NMR
(500 MHz, CDCl3) δ 6.82 (d, J ) 6.3 Hz, 1H), 6.07 (d, J ) 6.3
Hz, 1H), 5.17 (ABq, ∆ν ) 7.6 Hz, J ) 11.0 Hz, 2H), 0.95 (s,
9H), 0.10 (s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
153.6, 140.7, 137.7, 128.2, 128.0, 127.8, 127.6, 126.0, 76.3, 67.3,
25.8, 18.2, -4.6, -4.9; some resonances were not resolved from
those of the major isomer. E/Z mixture: IR (film, ATR) 3045,
2954, 1453, 1253, 1005 (s) cm-1; MS (APCI-LCMS, H2O/MeOH)
m/z (relative intensity) 356 ([M + H]+, 100), 256 (30), 224 ([M
- OTBS]+, 92). Anal. Calcd for C21H29NO2Si: C, 70.94; H, 8.22;
N, 3.94. Found: C, 71.16; H, 8.35; N, 4.04.
(S)-2-Hyd r oxyp r op a n a l O-Ben zyloxim e (3a ). A solution
of 2a (42 mg, 0.14 mmol) and tetrabutylammonium fluoride
(TBAF, 1 M in THF, 0.17 mL, 0.17 mmol) in THF (1.7 mL)
was stirred at ambient temperature for 1 h. Concentration in
vacuo and flash chromatography (5:1 hexane/EtOAc) furnished
3a (23.3 mg, 93% yield, inseparable 3.6:1 E/Z mixture) as a
colorless oil. E-Isomer: 1H NMR (500 MHz, CDCl3) δ 7.46 (d,
J ) 4.7 Hz, 1H), 7.38-7.30 (m, 5H), 5.08 (s, 2H), 4.42 (qd, J )
6.6, 4.8 Hz, 2.22 (br s, 1H), 1.34 (d, J ) 6.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 152.5, 137.2, 128.4, 128.3, 128.0, 76.1,
(anti): [R] 29 +112 (c 0.17, CHCl3); IR (film, ATR) 3450 (br),
D
1760 (s), 1210 (s), 1074 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ
7.48-7.40 (m, 5H), 5.04 (ABq, ∆ν ) 33 Hz, J ) 11.5 Hz, 2H),
4.22 (dd, J ) 8.5, 8.5 Hz, 1H), 4.17 (dd, J ) 8.3, 8.3 Hz, 1H),
3.78 (qd, J ) 6.7, 2.3 Hz, 1H), 3.53 (ddd, J ) 8.3, 8.3, 2.3 Hz,
1H), 1.45 (br s, 1H), 0.99 (d, J ) 6.8 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 159.9, 135.5, 19.9, 129.2, 128.8, 77.4, 63.1 (2C),
61.2, 17.3; MS m/z (relative intensity) 238 ([M + H]+, 100).
Disubstituted oxazolidinone trans-6 (syn): 1H NMR (500 MHz,
CDCl3) δ 5.03 (ABq, ∆ν ) 17.8 Hz, J ) 11.6 Hz, 2H), 4.44 (dq,
(53) A general statement describing materials and methods is
provided in the Supporting Information.
(54) Note that the theoretical yield is based on the portions of crude
material used for each step.
872 J . Org. Chem., Vol. 69, No. 3, 2004

Diastereoselective Additions of Hydroxymethyl and Vinyl Synthons
J ) 8.1, 6.3 Hz, 1H), 3.47 (ddd, J ) 12.4, 4.1, 3.0 Hz, 1H),
3.34 (ddd, J ) 12.5, 9.0, 2.3 Hz, 1H), 3.19 (ddd, J ) 8.04, 2.5,
2.5 Hz, 1H), 0.99 (d, J ) 6.8 Hz, 3H); some resonances were
not resolved from those of the major isomer. Disubstituted
oxazolidinone cis-6 (anti): [R] 29D -9.5 (c 0.11, CHCl3); IR (film,
These isomers were separated via acetonide 14b, which was
hydrolyzed (PPTS, methanol) to give an analytical sample of
the major diol anti-13b as a colorless viscous oil: [R] 27 +21
D
(c 0.83, CHCl3); IR (film) 3400 (br, s) cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.34-7.29 (m, 4H), 7.20-7.17 (m, 4H), 7.05-7.01 (m,
2H), 4.65 (br s, 1H), 4.05-4.00 (m, 1H), 3.88-3.80 (m, 2H),
2.99 (ddd, J ) 6.2, 3.7, 3.2 Hz, 1H), 2.57 (br s, 1H), 2.19 (br s,
1H), 1.70-1.60 (m, 1H), 1.50 (ddd, J ) 13.9, 9.6, 5.5 Hz, 1H),
1.17 (ddd, J ) 13.5, 8.6, 3.7, 1H), 0.92 (d, J ) 6.7 Hz, 3H),
0.88 (d, J ) 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 148.4,
129.3, 122.8, 120.5, 68.9, 62.0, 60.7, 41.9, 24.9, 23.4, 22.0; MS
m/z (relative intensity) 315 ([M + H]+, 80), 168 (100). Anal.
Calcd for C19H26N2O2: C, 72.57; H, 8.33; N, 8.91. Found: C,
72.75; H, 8.32; N, 8.87.
1
ATR) 3444 (br), 1754 (s) cm-1; H NMR (500 MHz, CDCl3) δ
7.46-7.37 (m, 5H), 5.00 (ABq, ∆ν ) 46 Hz, J ) 11.3 Hz, 2H),
4.55 (qd, apparent quintet, J ) 6.7 Hz, 1H), 3.87 (dd, J ) 12.3,
3.8 Hz, 1H), 3.63 (dd, J ) 12.3, 2.3 Hz, 1H), 3.43-3.39 (m,
1H), 1.65 (br s, 1H), 1.44 (d, J ) 6.6 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 159.1, 135.5, 129.5, 128.9, 128.6, 78.2, 72.1,
62.1, 58.0, 14.9; MS m/z (relative intensity) 238 ([M + H]+,
100). Anal. Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90.
Found: C, 60.57; H, 6.44; N, 5.82.
Hydr oxym eth yl Ad d ition to Hyd r a zon es. Gen er a l P r o-
ced u r e C: 2-Hyd r a zin o-1,3-d iols 13. A solution of R-hy-
droxyhydrazone (e.g., 10a -d 55) in dry CH2Cl2 (ca. 1 M) at 0
°C was treated sequentially with Et3N (1.3 equiv) and bro-
momethyldimethylsilyl chloride (1.3 equiv). Copious white
precipitate formed immediately. After being warmed to room
temperature over 0.5 h, the mixture was diluted with ether
(ca. 4 mL/mmol Et3N) and filtered through a short plug of silica
gel (elution with ether). Rapid flash chromatography (20:1 then
10:1 hexane/EtOAc) gave bromomethylsilyl ether 11 as a
colorless oil which was used immediately in the next step
(prolonged storage or prolonged exposure to silica gel led to
decomposition). A solution of the bromomethylsilyl ether 11
and tributyltin hydride (1.4 equiv) in benzene (ca. 0.02 M) was
deoxygenated (N2 via needle) for ca. 10 min. AIBN (10 mol %)
was added, and the mixture was deoxygenated for 5 min and
then heated at reflux for 0.5 h. If TLC indicated incomplete
reaction at this point, additional AIBN was added and heating
was continued for another 0.5 h. Concentration of the reaction
mixture afforded the colorless crude intermediate cyclic silane
(2R,3S)-(+)-2-(N,N-Dip h en ylh yd r a zin o)-5-m et h ylh ex-
i
a n e-1,3-d iol (13c, R ) P r ). From 10c (93 mg, 0.347 mmol)
via general procedure C was obtained 11c (124 mg, 85% yield)
as a colorless viscous oil. From 11c (123 mg, 0.293 mmol) was
obtained 13c, which was further purified by radial chroma-
tography to afford syn-13c (3 mg) and anti-13c (68 mg, 80%
combined yield, 96:4 diastereomeric ratio, anti isomer >96%
ee by Mosher ester analysis) as colorless viscous oils. Minor
diastereomer syn-13c: IR (film) 3401 (br, s) cm-1 1H NMR
;
(500 MHz, CDCl3) δ 7.32-7.28 (m, 4H), 7.20-7.18 (m, 4H),
7.05-7.00 (m, 2H), 4.65 (br s, 1H), 3.91 (dd, J ) 11.5, 2.4 Hz,
1H), 3.67-3.60 (m, 1H), 3.52 (dd, J ) 5.6, 5.3 Hz, 1H), 3.12
(ddd, J ) 6.4, 3.3, 3.3 Hz, 1H), 2.26 (br s, 1H), 2.10 (br s, 1H),
1.96-1.87 (m, 1H), 0.90 (d, J ) 6.5 Hz, 3H), 0.88 (d, J ) 6.7
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 148.5, 129.3, 122.9,
120.7, 76.5, 61.8, 59.4, 29.9, 19.7, 16.5; MS m/z (relative
intensity) 301 ([M + H]+, 85), 300 (M+, 30), 170 (95), 168 (100).
Major diastereomer anti-13c: [R] 20 +33 (c 1.3, CHCl3); IR
D
(film) 3410 (br, s) cm-1; H NMR (500 MHz, CDCl3) δ 7.34-
1
7.30 (m, 4H), 7.19-7.16 (m, 4H), 7.06-7.02 (m, 2H), 4.47 (br
1
12, which was analyzed by H NMR to determine the diaste-
s, 1H), 3.88-3.80 (ABX, J AB ) 11.4 Hz, J AX ) 3.7 Hz, J BX
)
reomer ratio (integral ratios for SiMe2 and CHNHNPh2
resonances). A solution of the cyclic silane 12 in THF/methanol
(1:1, ca. 0.1 M) was treated at room temperature with KF (3.5
equiv), KHCO3 (2 equiv) and H2O2 (30% aqueous solution, 10
equiv). After 0.5-2 d, the mixture was diluted with an equal
volume of ether, and 50% aqueous Na2S2O3 (ca. 0.2 mL/mmol
H2O2) was added. The mixture was filtered through Celite with
the aid of additional ether, concentrated, partitioned between
CH2Cl2 and brine, and dried (Na2SO4). Concentration and
gradient flash chromatography (hexane f EtOAc) provided
2-hydrazino-1,3-diol 13.
6.1 Hz, ∆νAB ) 15.9 Hz, 2H), 3.54 (dd, J ) 8.7, 3.0 Hz, 1H),
3.17 (ddd, J ) 6.2, 3.6, 3.5 Hz, 1H), 2.86 (br s, 1H), 2.40 (br s,
1H), 1.77-1.68 (m, 1H), 0.99 (d, J ) 6.5 Hz, 3H), 0.82 (d, J )
6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 148.4, 129.3, 122.8,
120.6, 76.1, 60.4, 59.3, 30.3, 19.5, 18.8; MS m/z (relative
intensity) 301 ([M + H]+, 100), 300 (M+, 45), 170 (98), 168 (65).
Anal. Calcd for C18H24N2O2: C, 71.97; H, 8.05; N, 9.33.
Found: C, 71.73; H, 8.24; N, 9.16.
(2R,3S)-(-)-2-(N,N-Dip h en ylh yd r a zin o)-3-p h en ylp r o-
p a n e-1,3-d iol (13d , R ) P h ). From 10d (104 mg, 0.344 mmol)
via general procedure C was obtained 11d (129 mg, 85% yield)
as a colorless viscous oil. From 11d (129 mg, 0.285 mmol) was
obtained 13d (54 mg, 57% yield, single diastereomer by 1H
NMR, 33% ee by Mosher ester analysis) as a colorless viscous
(2R,3S)-(+)-2-(N,N-Dip h en ylh yd r a zin o)bu ta n e-1,3-d i-
ol (13a , R ) Me). From 10a (361 mg, 1.02 mmol) via general
procedure C was obtained 11a (215 mg, 60% yield) as a
colorless viscous oil. From 11a (59 mg, 0.15 mmol) was
obtained 13a (30.9 mg, 76% yield, 79:21 diastereomeric ratio).
These isomers were separated via acetonide 14a , which was
hydrolyzed (PPTS, methanol) to give an analytical sample of
the major diol anti-13a (anti/syn ) 90:10) as a colorless viscous
oil. [R] 25 -5.4 (c 0.14, CHCl3, 33% ee); IR (film) 3390 (br)
D
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.36-7.27 (m, 9H), 7.12-
7.08 (m, 4H), 7.05-7.00 (m, 2H), 5.00 (dd, J ) 5.2, 2.1 Hz,
1H), 4.34 (br s, 1H), 3.84 (ddd, J ) 11.5, 5.7, 5.7 Hz, 1H), 3.76
(br d, J ) 11.5 Hz, 1H), 3.22 (ddd, J ) 5.3, 5.3, 4.1 Hz, 1H),
2.92 (br s, 1H), 2.00 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ
148.0, 140.5, 129.3, 128.6, 127.9, 126.2, 122.8, 120.5, 73.0, 63.4,
60.6; MS m/z (relative intensity) 335 ([M + H]+, 40), 170 (30),
168 (30), 107 (100). Anal. Calcd for C21H22N2O2: C, 75.42; H,
6.63; N, 8.38. Found: C, 75.56; H, 6.75; N, 8.25.
oil: [R] 27 +25 (c 0.71, CHCl3); IR (film) 3390 (br, s) cm-1; 1H
D
NMR (500 MHz, CDCl3) δ 7.34-7.28 (m, 4H), 7.19-7.15 (m,
4H), 7.05-7.01 (m, 2H), 4.53 (br s, 1H), 4.16-4.10 (m, 1H),
3.92-3.81 (m, 2H), 3.01 (ddd, J ) 6.8, 3.7, 3.4 Hz, 1H), 2.60
(br s, 1H), 2.11 (br s, 1H), 1.22 (d, J ) 6.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 148.4, 129.3, 122.9, 120.6, 67.0, 62.5, 60.6,
18.6; MS m/z (relative intensity) 273 ([M + H]+, 100), 168 (90)
(diastereomeric mixture). Anal. Calcd for C16H20N2O2: C,
70.56; H, 7.40; N, 10.29. Found: C, 70.27; H, 7.38; N, 10.08.
Ta n d em Th iyl Ad d ition -Cycliza tion : Vin yl Ad d ition
to Hyd r a zon es. Gen er a l P r oced u r e E: P r ep a r a tion of
R-(Vin yl)silyloxyh yd r a zon es 17 a n d 22a -d . A solution of
an R-hydroxyhydrazone (e.g., 15,55 10a -d 55) in dry CH2Cl2 (ca.
1 M) at 0 °C was treated sequentially with Et3N (1.3 equiv)
and chlorodimethylvinylsilane (16, 1.3 equiv). White precipi-
tate formed immediately. After being warmed to room tem-
perature over 5 h, the mixture was diluted with ether (ca. 4
mL/mmol Et3N) and filtered through a short plug of silica gel
(elution with ether). Flash chromatography (10:1 hexane/
EtOAc) gave silyl ethers 17 and 22 as colorless oils.
(2R,3S)-(+)-2-(N,N-Dip h en ylh yd r a zin o)-5-m et h ylh ex-
i
a n e-1,3-d iol (13b, R ) Bu ). From 10b (70 mg, 0.25 mmol)
via general procedure C was obtained 11b (103 mg, 83% yield)
as a colorless viscous oil. From 11b (103 mg, 0.238 mmol) was
obtained 13b (51 mg, 68% yield, 85:15 diastereomeric ratio
by 1H NMR, major isomer >96% ee by Mosher ester analysis).
2-(Dim eth ylvin ylsilyloxy)eth a n a l N,N-Dip h en ylh yd r a -
zon e 17. From 15 (300 mg, 1.32 mmol), 16 (0.23 mL, 1.71
(55) For preparation of this compound, see the Supporting Informa-
tion.
J . Org. Chem, Vol. 69, No. 3, 2004 873

Friestad and Massari
mmol), and Et3N (0.24 mL, 1.71 mmol) by general procedure
E was obtained 17 (381 mg, 93% yield) as a colorless oil: IR
(film) 3067, 2958, 1595, 1495 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.39-7.36 (m, 4H), 7.14-7.11 (m, 2H), 7.11-7.09 (m, 4H),
6.51 (t, J ) 5.1 Hz, 1H), 6.11 (dd, J ) 20.0, 14.7 Hz, 1H), 6.03
(dd, J ) 14.7, 4.1 Hz, 1H), 5.79 (dd, J ) 20.0, 4.1 Hz, 1H),
4.34 (d, J ) 5.1 Hz, 2H), 0.19 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 143.6, 137.1, 136.4, 133.4, 129.6, 124.2, 122.3, 63.5,
-2.0; MS (CI) m/z (relative intensity) 311 ([M + H]+, 100%),
168 (50). Anal. Calcd for C18H22SiN2O: C, 69.64; H, 7.14 N,
9.02. Found: C, 69.92; H, 7.26; N, 8.91.
(R)-(+)-2,3-Bis(d im et h ylvin ylsilyloxy)p r op a n a l N,N-
Dip h en ylh yd r a zon e (28). A solution of d-glyceraldehyde
N,N-diphenylhydrazone (29 mg, 0.11 mmol) in dry CH2Cl2 (1.1
mL) at 0 °C under nitrogen was treated sequentially with Et3N
(0.040 mL, 0.29 mmol) and 16 (0.048 mL, 0.29 mmol). A white
precipitate formed immediately. After being warmed to room
temperature over 5 h, the mixture was diluted with an equal
volume of ether and filtered through a short plug of silica gel
(elution with ether). Flash chromatography (10:1 hexane/
EtOAc) gave 28 (33 mg, 70% yield) as a colorless oil: [R] 29
D
+31.7 (c 1.28, CHCl3); IR (film) 3050, 2958, 1592, 1496 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.42-7.39 (m, 4H), 7.17-7.12
(m, 6H), 6.42 (d, J ) 6.2 Hz, 1H), 6.21-6.10 (m, 2H), 6.13-
6.00 (m, 2H), 5.81-5.77 (m, 2H), 4.53-4.45 (m, 1H), 3.70 (d,
J ) 5.5 Hz, 2H), 0.24 (s, 3H), 0.23 (s, 3H), 0.20 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 143.6, 137.9, 137.7, 137.3, 133.1,
133.0, 129.6, 124.1, 122.3, 74.0, 66.0, -1.3, -1.4, -2.0, -2.1;
MS (CI) m/z (relative intensity) 425 ([M + H]+, 100), 409 (54).
Anal. Calcd for C23H32N2O2Si2: C, 65.05; H, 7.59; N, 6.59.
Found: C, 65.29; H, 7.78; N, 6.44.
(S)-(-)-2-(Dim eth ylvin ylsilyloxy)p r op a n a l N,N-Dip h e-
n ylh yd r a zon e (22a , R ) Me). From 10a (718 mg, 3.00 mmol),
16 (0.53 mL, 3.90 mmol), and Et3N (0.54 mL, 3.90 mmol) by
general procedure E was obtained 22a (813 mg, 83% yield) as
a colorless oil: [R] 29 -21.8 (c 1.85, CHCl3); IR (film) 3050,
D
1
2969, 1591, 1496 cm-1; H NMR (500 MHz, CDCl3) δ 7.48-
7.45 (m, 4H), 7.24-7.21 (m, 6H), 6.55 (d, J ) 5.9 Hz, 1H), 6.26
(dd, J ) 20.3, 14.8 Hz, 1H), 6.11 (dd, J ) 14.8, 3.8 Hz, 1H),
5.90 (dd, J ) 20.3, 3.8 Hz, 1H), 4.72-4.69 (m, 1H) 1.45 (d, J
) 6.3 Hz, 3H), 0.35 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
143.9, 140.9, 137.9, 133.1, 129.7, 124.3, 122.4, 69.5, 22.6, -1.1,
-1.2; MS (CI) m/z (relative intensity) 325 ([M + H]+, 100),
168 (M, 20). Anal. Calcd for C19H24SiN2O: C, 70.33; H, 7.45;
N, 8.63. Found: C, 70.37; H, 7.48; N, 8.49.
(2S,3S)-2,3-Bis(d im et h ylvin ylsilyloxy)b u t a n a l N,N-
Dip h en ylh yd r a zon e (31). To a solution of diol 30 (1.46 g,
5.41 mmol), Et3N (2.10 mL, 15.1 mmol), and DMAP (64.4 mg,
0.394 mmol) in toluene (75 mL) was added 16 (1.88 mL, 13.6
mmol) at ambient temperature. After 2 h, the reaction mixture
was concentrated and partitioned between EtOAc and water.
The organic phase was washed with brine, dried (Na2SO4), and
concentrated. Flash chromatography afforded silyl ether 31
(1.844 g, 77% yield) as a colorless oil containing a mixture of
syn and anti diastereomers (dr 89:11). Major diastereomer: 1H
NMR (500 MHz, CDCl3) δ 7.39-7.36 (m, 4H), 7.16-7.14 (m,
2H), 7.10-7.08 (m, 4H), 6.37 (d, J ) 6.9 Hz, 1H), 6.20-6.05
(m, 2H), 6.05-5.90 (m, 2H), 5.80-5.70 (m, 2H), 4.22 (dd, J )
6.9, 6.3 Hz, 1H), 3.80 (dddd, apparent quintet, J ) 6.3 Hz,
1H), 1.07 (d, J ) 6.3 Hz, 3H), 0.21 (s, 3H), 0.20 (s, 3H), 0.152
(s, 3H), 0.147 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 143.8,
138.2, 138.1, 137.9, 132.8, 132.6, 129.6, 124.1, 122.3, 77.8, 71.2,
19.6, -1.2, -1.3. Diastereomeric mixture: IR (film) 3050, 2962,
1593, 1496 cm-1; MS (CI) m/z (relative intensity) 439 ([M +
H]+, 100), 337 (86), 168 (34). Anal. Calcd for C24H34N2O2Si2:
C, 65.71; H, 7.91; N, 6.39. Found: C, 66.11; H, 7.92; N, 6.39.
Gen er a l P r oced u r e F : Ta n d em Th iyl Ra d ica l Ad d i-
tion -Cycliza tion a n d Elim in a tion . A solution of silyl ether
and thiophenol (1.2 equiv) in cyclohexane (ca. 0.1 M) was
deoxygenated (nitrogen via needle) for ca. 10 min. AIBN (10
mol %) was added, and the mixture was deoxygenated for 5
min and then heated at reflux for 2-3 h. If TLC indicated
incomplete reaction at this point, additional AIBN was added
and heating continued for another 15 h. After concentration
of the reaction mixture, a solution of the residual oil in THF
(ca. 0.15 M) was treated at room temperature with a saturated
KF/MeOH solution (14 mL/mmol silyl ether). After 20 h, the
solution was diluted with hexane, washed with water, dried
(Na2SO4), and concentrated. Diastereomer ratios were deter-
mined by integration of 1H NMR spectra prior to flash
chromatography (10:1 f 5:1 hexane/EtOAc), which afforded
the hydrazino alcohols 19 and 23a -d as mixtures of diaster-
eomers.
(S)-(-)-2-(Dim eth ylvin ylsilyloxy)-4-m eth ylpen tan al N,N-
Dip h en ylh yd r a zon e (22b, R ) iBu ). From 10b (750 mg, 2.65
mmol), 16 (0.47 mL, 3.44 mmol), and Et3N (0.48 mL, 3.44
mmol) by general procedure E was obtained 22b (810 mg, 83%
yield) as a colorless oil: [R] 29D -13.2 (c 1.41, CHCl3); IR (film)
3050, 2956, 1595, 1496 cm-1 1H NMR (500 MHz, CDCl3) δ
;
7.40-7.37 (m, 4H), 7.17-7.14 (m, 2H), 7.11-7.09 (m, 4H), 6.35
(d, J ) 6.5 Hz, 1H), 6.15 (dd, J ) 20.2, 14.7 Hz, 1H), 6.03 (dd,
J ) 14.7, 3.7 Hz, 1H), 5.79 (dd, J ) 20.2, 3.7 Hz, 1H) 4.49
(ddd, J ) 8.1, 6.2, 6.2 Hz, 1H), 1.75-1.67 (m, 1H), 1.55 (ddd,
J ) 13.8, 8.1, 6.1 Hz, 1H), 1.38 (ddd, J ) 13.5, 7.6, 5.9 Hz,
1H), 0.96 (d, J ) 6.6 Hz, 3H), 0.93 (d, J ) 6.6 Hz, 3H), 0.21 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 143.9, 140.7, 137.9, 133.0,
129.7, 124.2, 122.4, 71.9, 45.3, 24.2, 23.1, 22.4, -1.1; MS (CI)
m/z (relative intensity) 367 ([M + H]+, 100), 168 (M, 20). Anal.
Calcd for C22H30SiN2O: C, 72.08; H, 8.25; N, 7.64; O. Found:
C, 72.35; H, 8.33; N, 7.48.
(S)-(+)-2-(Dim eth ylvin ylsilyloxy)-3-m eth ylbu tan al N,N-
i
Dip h en ylh yd r a zon e (22c, R ) P r ). From 10c (140 mg,
0.522 mmol), 16 (0.09 mL, 0.68 mmol), and Et3N (0.09 mL,
0.68 mmol) by general procedure E was obtained 22c (170 mg,
92% yield) as a colorless oil: [R] 29 +15.0 (c 1.38, CHCl3); IR
D
(film) 3050, 2958, 1594, 1496 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.40-7.37 (m, 4H), 7.15-7.14 (m, 2H), 7.11-7.09 (m, 4H),
6.35 (d, J ) 6.9 Hz, 1H), 6.15 (dd, J ) 20.3, 13.8 Hz, 1H), 6.00
(dd, J ) 13.8, 2.8 Hz, 1H), 5.80 (dd, J ) 20.3, 2.8 Hz, 1H),
4.05-4.10 (m, 1H), 1.75-1.70 (m, 1H), 0.93 (d, J ) 6.7 Hz,
3H), 0.84 (d, J ) 6.7 Hz, 3H), 0.19 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 144.0, 140.2, 138.1, 132.9, 129.8, 124.2, 122.4, 78.6,
33.8, 18.4, -1.1, -1.2; MS (CI) m/z (relative intensity) 353 ([M
+ H]+, 100), 168 (11). Anal. Calcd for C21H28SiN2O: C, 71.54;
H, 8.00; N, 7.96. Found: C, 71.67; H, 8.05; N, 8.05.
(S)-(-)-2-(Dim et h ylvin ylsilyloxy)-2-p h en yla cet a ld e-
h yd e N,N-Dip h en ylh yd r a zon e (22d , R ) P h ). From 10d
(520 mg, 1.72 mmol), 16 (0.31 mL, 2.23 mmol), and Et3N (0.31
mL, 2.23 mmol) by general procedure E was obtained 22d (500
mg, 75% yield) as a colorless oil: [R] 29D -74.4 (c 1.17, CHCl3);
N-(Dip h en yla m in o)vin ylglycin ol (19). From 17 (77 mg,
0.25 mmol), thiophenol (0.03 mL, 0.30 mmol), and AIBN (4
mg, 0.025 mmol) by general procedure F was obtained racemic
19 (34 mg, 54% yield) as a colorless oil: IR (film) 3391 (br, s)
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.31-7.28 (m, 4H), 7.17-
7.15 (m, 4H), 7.02-7.01 (m, 2H), 5.90 (ddd, J ) 17.7, 10.5, 7.5
Hz, 1H), 5.30-5.15 (m, 2H), 4.22 (s, 1H), 3.80-3.71 (m, 1H),
3.70-3.58 (m, 2H), 1.95 (br s, 1H); 13C NMR (125 MHz, CDCl3)
δ 148.0, 135.7, 129.1, 122.5, 120.4, 118.8, 63.9, 61.9; MS (CI)
m/z (relative intensity) 255 ([M + H]+, 42), 165 (100), 183 (27).
Anal. Calcd for C16H18N2O: C, 75.56; H, 7.13; N, 11.01.
Found: C, 75.31; H, 7.14; N, 10.78.
IR (film) 3060, 2959, 1592, 1495 cm-1 1H NMR (500 MHz,
;
CDCl3) δ 7.31-7.24 (m, 8H), 7.20-7.10 (m, 1H), 7.05-7.02 (m,
6H), 6.42 (d, J ) 6.7 Hz, 1H), 6.15 (dd, J ) 20.3, 14.9 Hz, 1H),
6.10 (dd, J ) 14.9, 3.9 Hz, 1H), 5.75 (dd, J ) 20.3, 3.9 Hz,
1H), 5.50 (d, J ) 6.7 Hz, 1H), 0.20 (s, 3H), 0.18 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 143.8, 142.0, 139.6, 137.6, 133.4,
129.8, 128.3, 127.3, 126.0, 124.4, 122.4, 75.3, -1.1, -1.2; MS
(CI) m/z (relative intensity) 387 ([M + H]+, 52), 168 (15). Anal.
Calcd for C24H26SiN2O: C, 74.57; H, 6.78; N, 7.25. Found: C,
74.86; H, 6.85; N, 7.29.
(2S,3R)-3-(N,N-Diph en ylh ydr azin o)-4-pen ten -2-ol (23a).
From 22a (94 mg, 0.29 mmol), thiophenol (0.03 mL, 0.35
874 J . Org. Chem., Vol. 69, No. 3, 2004

Diastereoselective Additions of Hydroxymethyl and Vinyl Synthons
mmol), and AIBN (4 mg, 0.029 mmol) by general procedure F
was obtained 23a as a mixture of diastereomers (60 mg, 77%
yield, anti/syn ) 90:10) as a pale yellow oil. For characteriza-
tion, both pure diastereomers were obtained via acetonide 26a .
18.3; MS (CI) m/z (relative intensity) 297 ([M + H]+, 90), 168
(100), 183 (30). Anal. Calcd for C19H24N2O: C, 76.99; H, 8.16;
N, 9.45. Found: C, 77.09; H, 8.20; N, 9.45.
(1S,2R)-2-(N,N-Dip h en ylh yd r a zin o)-1-p h en yl-3-bu ten -
1-ol (23d ). From 22d (75 mg, 0.19 mmol), thiophenol (0.02
mL, 0.23 mmol), and AIBN (3 mg, 0.019 mmol) by general
procedure F was obtained 23d as mixture of diastereomers
(38 mg, 59% yield, anti/syn ) >98:2) as pale yellow oil: IR
Major diastereomer (anti-23a ): [R] 31 +48.5 (c 1.98, CHCl3);
D
IR (film) 3435 (br, s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.33-
7.30 (m, 4H), 7.15-7.13 (m, 4H), 7.04-7.01 (m, 2H), 5.93 (ddd,
J ) 17.3, 10.4, 8.4 Hz, 1H), 5.33 (dd, J ) 10.4, 1.8 Hz, 1H),
5.26 (dd, J ) 17.3, 1.8 Hz, 1H), 4.10 (dddd, J ) 6.5, 6.5, 6.5,
2.7 Hz, 1H), 4.20-3.50 (br s, 1H), 3.43 (dd, J ) 8.4, 2.7 Hz,
1H), 2.55 (br s, 1H), 1.18 (d, J ) 6.5 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 148.1, 133.5, 129.2, 122.6, 120.4, 120.3, 66.53,
66.48, 18.1. Minor diastereomer (syn-23a ): IR (film) 3401 (br,
1
(film) 3447 (br, s) cm-1; H NMR (500 MHz, CDCl3) δ 7.30-
7.26 (m, 11H), 7.09-7.07 (m, 2H), 6.95-7.05 (m, 2H), 5.86
(ddd, J ) 18.4, 10.4, 8.1 Hz, 1H), 5.23 (d, J ) 10.4 Hz, 1H),
5.10 (d, J ) 17.3 Hz, 1H), 4.93 (d, J ) 4.5 Hz, 1H), 4.08 (s,
1H), 3.63 (dd, J ) 8.1, 4.6 Hz, 1H), 2.67 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 147.7, 140.2, 134.0, 129.1, 128.1, 127.5, 126.4,
122.6, 120.3, 120.3, 72.7, 66.8; MS (CI) m/z (relative intensity)
331 ([M + H]+, 46), 170 (100), 168 (60). Anal. Calcd for
s), 1588, 1496, 1272, 1073, 924 cm-1 1H NMR (500 MHz,
;
CDCl3) δ 7.30-7.26 (m, 4H), 7.16-7.15 (m, 4H), 7.11-6.95 (m,
2H), 5.73 (ddd, J ) 17.2, 10.3, 8.7 Hz, 1H), 5.18 (dd, J ) 10.3,
1.4 Hz, 1H), 5.15 (dd J ) 17.2, 1.4 Hz, 1H), 4.50 (br s, 1H),
3.90-3.86 (m, 1H), 1H), 3.35 (dd, J ) 7.9, 7.9 Hz, 1H), 2.10
(br s, 1H), 1.18 (d, J ) 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 148.0, 135.9, 129.0, 122.4, 120.6, 119.5, 69.5, 67.2, 20.4.
Diastereomeric mixture: MS (CI) m/z (relative intensity) 269
C
22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C, 80.45; H,
6.72; N, 8.76.
(2R,3R)-3-(N,N-Dip h en ylh yd r a zin o)-4-p en t en -1,2-d i-
ol (32). From 28 (75 mg, 0.19 mmol), thiophenol (0.02 mL,
0.23 mmol), and AIBN (3 mg, 0.019 mmol) by general
procedure F was obtained 32 after flash chromatography (10:1
f 1:1 hexane/EtOAc) as a mixture of diastereomers (16 mg,
64% yield, anti/syn ) 91:9) as a colorless oil: IR (film) 3399
(br, s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.31-7.28 (m, 4H),
7.13-7.11 (m, 4H), 7.03-7.00 (m, 2H), 5.90 (ddd, J ) 18.8,
10.4, 8.4 Hz, 1H), 5.28 (d, J ) 10.4 Hz, 1H), 5.22 (d, J ) 18.2
Hz, 1H), 3.98-3.95 (m, 1H), 3.70 (dd, J ) 11.5, 7.2 Hz, 1H),
3.63-3.60 (m, 2H), 2.70 (br s, 1H); 13C NMR (125 MHz, CDCl3)
δ 147.8, 133.8, 129.2, 122.8, 120.4, 120.1, 71.8, 63.8, 63.2; MS
(CI) m/z (relative intensity) 285 ([M + H]+, 77), 168 (100). Anal.
Calcd for C17H20N2O2: C, 71.81; H, 7.09; N, 9.85. Found: C,
71.32; H, 7.16; N, 9.41.
(2S,3S,4S)-4-(N,N-Dip h en ylh yd r a zin o)-5-h exen e-2,3-
d iol (33). From 32 (106.7 mg, 0.244 mmol, syn/anti ) 89:11),
thiophenol (60 µL, 0.58 mmol), and AIBN (2.7 mg, 0.016 mmol)
by general procedure F was obtained 33 (46.2 mg, 63% yield)
as a colorless oil as an 88:12 diastereomeric mixture. Major
diastereomer (2S,3S,4S)-33: 1H NMR (500 MHz, CDCl3) δ
7.32-7.29 (m, 4H), 7.12-7.10 (m, 4H), 7.04-7.00 (m, 2H), 5.92
(ddd, J ) 18.8, 10.3, 8.4 Hz, 1H), 5.35-5.20 (m, 2H), 3.82
(dddd, apparent quintet, 1H), 3.65-3.60 (m, 2H), 2.90-2.60
(br s, 2H), 1.70-1.45 (br s, 1H), 1.11 (d, J ) 6.3 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 147.8, 133.5, 129.3, 122.8, 120.5,
120.1, 75.1, 67.8, 63.2, 18.4. Diastereomeric mixture: IR (film)
3401 (br, s) cm-1; MS (CI) m/z (relative intensity) 299 ([M +
H]+, 48), 168 (100). Anal. Calcd for C18H22N2O2: C, 72.46; H,
7.43; N, 9.39. Found: C, 72.34; H, 7.48; N, 9.30.
([M + H]+, 100), 168 (98), 183 (36). Anal. Calcd for C17H20
-
N2O: C, 76.09; H, 7.51; N, 10.44. Found: C, 76.27; H, 7.67; N,
10.18.
(3R,4S)-3-(N,N-Diph en ylh ydr azin o)-6-m eth yl-1-h epten -
4-ol (23b). From 22b (400 mg, 1.09 mmol), thiophenol (0.13
mL, 1.31 mmol), and AIBN (17 mg, 0.11 mmol) by general
procedure F was obtained 23b as a mixture of diastereomers
(232 mg, 68% yield, anti/syn ) 94:6) as a pale yellow oil. For
characterization, the pure major diastereomer was obtained
via acetonide 26b. Major diastereomer (anti-23b): [R] 27
D
+26.3 (c 0.58, CHCl3); IR (film) 3447 (br, s) cm-1
;
1H NMR
(500 MHz, CDCl3) δ 7.32-7.29 (m, 4H), 7.13-7.11 (m, 4H),
7.03-7.00 (m, 2H), 5.87 (ddd, J ) 19.1, 10.4, 8.6 Hz, 1H), 5.30
(dd, J ) 10.4, 1.7 Hz, 1H), 5.22 (dd, J ) 19.1, 1.8 Hz, 1H),
4.04 (s, 1H), 4.01-3.96 (m, 1H), 3.40 (dd, J ) 8.5, 2.3 Hz, 1H),
2.42 (dd, J ) 2.1, 1.1 Hz, 1H), 1.79-1.71 (m, 1H), 1.44 (ddd, J
) 13.9, 9.3, 5.5 Hz, 1H), 1.11-1.05 (m, 1H), 0.90 (d, J ) 6.6
Hz, 1H), 0.87 (d, J ) 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 148.1, 133.5, 129.2, 122.6, 120.3, 120.1, 68.2, 65.8, 41.6, 24.6,
23.4, 22.0; MS (CI) m/z (relative intensity) 311 ([M + H]+, 98),
168 (M, 100), 183 (33). Diastereomeric mixture: Anal. Calcd
for C20H26N2O: C, 77.38; H, 8.44; N, 9.02. Found: C, 77.44;
H, 8.41; N, 8.92.
(3S,4R)-4-(N,N-Dip h en ylh yd r a zin o)-2-m eth yl-5-h exen -
3-ol (23c). From 22c (5.00 g, 14.17 mmol), thiophenol (1.74
mL, 17.00 mmol), and AIBN (232 mg, 1.42 mmol) by general
procedure F was obtained anti-23c as a single diastereomer
after crystallization from hexane (3.77 g, 89% yield). In a
smaller scale experiment, the crude product had a diastereo-
mer ratio of 98:2 (anti/syn). Major diastereomer (anti-23c): mp
100-102 °C (from hexane/ether); [R] 29D +64.6 (c 1.51, CHCl3);
IR (film) 3554 (br, s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.33-
7.30 (m, 4H), 7.13-7.11 (m, 4H), 7.01-7.04 (m, 2H), 5.95 (ddd,
J ) 19.1, 10.4, 8.7 Hz, 1H), 5.32 (dd, J ) 10.4, 1.5 Hz, 1H),
5.27 (dd, J ) 19.0, 1.4 Hz, 1H), 3.93 (br s, 1H), 3.61 (dd, J )
8.7, 2.3 Hz, 1H), 3.50 (dd, J ) 9.1, 1.7 Hz, 1H), 2.70 (s, 1H),
1.65 (dddd, J ) 9.1, 6.6, 6.6, 6.6 Hz, 1H), 1.02 (d, J ) 6.6 Hz,
3H), 0.79 (d, J ) 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
148.1, 133.2, 129.2, 122.7, 120.5, 120.0, 75.2, 63.2, 30.1, 19.7,
Ack n ow led gm en t . We thank the NSF (CHE-
0096803) for generous support of this work.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures (including general procedures A, B, D, and G) and
characterization data for 9, 10, 14, 15, 20, 21, 25-27, 29, and
30. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O035405R
J . Org. Chem, Vol. 69, No. 3, 2004 875