(S)-2-(Dibenzylamino)-3-phenylpropanal as a chiral auxiliary: A new strategy for the asymmetric synthesis of 2-substituted alcohols

Article abstract of DOI:10.1016/S0957-4166(98)00120-7

The high levels of 1,2-stereocontrol observed in nucleophilic additions to (S)-2-(dibenzylamino)-3-phenylpropanal (available in three high-yielding steps from L-phenylalanine) can be converted to remote 1,4-stereocontrol by a stereospecific rearrangement

Full text of DOI:10.1016/S0957-4166(98)00120-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1427–1440
(S)-2-(Dibenzylamino)-3-phenylpropanal as a chiral auxiliary: a
new strategy for the asymmetric synthesis of 2-substituted
alcohols
Jonathan Clayden,a,∗ Catherine McCarthy a and John G. Cumming b
aDepartment of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
bZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Received 16 February 1998; accepted 19 March 1998
Abstract
The high levels of 1,2-stereocontrol observed in nucleophilic additions to (S)-2-(dibenzylamino)-3-
phenylpropanal (available in three high-yielding steps from L-phenylalanine) can be converted to remote
1,4-stereocontrol by a stereospecific rearrangement if the nucleophile is a vinyl anion equivalent. Ozonolysis of
the product followed by reductive work-up returns an enantiomerically pure 2-substituted alcohol, along with
the (S)-2-(dibenzylamino)-3-phenylpropan-1-ol precursor to the starting aldehyde, which functions as a chiral
auxiliary. The sequence provides a new strategy for the use of aldehydes as chiral auxiliaries in the synthesis of
chiral alcohols bearing oxygen- or carbon-based 2-substituents. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Two things are required of chiral auxiliaries above all else: they must induce high levels of stereocon-
trol and they must be straightforwardly removable. These two requirements can sit uneasily together,
since straightforward removal usually means an amide or ester linkage, which in turn necessarily
introduces unhelpfully non-stereogenic atoms between the auxiliary and the nearest point on the substrate
at which reaction can occur. The best auxiliaries take all this in their stride, and levels of 1,4-asymmetric
induction of >95:5 are the norm for, for example, chiral oxazolidinones.1
We set out to avoid the problem of spatial separation between auxiliary and new stereogenic centre
by developing a new chiral auxiliary strategy which would exploit the high levels of 1,2-asymmetric
induction characteristic of nucleophilic additions to some chiral aldehydes.2 Our plan is outlined in
Scheme 1. A stereospecific rearrangement converts the 1,2-relationship created by the addition into
∗
Corresponding author. E-mail: j.p.clayden@man.ac.uk
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00120-7

1428
J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
a 1,4-relationship across a trans double bond.3 Ozonolysis removes the aldehyde auxiliary from the
functionalised substrate, which is also a 2-substituted aldehyde. The stereospecific rearrangement means
that in principle the same degree of stereocontrol should be obtainable whatever substituent Z we choose
to introduce, and in this paper we describe our success in applying this strategy to the synthesis of esters,
amides and alcohols.
Scheme 1. Exploiting 1,2-asymmetric induction in a new chiral auxiliary strategy
2. Results and discussion
Stereocontrol in the additions of nuleophiles to α-chiral aldehydes is well understood in terms of
the Felkin–Anh transition state4–6 and (depending on aldehyde and nucleophile) chelation control.7,8
Reetz has described a group of 2-amino aldehydes9,10 whose reactions are characterised by high 1,2-
stereoselectivity and which can be made straightforwardly from available amino acids,11 and we chose
one of these, (S)-2-(dibenzylamino)-3-phenylpropanal 4, as our auxiliary. Reetz’s route10,12 to 4 is shown
in Scheme 2, but we found that the aldehyde product from the Swern oxidation of 3 was hard to purify,
and while it could be used crude, it could not be stored for later use. We prefer the method of Beaulieu
and Wernic13 (Scheme 3), which proceeds via dibenzylation of phenylalaninol 5 and avoids both the
LiAlH4 reduction of 2 (with stoichiometric production of benzyl alcohol) and the Swern oxidation of
Reetz’s route. We found that the aldehyde 4 made by pyridine–sulfur trioxide oxidation of 3 needed no
purification and could be stored for several weeks without decomposition.
Scheme 2. Reetz’s route to 4
Scheme 3. Beaulieu and Wernic’s route to 4
We needed to add a vinyl anion equivalent to aldehyde 4 (Scheme 1). Noting that lithiated phenyl-
acetylene gives >96:4 anti diastereoselectivity on addition to 4,9,10,14 we decided to use a lithiated alkyne
and subsequently to reduce to the alkene. Reaction of 4 with lithiated 1-octyne gave a 96:4 ratio of
diastereoisomers by HPLC, which were separable by chromatography, allowing us to isolate anti-615 in
78% yield. We found that LiAlH4 was a more reliable E-selective reducing agent16 for this alkyne than
RedAl®17 giving the E-allylic alcohol 7 in 66% yield.18

J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
1429
Stereospecific [2,3] and [3,3]-sigmatropic rearrangements19–21 and related stereospecific allylic sub-
stitutions of derivatives of allylic alcohols have been used to introduce oxygen,22–25 carbon,26–32
nitrogen,33–37, hydrogen,38 silicon,39,40 and sulfur41-based functional groups. We chose to investigate
methods for the first two, and examined the application of three reactions: palladium(II)-catalysed allylic
ester rearrangement22 and the Johnson42 and Eschenmoser43 variants of the Claisen26 rearrangement.
Palladium(II)-catalysed rearrangement of allylic esters is reliably stereospecific,23–25,44,45 and with
both the starting material and product of the reaction being esters the course of the reaction is controlled
largely by the relative degree of steric encumbrance they experience.23,44 We made acetate 8 from 7 and
treated it with a Pd(II) catalyst, (MeCN)2PdCl2, in THF at 20°C. After 24 h, a product 9 was evident
by TLC, and after 96 h this product accounted for 30% of the reaction mixture. However, this 70:30
ratio appeared to represent thermodynamic equilibrium between starting material 8 and product 9, and
remained unchanged even after a further 96 h. Heating the mixture did not improve the situation, and
resulted in poor recovery and apparent decomposition of the catalyst to palladium metal.
The steric driving force for the reaction — repulsion between the migrating carboxylate and the allylic
NBn2 group — is evidently insufficient to drive this reaction to completion. Aiming to increase steric
hindrance, we made the propionate ester 10, and tried rearranging that. The result was much more
encouraging, and after 72 h, the reaction mixture contained 85% of the rearranged product 11, which
we were able to isolate in 77% yield.
Unlike this stepwise46,47 palladium(II)-catalysed rearrangement, the Claisen rearrangement,26 and
its Johnson42,48 (using orthoesters to produce esters) and Eschenmoser43,49 (using amide acetals to
produce amides) variants are true stereospecific [3,3]-sigmatropic processes. Both the Johnson–Claisen
and Eschenmoser–Claisen rearrangements were attractive to us in the context of this project since they
provide single step methods for the stereospecific replacement, with allylic rearrangement, of the oxygen
functionality of our allylic alcohol with a carbon-based fragment.
We treated allylic alcohol 7 with triethyl orthoacetate and heated it to 100°C in toluene.30,42,48 After 20
h, we were able to isolate the rearranged γ,δ-unsaturated ester 12 in 79% yield. The amide 13 could be
formed similarly in 87% yield by heating the allylic alcohol with dimethyl acetamide diethyl acetal.43,49

1430
J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
Table 1
Cleavage of 11–13 by ozonolysis to 2-substituted alcohols 14–16 and auxiliary precursor 3
The three rearranged products — two esters 11, 12 and an amide 13 — all appeared to be single
diastereoisomers by 1H and 13C NMR, though we had to wait till we had cleaved auxiliary from product
to be confident that the rearrangements had been fully stereospecific.
This was the next task, and we set out to use ozonolysis to do it. Tertiary amines, and particularly
tertiary benzylamines, are susceptible to oxidation by ozone either at nitrogen or, in the case of
benzylamines, at the benzylic carbon adjacent to the nitrogen atom.50,51 We sought to prevent these
unwanted oxidations by carrying out our ozonolysis in the presence of 1–5 equiv. of HCl, which we
introduced by adding acetyl chloride to the methanol solvent. Although ozonolysis with dimethyl sulfide
work-up would be expected to regenerate our aldehyde auxiliary, we envisaged difficulties isolating the
two aldehyde products without racemisation or decomposition, so we decided to reduce the ozonide
directly to two alcohols 3 and 14, 15 or 16 using NaBH4.
The results of our attempts are shown in the Table 1. The addition of HCl was essential for a clean
reaction — without it, the only identifiable product was benzyl alcohol (entry 1), presumably originating
from oxidation of the NBn2 group. Adding 2–3 equiv. of HCl slowed oxidation at nitrogen to the point
where reasonable recoveries of the auxiliary 3 could be achieved (71% in entry 2), and it is notable that
reactions returning starting material also gave better yields of 3: presumably, alkene oxidation is faster
than oxidation of the protonated amine but not by much. Protonation at nitrogen evidently also slowed
the rate of oxidation of the alkene too, and to get acceptable yields of the products it was necessary
to lengthen reaction time to 80 minutes or more (entries 3–5). The cleaner, but yet slower, reactions at
−78°C were the best compromise and gave acceptable yields of products from 11, 12 and 13 (entries
7–9).
The products 14 and 15 were susceptible to further reaction under the conditions of the ozonolysis.
Cleavage of 11 to the 2-acyloxy alcohol 14 was always accompanied by acyl transfer to the primary

J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
1431
hydroxyl group, giving variable yields of 17, and 17 was the sole product in the presence of 4 equiv. of
HCl. We were able to convert mixtures of 14 and 17 to the bis-propionate 18 for characterisation. The
ester 15 was susceptible to lactonisation to give 19, and varying amounts of 19 accompanied 15 isolated
from the ozonolysis of 12.
The enantiomeric excess of the products confirmed the stereoselectivity of the addition and stereo-
specificity of the rearrangement. Mosher’s MTPA esters52,53 20 and 21 of alcohols 3 and 16 with (ꢀ)-
1
MTPACl gave two clear sets of NMR signals in the H NMR, and the absence of one of these sets of
signals from the NMR of the esters made with ozonolysis products and with (+)-MTPACl confirmed that
the enantiomeric excess of recovered 3 was >96% and that of 16 was >90% (Fig. 1). Alcohol 14 gave
a mixture of inseparable regioisomeric MTPA esters 22 and 23, but the absence of diastereoisomeric
signals from the mixture of 22 and 33 made from 14 with (+)-MTPACl indicated an ee of >90%. We
were unable to make the MTPA ester from the lactonisable ester 15, though comparison of the optical
rotation of known lactone 1954 with its literature value did at least enable us to confirm the configuration
of the new chiral centre, which we had assigned using the known9,10 preference for anti product formation
from 3, along with the stereospecificity of the rearrangements.
While 14 could be more simply made by asymmetric dihydroxylation55 (notwithstanding the question
of selective protection56), the ester 15 (or lactone 19) and amide 16 are not available by another
straightforward route. In principle, many other related products are available simply by varying the nature
of the rearrangement. Similar rearrangement-based approaches to 1,2-difunctionalised compounds have
been employed by Thomas36,37 and by Larchevêque,57 but ours is the first demonstration of the use of
an aldehyde as a recyclable chiral auxiliary. We are currently investigating other aldehydes which show
very high diastereofacial bias58 as auxiliaries for use with this strategy.
3. Experimental
Infra-red spectra were recorded on an ATi Genesis Series FTIR. NMR spectra were recorded at 300
MHz on a Varian XL300 spectrometer (1H) or at 75 MHz on a Bruker XC300 spectrometer (13C). All
chemical shifts are quoted in parts per million downfield from tetramethylsilane. Mass spectra were
recorded using chemical ionisation (CI) on a Fisons VG Trio 2000 (EI/CI) or a Concept IS (HRMS)
spectrometer.

1432
J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
Fig. 1. Portions of the 1H NMR spectrum of (a) ester 20 from recovered 3 and (+)-MTPA; (b) ester 20 from 3 and (ꢀ)-MTPA;
(c) ester 21 from 16 and (+)-MTPA; (d) ester 21 from 16 and (ꢀ)-MTPA
High-performance liquid chromatography was carried out on a Waters Z module (10 cm by 8
mm, packed SiO2 stationary phase) at room temperature using a Waters 510 pump, eluting with 4:1
hexane:ethyl acetate, flow rate 2 ml/min, 20 µl injection, detection Perkin–Elmer LC-480 Diode Array
system using UV absorbance at 255 nm. Flash chromatography59 was performed using Merck silica gel
60H (40–63 µ, 230–300 mesh) as the stationary phase. Thin layer chromatography (TLC) was performed
using Macherey–Nagel 0.25 mm silica gel pre-coated plastic sheets with fluorescent indicator UV254
.
Tetrahydrofuran (THF) and diethylether were dried over sodium and distilled under dry nitrogen using
benzophenone as an indicator. Dichloromethane was distilled from calcium hydride. Toluene was dried
and distilled using a Dean–Stark apparatus and stored over 4 Å molecular sieves. DMSO was distilled
and stored over 4 Å molecular sieves.

J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
1433
3.1. (S)-2-Amino-3-phenylpropan-1-ol 5
The title compound was prepared by the method of Beaulieu and Wernic.13 L-Phenylalanine (20 g,
0.121 mol) was added to a stirred suspension of NaBH4 (11.45 g, 0.303 mol) in THF (250 ml) at
room temperature. The flask was immersed in a ice-water bath and a solution of carefully prepared
conc. H2SO4 (8.06 ml, 0.151 mol) in ether (22 ml) was added dropwise at such a rate to maintain the
reaction mixture below 20°C (addition time approx. 30 min). The reaction mixture was stirred at room
temperature overnight and MeOH (10 ml) was carefully added to destroy excess borane. The solvent was
removed under reduced pressure, 6 M NaOH (100 ml) was added and mixture heated to reflux for 3 h.
The solution was allowed to cool, filtered through a pad of Celite, and extracted with dichloromethane.
The combined extracts were washed with water (100 ml) and evaporated under reduced pressure to yield
the title compound as a pale yellow oil (17.3 g, 95%); [α]D25=−20 (c=4, EtOH); δH (300 MHz; CDCl3),
7.4–7.0 (5H, m, ArH), 3.65 (1H, dd, J 10.5 and 4, CHAHBOH), 3.4 (1H, dd, J 10.5 and 7, CHAHBOH),
3.2 (1H, tdd, J 8, 5 and 4, CHNH2), 2.8 (1H, dd, J 13.5 and 5, PhCHAHB) and 2.55 (1H, dd, J 13.5 and
8.5, PhCHAHB); δC (75 MHz; CDCl3) 132.0, 129.1, 128.5, 126.3 (Ar), 66.4 (CH2OH), 54.1 (CHN) and
40.9 (PhCH2); m/z 152 (100%, M+1). [Found: (M+H)+, 152.1082. C9H13NO requires M+H, 152.1075.]
3.2. (S)-2-(Dibenzylamino)-3-phenylpropan-1-ol 3
By the method of Beaulieu and Wernic,13 benzyl bromide (37.2 ml, 0.312 mol) was added to a stirred
mixture of the crude amino alcohol 5 (21.4 g, 0.142 mol) and anhydrous potassium carbonate (49 g,
0.355 mol) in ethanol (600 ml). After stirring for 3 days at room temperature, the suspension was
filtered and concentrated under reduced pressure. Ethyl acetate was added and the solution was washed
with water, sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and evaporated
under reduced pressure to give a crystalline yellow solid, which was recrystallised from ethyl acetate to
yield the alcohol 3 (47 g, 99%) as a yellow solid, m.p. 69–72°C (lit.13, 72–74°C); [α]D25=+7.6 (c=4,
EtOH); νmax/cm−1 (evap. film) 3430 (OH), 3026 (CH), 1602 (Ar) and 1453; δH (300 MHz; CDCl3),
7.6–7.0 (15H, m, ArH), 4.0 [2H, d, J 14, N(CHAHBPh)2], 3.6 [2H, d, J 14, N(CHAHBPh)2], 3.6 (1H,
m, CHAHBOH), 3.4 (1H, dd, J 11.8 and 4, CHAHBOH), 3.2 (2H, m, PhCHAHBCHN) and 2.5 (1H, dd,
J 14, 10.5, PhCCHAHB); δC (75 MHz; CDCl3) 139.1, 139.0, 129.1, 129.0, 128.6, 128.5, 127.3, 126.2
(Ar), 60.9 (CH2OH), 60.4 (CHN), 53.3 [N(CH2Ph)2], 31.8 (PhCH2CHN); m/z 332 (100%, M+1) [Found:
(M+H)+, 332.2017. C23H25NO requires M+H, 332.2014.]
3.3. (S)-2-(Dibenzylamino)-3-phenylpropanal 4
By the method of Beaulieu and Wernic,13 pyridine–sulfur trioxide complex (15.9 g, 0.10 mol) in
DMSO (60 ml) was added in small portions over 20–30 mins to a solution of (S)-2-(dibenzylamino)-3-
phenylpropan-1-ol 3 (20 g, 0.06 mol) and Et3N (15.3 ml, 0.11 mol) in DMSO (60 ml) at 0°C. The mixture
was allowed to warm to room temperature, and after 2 h the reaction was quenched with ice–water (100
ml) and extracted with ethyl acetate (3×40 ml). The extracts were washed with water (100 ml), dried
over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the aldehyde
4 (19.3 g, 98%) which was used without further purification; [α]D25=−88.0 (c=2, EtOH); νmax/cm−1
(film) 1729 (C_O), 1494 and 1453; δH (300 MHz; CDCl3) 9.8 (1H, s, CHO), 7.35–7.0 (15H, m, ArH),
3.9 [2H, d, J 14, N(CHAHBPh)2], 3.75 [2H, d, J 14, N(CHAHBPh)2], 3.62 (1H, t, J 7.3, CHN), 3.2 (1H,
dd, J 14.5 and 8, PhCHAHB) and 3.0 (1H, dd, J 14.5 and 6.5, PhCHAHB); δC (75 MHz; CDCl3) 202.1

1434
J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
(C_O), 139.0, 139.8, 129.4, 129.2, 128.5, 128.3, 127.3, 126.2 (Ar), 68.4 (CHN), 54.8 (CH2N) and 30.0
(PhCH2CHN); m/z 330 (100%, M+1). [Found: (M+H)+, 330.1860. C23H23NO requires M+1, 330.1858.]
3.4. (2S,3R)-2-(Dibenzylamino)-1-phenylundec-4-yn-3-ol 6
Butyl lithium (43 ml of a 1.6 M solution, 0.069 mol) was added to a solution of 1-octyne (10.2 ml,
0.069 mol) in THF (150 ml) at −78°C. After 30 min, a solution of the aldehyde 4 (15 g, 0.046 mol) in
THF (150 ml) was added dropwise. The mixture was stirred at −78°C for 20 min and warmed to room
temperature. After 20 min, saturated ammonium chloride solution (300 ml) was added and the mixture
was extracted with dichloromethane (3×200 ml). The combined organic fractions were washed with
water, dried over sodium sulfate and evaporated under reduced pressure to give a crude product which
was purified by flash chromatography [95:5 petroleum ether (b.p. 40–60°C): ether] to give the alkyne 6
(15.7 g, 78%) as a yellow oil, Rf [95:5 petroleum ether (b.p. 40–60°C): ether] 0.32; [α]D25=+23.2 (c=2,
EtOH); νmax (film)/cm−1 3400 (OH), 2250 (C^C), 1601 (Ar), 1494 and 1453; δH (300 MHz; CDCl3)
7.5–7.0 (15H, m, Ar), 4.3 [2H, d, J 14, N(CHAHBPh)2], 4.0 (1H, fine m, CHOH), 3.4 [2H, d, J 14,
N(CHAHBPh)2], 3.1 (1H, dd, J 12 and 3.5, PhCHAHB), 3.0 (1H, m, CHN), 2.9 (1H, dd, J 12 and 10,
PhCHAHB), 2.15 (2H, dt, J 2 and 7, CHOHCH2), 1.4–1.0 [8H, m, (CH2)4Me] and 0.8 (3H, t, J 7, Me);
δC (75 MHz; CDCl3) 139.0, 138.8, 129.2, 129.1, 128.9, 128.4, 127.3, 126.3 (Ar), 87.6, 79.9 (C^C), 62.5
(CHOH), 60.4 (CHN), 54.9 (CH2N), 31.6, 31.3, 28.6, 28.5, 22.4, 18.8 and 13.9 [(CH2)5Me+PhCH2CH];
m/z 440 (100%, M+1). [Found: (M+H)+, 440.2945. C31H37NO requires M+H, 440.2953.]
HPLC analysis of the crude product indicated a 96:4 ratio of diastereoisomers.
3.5. (E,2S,3R)-2-(Dibenzylamino)-1-phenylundec-4-en-3-ol 7
A solution of the alkyne 6 (4.6 g, 10 mmol) in THF (100 ml) was added to a stirred solution of
LiAlH4 (1.58 g, 42 mmol) in THF (100 ml) at 0°C. The mixture was heated to reflux for 5 h and
cooled. Saturated sodium bicarbonate solution (0.5 ml) was carefully added and a dense white precipitate
formed. The mixture was filtered through a pad of Celite and concentrated under reduced pressure. Flash
chromatography [4:1 petroleum ether (b.p. 40–60°C): ether] gave the alkene 7 (2.89 g, 66%) as a yellow
oil; Rf [4:1 petroleum ether (b.p. 40–60°C): ether] 0.32; [α]D25=−16.0 (c=2, EtOH); νmax (film)/cm−1
3400 (OH), 1601 (Ar) and 1453; δH (300 MHz; CDCl3) 7.4–7.0 (15H, m, Ar), 5.8 (1H, dt, J15.5 and
7, CH_CHCH2), 5.65 (1H, dd, J15.5 and 7, CH_CHCH2), 4.0 (1H, m, CHOH), 3.9 [2H, d, J 14,
N(CHAHBPh)2], 3.6 [2H, d, J 14, N(CHAHBPh)2], 3.1 (2H, m, PhCHAHBCHN), 2.8 (1H, dd, J 15 and
8, PhCHAHB), 2.0 (2H, q, J 17, CH_CHCH2), 1.3 [8H, m, (CH2)4Me] and 0.9 (3H, t, J 7, Me); δC (75
MHz; CDCl3) 140.0, 139.5, 132.3, 130.1, 129.3, 128.9, 128.4, 128.3, 127.1, 126.1 (Ar and C_C), 71.1
(CHOH), 63.4 (CHN), 55.0 (CH2N), 32.4, 31.9, 31.7, 29.2, 28.9, 22.6, 14.1 [(CH2)5Me and PhCH2CH];
m/z 442 (100%, M+1). [Found: (M+H)+, 442.3110. C31H39NO requires M+H, 442.3119.]
3.6. (E,2S,3R)-2-(Dibenzylamino)-1-phenylundec-4-en-3-yl acetate 8
Acetic anhydride (4.3 ml, 45 mmol) was added dropwise to a solution of the alcohol 7 (1.0 g, 2.27
mmol) in pyridine (4 ml) and the mixture was stirred under nitrogen for 24 h. Ethyl acetate (20 ml) was
added, and the solution washed with 2 M HCl (3×20 ml), saturated aqueous sodium bicarbonate solution,
20% aqueous copper sulfate soln. and brine. The organic fractions were dried (Na2SO4) and the solvent
evaporated under reduced pressure to give a crude product. Flash chromatography [4:1 petroleum ether
(b.p. 40–60°C): ether] gave the acetate 8 (0.88 g, 80%) as a yellow oil, Rf [5:1 petroleum ether (b.p.

J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
1435
40–60°C): ether] 0.34; [α]D25=+13.2 (c=2, EtOH); νmax/cm−1 (film) 1737 (C_O), 1494 and 1453; δH
(300 MHz; CDCl3) 7.4–7.0 (15H, m, Ar), 5.7 (2H, m, CH_CHCHOAc), 5.4 (1H, dd, J 15.5 and 7,
CH_CHCHOAc), 3.7 [4H, AB m, N(CH2Ph)2], 3.1 (2H, m, PhCHAHBCHN), 2.8 (1H, dd, J 14 and 5,
PhCHAHBCNH), 2.1 (2H, m, CH_CHCH2), 2.0 (3H, s, OCOMe), 1.3 [8H, m, (CH2)4] and 0.9 (3H,
t, J 7, CH2Me); δC (75 MHz; CDCl3) 170.1 (C_O), 140.4, 139.6, 134.2, 129.2, 128.6, 128.2, 128.1,
128.0, 127.6, 126.8, 125.7 (C_C and Ar), 74.3 (CHOAc) 61.6 (CHN), 53.9 (CH2N), 32.6, 32.2, 31.6,
28.8, 28.7, 22.5, 21.3, 14.0 [(CH2)4Me+PhCH2CH+OCOMe]; m/z 484 (100%, M+1). [Found: (M+H)+,
484.3215. C33H41NO2 requires M+H, 484.3222.]
3.7. (E,2S,5R)-2-(Dibenzylamino)-1-phenylundec-3-en-5-yl acetate 9
Bis(acetonitrile) palladium(II) chloride (6.5 mg, 0.025 mmol) was added to a stirred solution of the
acetate 8 (0.158 g, 0.25 mmol) in dry THF (4 ml) at room temperature under nitrogen. The red–brown
mixture was stirred under nitrogen for 4 days at 30°C and evaporated under reduced pressure to yield a
crude product which 1H NMR showed to contain a 70:30 mixture of 8 and 9. Flash chromatography [1:4
petroleum ether (b.p. 40–60°C): ether] gave the rearranged acetate 9 (31 mg, 24%) as a yellow oil, Rf
[1:4 petroleum ether (b.p. 40–60°C): ether] 0.34; δH (300 MHz; CDCl3) 7.3–7.0 (15H, m, Ar), 5.7 (1H,
dd, J 14.5 and 8.5, CH_CHCHOAc) 5.2 (2H, m, CH_CHCHOAc), 3.8 [2H, d, J 14, N(CHAHBPh)2],
3.3 [2H, d, J 14, N(CHAHBPh)2], 3.3 (1H, m, CHNBn2), 2.9 (1H, dd, J 14 and 7, PhCHAHB), 2.7 (1H,
m, PhCHAHB), 2.0 (3H, s, OCOMe), 1.5 (2H, m, AcOCHCH2), 1.2 [8H, m, (CH2)4] and 0.8 (3H, t, J 7,
Me).
The 70:30 ratio remained unchanged after a further 48 h, and heating the THF to 50°C gave a black
precipitate of palladium metal.
3.8. (E,2S,3R)-2-(Dibenzylamino)-1-phenylundec-4-en-3-yl propionate 10
Triethylamine (0.32 ml, 2.27 mmol), 4-(N,N-dimethylamino)pyridine (14 mg, 0.11 mmol) and pro-
pionyl chloride (0.2 ml, 2.27 mmol) were added to a stirred solution of the alcohol (0.5 g, 1.13 mmol)
in dichloromethane (5 ml) at room temperature. After 3 days the dichloromethane (20 ml) was added
and the solution was washed with water (3×20 ml) and dried (Na2SO4) The solvent was removed
under reduced pressure and the crude product was purified by flash chromatography [6:1 petroleum
ether (b.p. 40–60°C): ether] to give the propionate 10 as a yellow oil (1.56 g, 63%), Rf [6:1 petroleum
ether (b.p. 40–60°C): ether] 0.42; [α]D25=−29.6 (c=2, EtOH); νmax/cm−1 (film) 1736 (C_O); δH
(300 MHz; CDCl3) 7.2–6.9 (15H, m, Ar), 5.6 (2H, m, CH_CHCHOAc), 5.3 (1H, dd, J 15.5 and
7, CH_CHCHOAc), 3.65 [2H, d, J 14, N(CHAHBPh)2], 3.5 [2H, d, J 14, N(CHAHBPh)2], 3.0 (2H,
m, PhCHAHBCHN), 2.75 (1H, dd, J 14 and 5, PhCHAHBCNH), 2.2 (2H, ABX3, JAB 16.4, JAX 7.5
and JBX 7.5, OCOCH2Me), 2.0 [2H, q, J 7, CH2(CH2)4Me], 1.2 [8H, m, (CH2)4], 1.0 (3H, t, J 7.5,
OCOCH2Me) and 0.9 [3H, t, J 7, (CH2)4Me]; δC (75 MHz; CDCl3) 173.4 (C_O), 140.5, 139.5, 133.9,
129.3, 128.6, 128.3, 127.9, 127.7, 126.7, 125.7 (Ar and C_C), 73.8 (OCH), 61.7 (CHN), 53.9 (CH2N),
32.6 (OCOCH2Me), 32.2, 31.6, 29.6, 28.8, 27.9, 22.5, 14.0 and 8.9 [(CH2)5Me+PhCH2+OCOCH2Me];
m/z 498 (100%, M+1). [Found: (M+H)+, 498.3364. C34H43NO2 requires M+H, 498.3372.]
3.9. (E,2S,5R)-2-(Dibenzylamino)-1-phenylundec-3-en-5-yl propionate 11
Bis(acetonitrile) palladium(II) chloride (45 mg, 0.08 mmol) was added to a stirred solution of the
propionate 10 (0.4 g, 0.8 mmol) in dry THF (50 ml) at room temperature under nitrogen. The red–brown

1436
J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
mixture was stirred under nitrogen for 3 days at room temperature and evaporated under reduced
pressure to yield a crude product which was purified by flash chromatography [4:1 petroleum ether (b.p.
40–60°C): ether] to give the rearranged propionate 11 (0.3 g, 77%) as a yellow oil, Rf [7:1 petroleum
ether (b.p. 40–60°C): ether] 0.25; [α]D25=−32.8 (c=2, EtOH); νmax/cm−1 (film) 1735 (C_O); δH (300
MHz; CDCl3) 7.2–6.9 (15H, m, Ar), 5.7 (1H, dd, J 14.5 and 8.5 CH_CHCHOCOEt), 5.2 (2H, m,
CH_CHCHOCOEt), 3.7 [2H, d, J 14, N(CHAHBPh)2], 3.3 [2H, d, J 14, N(CHAHBPh)2], 3.3 (1H, m,
NCH), 2.9 (1H, dd, J 14 and 7, PhCHAHB), 2.7 (1H, dd, J 15 and 7, PhCHAHB), 2.2 (2H, ABX3 m,
OCOCH2Me), 1.5 (2H, m, OCHCH2), 1.2 [8H, m, (CH2)4], 1.1 (3H, t, J 7, OCOCH2Me), 0.8 [3H, t, J 7,
(CH2)4Me]; δC (75 MHz; CDCl3) 173.6 (C_O), 139.9, 139.4, 132.4, 130.4, 129.5, 128.4, 128.1, 127.9,
126.6, 125.8 (Ar and C_C), 74.1 (CHOCO), 61.2 (CHN), 53.6 (CH2N), 38.6 (COCH2Me), 34.5, 31.7,
28.9, 27.9, 25.1, 22.5, 14.0 and 9.2 [(CH2)5Me+COCH2Me+PhCH2CH]; m/z 498 (100%, M+1). [Found:
(M+H)+, 498.3367. C34H43NO2 requires M+H, 498.3372.]
3.10. (E,3S,30S)-Ethyl-3-(30-dibenzylamino-40-phenylbut-10-en-10-yl)nonanoate 12
Triethyl orthoacetate (0.25 ml, 1.36 mmol) and propionic acid (2 µl, 0.03 mmol) were added to a
solution of alcohol 7 (0.2 g, 0.45 mmol) in toluene (20 ml). The solution was heated to reflux for 20
h, cooled, concentrated under reduced pressure and purified by flash chromatography [4:1 petroleum
ether (b.p. 40–60°C): ether] to give the ester 12 as a pale yellow oil (0.18 g, 79%); Rf [4:1 petroleum
ether (b.p. 40–60°C): ether] 0.48; [α]D25=−30.8 (c=2, EtOH); νmax/cm−1 (film) 1735 (C_O); δH (300
MHz; CDCl3) 7.2–7.0 (15H, m, Ar), 5.4 (1H, dd, J 15.5 and 8.5, NCHCH_CH), 5.1 (1H, dd, J 15.5
and 8.5, NCHCH_CH), 4.0 (2H, ABX3 m, OCH2), 3.8 [2H, d, J 14, N(CHAHBPh)2], 3.3 [2H, d, J 14,
N(CHAHBPh)2], 3.2 (1H, m, CHN), 2.9 (1H, dd, J 14 and 8, PhCHAHB), 2.6 (1H, dd, J 14 and 7.5,
PhCHAHB), 2.5 (1H, m, CH_CHCHCH2), 2.2 (1H, dd, J 14.5 and 6.3, EtOCOCHAHB), 2.1 (1H, dd,
J 14.5 and 6.3, EtOCOCHAHB), 1.2 [10H, m, (CH2)5], 1.1 (3 H, t, J 7, OCH2Me) and 0.8 (3H, t, J
7, CH2CH2Me); δC (75 MHz; CDCl3) 172.5 (C_O), 140.1, 139.6, 136.9, 129.5, 128.4, 128.0, 127.8,
126.6, 126.5, 125.7 (C_C and Ar), 61.3 (CH2O), 60.1 (CNH), 53.5 (CH2N), 40.5 (CH2CO2Et), 39.4,
38.9, 34.7, 31.8, 29.0, 27.2, 22.6, 14.2 and 14.0 [(CH2)5Me+PhCH2+OCH2Me]; m/z 512 (100%, M+1)
and 420 (80, M−Bn). [Found: (M+H)+, 512.3532. C35H45NO2 requires M+H, 512.3528.]
3.11. (E,3S,30S)-N,N-Dimethyl-3-(30-dibenzylamino-40 -phenylbut-10-en-10-yl)nonanamide 13
N,N-Dimethylacetamide dimethyl acetal (0.2 ml, 1.22 mmol) was added to a solution of alcohol 7
(0.2 g, 0.45 mmol) in toluene (10 ml). The solution was heated to reflux for 20 h, cooled, and poured
into dichloromethane (25 ml) and saturated aqueous NH4Cl (25 ml). The layers were separated, and
the aqueous layer extracted with dichloromethane (2×25 ml). The combined organic fractions were
dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography
[2:1 petroleum ether (b.p. 40–60°C):ether] yielded the amide 13 as a pale yellow oil (0.2 g, 87%); Rf
(EtOAc) 0.27; [α]D25=28.8 (c=2, EtOH); νmax/cm−1 (film) 1648 (C_O), 1493 and 1453; δH (300 MHz;
CDCl3) 7.2–7.0 (15H, m, Ar), 5.4 (1H, dd, J 15 and 8.7, NCHCH_CH), 5.1 (1H, dd, J 15 and 8.8,
NCHCH_CH), 3.7 [2H, d, J 14, N(CHAHBPh)2], 3.3 [2H, d, J 14, N(CHAHBPh)2], 3.2 (1H, m, CHN),
2.9 (1H, dd, J 13.5 and 9, PhCHAHB), 2.8 (6H, s, NMe2), 2.6 (1H, dd, J 14 and 7.7, PhCHAHB), 2.5
(1H, m, CH_CHCHCH2), 2.1 (2H, d, J 7, CH2CONMe2), 1.2 [10H, m, (CH2)5] and 0.8 (3H, t, J 7,
CH2Me); δC (75 MHz; CDCl3) 171.9 (C_O), 140.2, 139.8, 137.7, 129.5, 128.5, 128.0, 127.8, 127.6,
126.6, 125.7 (Ar and C_C), 61.6 (CHN), 53.5 (CH2N), 39.7, 39.2, 39.1, 37.4, 34.8, 31.9, 29.2, 27.5,

J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
1437
22.7, 14.1 [(CH2)5Me+PhCH2CH+CHCONMe2]; m/z 511 (100%, M+1) and 419 (80, M−Bn). [Found:
(M+H)+, 511.3680. C35H43N2O requires M+H, 511.3688.]
3.12. Ozonolysis of (E,2S,5R)-2-(dibenzylamino)-1-phenylundec-3-en-5-yl propionate 11
Acetyl chloride (29 µl, 0.4 mmol) was added dropwise to methanol (8 ml) under nitrogen at room
temperature. The mixture was stirred for 1 h and was then added dropwise to a solution of the ester
11 (0.1 g, 0.2 mmol). After 30 min, the reaction mixture was cooled to 0°C and was treated with a
steady stream of ozone in oxygen for 60 min. Excess ozone was removed by passing a stream of oxygen
through the reaction mixture for 10 min, and the reaction mixture diluted with 50% aqueous ethanol
(8 ml). Sodium borohydride (76 mg, 2 mmol) was carefully added, the reaction mixture was allowed
to warm to 23°C and was stirred for a further 1 h. Concentrated hydrochloric acid (0.5 ml) and EtOAc
(30 ml) were added. The solution was washed with saturated aqueous NaHCO3 (10 ml), water (10 ml)
and brine (10 ml), dried (Na2SO4) and concentrated under reduced pressure to give a crude product
mixture. Flash chromatography [2:1 petroleum ether (b.p. 40–60°C):ether] gave (S)-2-(dibenzylamino)-
3-phenylpropan-1-ol 3 (46 mg, 71%) as a white solid, [α]D25=−14.4 (c=2, EtOH), spectroscopically
identical with the material derived directly from L-phenylalanine.
Also obtained was a mixture of the esters 14 and 17 (13 mg, 33%).
In the same way but with acetyl chloride (43 µl, 0.6 mmol), ozonolysis for 2 h at −78°C gave, after
purification by flash chromatography, (S)-2-(dibenzylamino)-3-phenylpropan-1-ol 3 (29 mg, 44%).
Also obtained was (R)-1-hydroxyoct-2-yl propionate 14 as a yellow oil (11 mg, 28%); Rf [1:4
petroleum ether (b.p. 40–60°C): ether] 0.31; [α]D25=−17.2 (c=2, EtOH); δH (300 MHz; CDCl3) 4.8 (1H,
dq, J 3 and 6.5, CHOCOEt), 3.6 (2H, m, CH2OH), 2.3 (2H, q, J 7.5 and 15, OCOCH2CH3), 1.5 [2H, m,
CH2(CH2)4Me], 1.2 [8H, m, (CH2)4Me], 1.1 (3H, t, J 7.5, OCOCH2Me) and 0.8 (3H, t, J 7, (CH2)4Me);
δC (75 MHz; CDCl3) 174.8 (C_O), 75.5 (CHOCO), 64.9 (CH2OH), 31.6, 30.4, 29.0, 27.7, 25.2, 22.4,
13.9, 9.1 [(CH2)5Me+Et]; m/z 203 (100%, M+1). [Found: (M+H)+, 203.1649. C11H22O3 requires M+H,
203.1569.]
Also obtained was (R)-2-hydroxyoct-1-yl propionate 17 as a yellow oil (6 mg, 15%); Rf [3:1 petroleum
ether (b.p. 40–60°C): ether] 0.26; [α]D25=−12.8 (c=2, EtOH); δH (300 MHz; CDCl3) 4.1 (1H, dd, J 11
and 4, EtOCOCHAHB), 3.9 (1H, dd, J 11 and 4, EtOCOCHAHB), 3.8 (1H, m, CHOH), 2.3 (2H, dd, J 7.5
and 3, OCOCH2CH3), 1.4 [2H, m, CH2(CH2)4Me], 1.2 [8H, m, (CH2)4Me], 1.1 (3H, t, J 7.5, OCH2Me)
and 0.8 (3H, t, J 7, OCCH2Me); δC (75 MHz; CDCl3) 174.5 (C_O), 68.4 (CHOH), 64.5 (CH2OCO),
33.5, 32.0, 28.5, 27.5, 25.0, 22.5, 14.0, 9.0 [(CH2)5Me+Et]; m/z 203 (100%, M+1). [Found: (M+H)+,
203.1647. C11H22O3 requires M+H, 203.1569.]
3.13. Ozonolysis of (E,3S,30S)-ethyl-3-(30-dibenzylamino-40-phenylbut-10-en-10-yl)nonanoate 12
In the same way but with acetyl chloride (43 µl, 0.6 mmol), ozonolysis for 2 h 30 min at −78°C gave,
after purification by flash chromatography, (S)-2-(dibenzylamino)-3-phenylpropan-1-ol 3 (22 mg, 33%).
Also obtained was the unstable (R)-ethyl-2-hydroxymethylnonanoate 15 (20 mg, 47%) as a yellow oil;
Rf [3:1 petroleum ether (b.p. 40–60°C): ether] 0.25; δH (300 MHz; CDCl3) 4.1 (2H, q, J 7.5, OCH2CH3),
3.6 (1H, dd, J 10.5 and 4, CHAHBOH), 3.4 (1H, m, CHAHBOH), 2.3 (2H, m, EtOCOCH2), 1.9 (1H, m,
HOCH2CH), 1.5 (2H, m, CH2(CH2)4Me), 1.2 [11H, m, OCH2CH3+(CH2)4Me] and 0.8 [3H, t, J 7,
(CH2)4Me].
Also obtained was (R)-4-hexylfuran-2-one 19 (13 mg, 31%) as a yellow oil; Rf [3:1 petroleum ether
(b.p. 40–60°C): ether] 0.48; [α]D25=+2.8 (c=1, EtOH) [lit.54 [α]D25=+4.7 (c=1.69, CHCl3)]; δH (300

1438
J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
MHz; CDCl3) 4.3 (1H, dd, J 9 and 8, CHAHBO), 3.8 (1H, dd, J 9 and 8, CHAHBO), 2.6 (1H, dd, J 16.5
and 8, CHAHBCO), 2.5 (1H, septet, J 7.5, CHCH2O), 2.1 (1H, dd, J 7.5 and 16, CHAHBCO), 1.4 [2H,
m, CH2(CH2)4Me], 1.2 [8H, m, (CH2)4Me] and 0.8 (3H, t, J 7, Me); δC (75 MHz; CDCl3) 164.5 (C_O),
73.4 (CH2O) 35.7 (CH2CO), 34.5, 33.1, 31.5, 29.1, 27.3, 22.5 and 13.9 [(CH2)5Me]; m/z 188 (100%,
M+18).
3.14. Ozonolysis of (E,3S,30S)-N,N-dimethyl-3-(30-dibenzylamino-40-phenylbut-10-en-10-yl)nonan-
amide 13
In the same way, but with acetyl chloride (43 µl, 0.57 mmol), ozonolysis for 80 min at 0°C gave, after
purification by flash chromatography [2:1 petroleum ether (b.p. 40–60°C): ether], (S)-2-(dibenzylamino)-
3-phenylpropan-1-ol 3 (50 mg, 63%).
Also obtained was (R)-2-hydroxymethyl-N,N-dimethylnonanamide 16 (25 mg, 75%) as a yellow oil;
Rf [3:2 petroleum ether (b.p. 40–60°C): ether] 0.44; [α]D25=−14.4 (c=2, EtOH); νmax/cm−1 (film) 1628
(C_O); δH (300 MHz; CDCl3) 3.7 (1H, dd, J 11 and 4, CHAHBOH), 3.5 (1H, dd, J 11 and 8, CHAHBOH),
3.1 (3H, s, NMeAMeB), 3.0 (3H, s, NMeAMeB), 2.5 (1H, dd, J 16 and 4, OCCHAHB), 2.4 (1H, dd, J 16 and
9, OCHAHB), 2.1 (1H, m, HOCH2CH), 1.3 [10H, m, (CH2)5] and 0.8 (3H, t, J 7, CH2Me); δC (75 MHz;
CDCl3) 173.7 (C_O), 66.7 (CH2OH), 37.6 (CH2CONMe2), 37.5, 36.9, 35.6, 32.0, 31.7, 29.4, 27.0, 22.5,
14.0 [(CH2)5Me+CHCH2CONMe2]; m/z 216 (100%, M+1). [Found: (M+H)+, 216.1968. C12H25NO2
requires M+H, 216.1963.]
3.15. (S)-Octane-1,2-diyl dipropionate 18
Triethylamine (41 µl, 0.3 mmol), 4-(dimethylamino)pyridine (2 mg, 0.015 mmol) and propionyl
chloride (27 µl, 0.3 mmol) were added to a mixture of the isomeric hydroxyesters 14 and 17 (31 mg,
0.15 mmol) in dichloromethane (5 ml) at room temperature. After 3 days, dichloromethane (10 ml)
was added and the mixture was washed with water (3×10 ml) and dried (Na2SO4) and the solvent was
removed under reduced pressure. Flash chromatography [1:1 petroleum ether (b.p. 40–60°C): ether] gave
the diester 18 (31.6 mg, 82%) as a yellow oil, Rf [2:1 petroleum ether (b.p. 40–60°C): ether] 0.36; δH
(300 MHz; CDCl3) 5.0 (1H, dq, J 3 and 6, CHOCOEt), 4.2 (1H, dd, J 9 and 3.5, CHAHBOCOEt), 4.0
(1H, dd, J 12 and 9, CHAHBOCOEt), 2.2 (4H, q, J 8, CH3CH2CO×2), 1.5 [2H, m, CH2(CH2)4Me], 1.2
[8H, m, (CH2)4Me], 1.05 (3H, t, J 8), 1.04 (3H, t, J 8) (CH3CH2CO×2) and 0.8 [3H, m, (CH2)4Me]; δC
(75 MHz; CDCl3) 174.0 (C_O); 71.0 (CHOCOEt), 65.0 (CH2OCOEt), 32.0, 31.4 (MeCH2CO×2), 29.8,
29.4, 27.4, 27.2, 25.0, 22.2, 14.0 and 9.5; m/z 276 (100%, M+18). [Found: (M+H)+, 259.1922. C14H26O4
requires M+H, 259.1909.]
Acknowledgements
We are grateful to the EPSRC for an Industrial CASE Quota Award (to CMcC), and to the University
of Manchester’s Research Support Fund and the Royal Society for Research Grants.
References
1. Evans, D. A. In Asymmetric Synthesis Vol. 3, Morrison, J. D., Editor, Academic Press, New York, 1984, p. 2.

J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
1439
2. Huryn, D. M. In Comprehensive Organic Synthesis, Vol. 1, Trost, B. M.; Fleming, I., Editors, Pergamon, Oxford, 1990, p.
49.
3. For a discussion, see Clayden, J.; Collington, E. W.; Lamont, R. B.; Warren, S. Tetrahedron Lett., 1993, 34, 2203.
4. Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett., 1968, 2199.
5. Anh, N. T.; Eisenstein, O. Nouv. J. Chim., 1977, 1, 61.
6. Anh, N. T. Top. Curr. Chem., 1980, 88, 145.
7. Reetz, M. T. Acc. Chem. Res., 1993, 26, 462.
8. Cram, D. J.; Abd Elhafez, F. A. J. Am. Chem. Soc., 1952, 74, 5828.
9. Reetz, M. Angew. Chem., Int. Ed. Engl., 1991, 30, 1531.
10. Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed. Engl., 1987, 26, 1141.
11. Jurczak, J.; Golebiowski, A. Chem. Rev., 1989, 89, 149.
12. O’Brien, P.; Powell, H. R.; Raithby, P. R.; Warren, S. J. Chem. Soc., Perkin Trans. 1, 1997, 1031.
13. Beaulieu, P. L.; Wernic, D. J. Org. Chem., 1996, 61, 3635.
14. Organolithiums typically add to 4 with non-chelation control. See also Andrés, J. M.; Barrio, R.; Martínez, M. A.; Pedrosa,
R.; Pérez-Encabo, A. J. Org. Chem., 1996, 61, 4210.
15. Stereochemistry was assigned by precedent for similar reactions,10 and later confirmed by the sign of the optical rotation
of 19.
16. Grant, B.; Djerassi, C. J. Org. Chem., 1974, 39, 968.
17. Málek, J. Org. Reac., 1985, 34, 1.
18. Compare Ref. 48 and Garner, P.; Park, J. M.; Malecki, E. J. Org. Chem., 1988, 53, 4395; Takikawa, H.; Maeda, T.; Mori,
K. Tetrahedron Lett., 1995, 36, 7689.
19. Hill, R. K. In Asymmetric Synthesis, Vol. 3, Morrison, J. D., Editor, Academic Press, New York, 1985, p. 503.
20. Altenbach, H. J. FGI by allylic rearragement. In Comprehensive Organic Synthesis, Vol. 6, Trost, B. M.; Fleming, I.,
Editors, Pergamon, Oxford, 1990, p. 829.
21. Frauenrath, H. In Houben–Weyl, Methoden der Organischen Chemie, Vol. E21d, 1995.
22. Overman, L. E. Angew. Chem., Int. Ed. Engl., 1984, 23, 579.
23. Grieco, P. A.; Takigawa, T.; Bongers, S. L.; Tanaka, T. J. Am. Chem. Soc., 1980, 102, 7587.
24. Danishefsky, S. J.; Cabal, M. P.; Chow, K. J. Am. Chem. Soc., 1989, 111, 3456.
25. Clayden, J.; Warren, S. J. Chem. Soc., Perkin Trans. 1, 1993, 2913.
26. Bennett, G. B. Synthesis, 1977, 589.
27. Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org. Chem., 1991, 56, 3572.
28. Paterson, I.; Hulme, A. N. J. Org. Chem., 1995, 60, 3288.
29. Hartley, R. C.; Richards, I. C.; Warren, S. J. Chem. Soc., Perkin Trans. 1, 1996, 359.
30. McKinney, J. A.; Eppley, D. F.; Keenan, R. M. Tetrahedron Lett., 1994, 35, 5985.
31. Ibuka, T.; Habashita, H.; Funakoshi, S.; Fujii, N.; Oguchi, Y.; Uyehara, T.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl.,
1990, 29, 801.
32. Tomooka, K.; Nagasawa, A.; Wei, S.-Y.; Nakai, T. Tetrahedron Lett., 1996, 37, 8895, 8899.
33. Overman, L. E. Acc. Chem. Res., 1980, 13, 218.
34. Ichikawa, Y.; Tsuboi, K.; Isobe, M. J. Chem. Soc., Perkin Trans. 1, 1994, 2791.
35. Metz, P.; Mues, C.; Schoop, A. Tetrahedron, 1992, 48, 1071.
36. Savage, I.; Thomas, E. J. J. Chem. Soc., Chem. Commun., 1989, 717.
37. Chen, A.; Savage, I.; Thomas, E. J.; Wilson, P. D. Tetrahedron Lett., 1993, 34, 6769.
38. Myers, A. G.; Zheng, B. Tetrahedron Lett., 1996, 37, 4841.
39. Fleming, I.; Winter, S. B. D. Tetrahedron Lett., 1995, 36, 1733.
40. Suginome, M.; Matsumoto, A.; Ito, Y. J. Am. Chem. Soc., 1996, 118, 3061.
41. Chambers, M. S.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1, 1997, 417.
42. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem.
Soc., 1970, 92, 741.
43. Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta, 1964, 47, 2425.
44. Takatsuto, S.; Ishiguro, M.; Ikekawa, N. J. Chem. Soc., Chem. Commun., 1982, 258.
45. Bloch, R.; Gasparini, G. J. Org. Chem., 1989, 54, 3370.
46. Henry, P. M. J. Am. Chem. Soc., 1972, 94, 5200.
47. Oehlschlager, A. C.; Mishra, P.; Dhami, S. Can. J. Chem., 1984, 62, 791.
48. Heneghan, M.; Procter, G. Synlett, 1992, 489.

1440
J. Clayden et al. / Tetrahedron: Asymmetry 9 (1998) 1427–1440
49. Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am. Chem. Soc., 1995, 117, 3448.
50. Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis, Vol. 7, Trost, B. M.; Fleming, I., Editors, Pergamon, Oxford,
1990, p. 558.
51. Bailey, P. S. Ozonation in Organic Chemistry, Academic Press, New York, 1982.
52. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem., 1969, 34, 2543.
53. Ward, D. E.; Rhee, C. K. Tetrahedron Lett., 1991, 32, 7165.
54. Kosugi, H.; Tagami, K.; Takahashi, A.; Kana, H.; Uda, H. J. Chem. Soc., Perkin Trans. 1, 1989, 935.
55. Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev., 1994, 94, 2483.
56. see, for an alternative solution, Poppe, L.; Novák, L.; Katjár-Peredy, M.; Szántay, C. Tetrahedron, Asymmetry, 1993, 4,
2211.
57. Imogaï, H.; Petit, Y.; Larchevêque, M. Tetrahedron Lett., 1996, 37, 2573.
58. Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron Lett., 1996, 37, 5577.
59. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem., 1978, 43, 2923.