Probing competitive and co-operative hydroxyl and ammonium hydrogen-bonding directed epoxidations

Article abstract of DOI:10.1021/acs.joc.7b01774

The diastereoselectivities and rates of epoxidation (upon treatment with Cl₃CCO₂H then m-CPBA) of a range of cis- and trans-4- aminocycloalk-2-en-1-ol derivatives (containing five-, six-, and seven-membered rings) have been investigated. In all cases where the two potential directing groups can promote epoxidation on opposite faces of the ring scaffold, evidence of competitive epoxidation pathways, promoted by hydrogen-bonding to either the in situ formed ammonium moiety or the hydroxyl group, was observed. In contrast to the relative directing group abilities already established for the sixmembered ring system (NHBn ? OH > NBn₂), an N,N-dibenzylammonium moiety appeared more proficient than a hydroxyl group at directing the stereochemical course of the epoxidation reaction in a five- or seven-membered system. In the former case, this was rationalized by the drive to minimize torsional strain in the transition state being coupled with assistance from hydrogenbonding to the ammonium moiety. In the latter case, this was ascribed to the steric bulk of the ammonium moiety disfavoring conformations in which hydrogen-bonding to the hydroxyl group results in direction of the epoxidation to the syn face. In cases where the two potential directing groups can promote epoxidation on the same face of the ring scaffold, an enhancement of epoxidation diastereoselectivity was not observed, while introduction of a second, allylic heteroatom to the substrate results in diminishment of the rate of epoxidation in all cases. Presumably, reduction of the nucleophilicity of the olefin by the second, inductively electron-withdrawing heteroatom is the dominant factor, and any assistance to the epoxidation reaction by the potential to form hydrogen-bonds to two directing groups rather than one is clearly unable to overwhelm it.

Full text of DOI:10.1021/acs.joc.7b01774

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Article
Probing Competitive and Co-operative Hydroxyl and
Ammonium Hydrogen-Bonding Directed Epoxidations
Marta Brambilla, Meabh B Brennan, Kristína Csatayová, Stephen G. Davies, Ai M. Fletcher,
Alice M. R. Kennett, James A. Lee, Paul M. Roberts, Angela J. Russell, and James E. Thomson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01774 • Publication Date (Web): 31 Aug 2017
Downloaded from http://pubs.acs.org on August 31, 2017
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The Journal of Organic Chemistry
Probing Competitive and Co-operative Hydroxyl and Ammonium
Hydrogen-Bonding Directed Epoxidations
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Marta Brambilla, Méabh B. Brennan, Kristína Csatayová,† Stephen G. Davies,* Ai M. Fletcher,
Alice M. R. Kennett, James A. Lee, Paul M. Roberts, Angela J. Russell, and James E. Thomson
Department of Chemistry, Chemistry Research Laboratory,
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University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
steve.davies@chem.ox.ac.uk
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ABSTRACT: The diastereoselectivities and rates of epoxidation (upon treatment with Cl3CCO2H then mꢀ
CPBA) of a range of cisꢀ and transꢀ4ꢀaminocycloalkꢀ2ꢀenꢀ1ꢀol derivatives (containing fiveꢀ, sixꢀ and sevenꢀ
membered rings) have been investigated. In all cases where the two potential directing groups can promote
epoxidation on opposite faces of the ring scaffold, evidence of competitive epoxidation pathways, promoted
by hydrogenꢀbonding to either the in situ formed ammonium moiety or the hydroxyl group, was observed. In
contrast to the relative directing group abilities already established for the sixꢀmembered ring system (NHBn
>> OH > NBn2), an N,Nꢀdibenzylammonium moiety appeared more proficient than a hydroxyl group at
directing the stereochemical course of the epoxidation reaction in a fiveꢀ or sevenꢀmembered system. In the
former case, this was rationalised by the drive to minimise torsional strain in the transition state being
coupled with assistance from hydrogenꢀbonding to the ammonium moiety. In the latter case, this was
ascribed to the steric bulk of the ammonium moiety disfavouring conformations in which hydrogenꢀbonding
to the hydroxyl group results in direction of the epoxidation to the syn face. In cases where the two potential
directing groups can promote epoxidation on the same face of the ring scaffold, an enhancement of
epoxidation diastereoselectivity was not observed, whilst introduction of a second, allylic heteroatom to the
substrate results in diminishment of the rate of epoxidation in all cases. Presumably, reduction of the
nucleophilicity of the olefin by the second, inductively electronꢀwithdrawing heteroatom is the dominant
factor, and any assistance to the epoxidation reaction by the potential to form hydrogenꢀbonds to two
directing groups rather than one is clearly unable to overwhelm it.
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Introduction
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The ability to both accurately predict and be able to exert total control over the stereochemical
outcome of a given reaction might be considered a Holy Grail of organic synthesis.1,2 As such, a substrateꢀ
directed reaction3 is an attractive means to achieve a diastereoselective transformation. In these processes the
substrate is equipped with some structural feature that is able to influence the stereochemical course of the
reaction. Perhaps one of the earliest and most widely recognized examples of this tactic is the
diastereoselective epoxidation of a chiral allylic alcohol with a peracid, the stereochemical outcome of which
is rationalized by invoking a hydrogenꢀbond between the allylic hydroxyl group ‘donor’ and the peracid
‘acceptor’ in the transition state.4 Teranishi et al. have reported the diastereoselectivities of epoxidation of
the homologous series of cycloalkꢀ2ꢀenꢀ1ꢀols 1–3 upon treatment with mꢀCPBA in CH2Cl2 at 0 °C for 24 h:5
diastereoselective epoxidation of the syn face occurs in each case, with the levels of diastereoselectivity
being dependent on the ring size. Epoxidation of sevenꢀmembered ring substrate 3 proceeds with only
modest diastereoselectivity,6 whilst higher levels of diastereoselectivity are observed for fiveꢀmembered ring
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substrate 17 and sixꢀmembered ring substrate 28 (Scheme 1).
SCHEME 1a
OH
OH
(i)
84:16 dr
O
[syn:anti]
1
4
OH
OH
(i)
95:5 dr
O
[syn:anti]
2
5
HO
HO
(i)
61:39 dr
O
[syn:anti]
3
6
aReagents and Conditions: (i) mꢀCPBA, CH2Cl2, 0 °C, 24 h.
We have investigated the related epoxidation of a range of chiral allylic amines, reliant on a strategy
involving initial treatment with a strong Brønsted acid (e.g., Cl3CCO2H, F3CCO2H, TsOH, HBF4) to effect
protonation of the nitrogen atom, and hence offer protection against Nꢀoxidation.9 The N−H proton of the
resultant ammonium moiety is capable of acting as a hydrogenꢀbond donor to direct epoxidation upon
addition of a peracid (e.g., mꢀCPBA, F3CCO3H) to the proximal face of the olefin. For example, treatment of
Nꢀbenzylꢀ or N,Nꢀdibenzylꢀprotected cycloalkꢀ2ꢀenꢀ1ꢀamine derivatives 7–12 with 5.0 equiv of Cl3CCO2H
then 1.05 or 1.6 equiv of mꢀCPBA gave the corresponding epoxides 13–18.10–13 The stereochemical outcome
of the epoxidation was influenced not only by the ring size but also by the nature of the amino substituent,
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although in all cases the amino substituent provided equivalent or better diastereoselectivity of epoxidation
than the analogous hydroxyl group. The fiveꢀ and sixꢀmembered ring substrates 7–10 underwent epoxidation
on the face syn to the amino substituent (regardless of its identity) with very high levels of
diastereoselectivity (≥95:5 dr), leading to the corresponding synꢀepoxides 13–16.10–13 This sense of
diastereoselectivity is in accord with that elicited during the epoxidations of both of the corresponding allylic
alcohols (cyclopentꢀ2ꢀenꢀ1ꢀol 1 and cyclohexꢀ2ꢀenꢀ1ꢀol 2) upon treatment with a range of peracids,7,8 and is
consistent with hydrogenꢀbonding between the in situ formed ammonium ion and the oxidant resulting in
delivery of the latter to the proximal face. In the fiveꢀmembered ring substrates 7 and 8, the synꢀselectivity
may also be inherently favoured by minimization of torsional strain in the transition state.11,14,15 Within the
sevenꢀmembered ring substrates, epoxidation of 11 gave synꢀepoxide 17 in 85:15 dr.16 This is consistent with
the diastereoselectivity elicited upon epoxidation of cycloheptꢀ2ꢀenꢀ1ꢀol 3 with a range of peracids, which
proceeds to give the synꢀepoxide 6 in ~2:1 dr.5,6 In contrast, epoxidation of 12 gave antiꢀepoxide 18 in 94:6
dr (88% conversion).11,16 This outcome is anomalous on two counts when compared to 3 and 11: firstly, it is
significantly more diastereoselective, and secondly, it proceeds on the face anti to the directing group. We
have previously rationalized these observations11,16 as the result of the N,Nꢀdibenzylammonium moiety
playing two distinct roles: (i) its large steric bulk enforces a wellꢀdefined sevenꢀmembered chair
conformation17 (as present in the Xꢀray crystal structures of 12, the corresponding HBr salt 12·HBr and
epoxide 18) upon the otherwise conformationally promiscuous sevenꢀmembered ring;17 (ii) hydrogenꢀ
bonding between the ammonium moiety and the peracid assists in epoxidation of the proximal face in this
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conformer (Scheme 2).11,14
SCHEME 2a
aReagents and Conditions: (i) Cl3CCO2H (5.0 equiv), mꢀCPBA (1.05 equiv), CH2Cl2, rt, 3.5 h; (ii) Cl3CCO2H (5.0 equiv), mꢀ
CPBA (1.6 equiv), CH2Cl2, rt, 21 h; (iii) Cl3CCO2H (5.0 equiv), mꢀCPBA (2.5 equiv), CH2Cl2, rt, 20 min.
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We have recently explored the epoxidations of Nꢀbenzylꢀ and N,Nꢀdibenzylꢀprotected transꢀ4ꢀ
aminocyclohexꢀ2ꢀenꢀ1ꢀol 19 and 20.18,19 These are privileged structures within which the relative directing
abilities of the various substituents may be evaluated, as in either of the possible halfꢀchair conformations
(19A/20A and 19B/20B) of the sixꢀmembered rings, the allylic amino (and hence in situ formed ammonium)
moiety and the allylic hydroxyl group are located in identical environments (e.g., both pseudoꢀequatorial in
the ground states 19A and 20A). Epoxidation of Nꢀbenzylꢀprotected transꢀ19 resulted in complete
diastereoselectivity (>95:5 dr) for production of epoxide 21 (i.e., epoxidation exclusively on the face of the
olefin syn to the in situ formed ammonium moiety); Nꢀbenzylation of the crude reaction mixture gave 22 in
64% yield. This result suggests that the Nꢀbenzylammonium moiety is superior to the hydroxyl group as a
directing group. In contrast, epoxidation of N,Nꢀdibenzylꢀprotected transꢀ20 gave a separable 25:75 mixture
of epoxides 22 and 23, respectively (i.e., the major product 23 results from epoxidation on the face of the
olefin syn to the hydroxyl group), suggesting that the hydroxyl group is a better directing group than the
N,Nꢀdibenzylammonium moiety in an identical environment. From the results of these studies, it followed
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that the order of directing group ability is: NHBn >> OH > NBn218,19 (Scheme 3).
SCHEME 3a
NHBn
NHBn
(i)
O
>95:5 dr
OH
OH
trans-19, 97:3 dr
21, >95:5 dr
(ii)
NBn2
NBn2
NBn2
OH
(iii)
+
O
O
25:75 dr
[22:23]
OH
OH
trans-20, >99:1 dr
22, >99:1 dr
23, >99:1 dr
64% (from 19)
-
19% (from 20)* 44% (from 20)
NRBn
NRBn
HO
OH
19A, R = H
19B, R = H
20A, R = Bn
20B, R = Bn
aReagents and Conditions: (i) Cl3CCO2H (10 equiv), mꢀCPBA (5.0 equiv), CH2Cl2, rt, 30 min; (ii) BnBr, iPr2NEt, DMAP, CH2Cl2,
rt, 24 h; (iii) Cl3CCO2H (10 equiv), mꢀCPBA (5.0 equiv), CH2Cl2, rt, 3.5 h. * Sample isolated in 95:5 dr [22:23].
The epoxidations of the diastereoisomeric compounds cisꢀ24 and cisꢀ25 were also explored.19 In
these cases, the corresponding epoxides 26 and 27 were obtained as the exclusive products, which result
from reaction on the face syn to both the amino (ammonium) moiety and the hydroxyl group, as may be
expected; in the former case Nꢀbenzylation of the crude reaction mixture to facilitate purification gave 27,
which was thus isolated in 59% yield from 24 and 63% yield from 25 (Scheme 4). These results are
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consistent with the epoxidation being directed by either the hydroxyl group or the ammonium moiety, or
indeed both. However, the relative contributions from hydrogenꢀbonding to either of the two potential
directing groups cannot be easily dissected; a matter that can be further complicated by issues of geometry,
as the two potential directing groups now do not occupy identical environments in either of the possible halfꢀ
chair conformations of the sixꢀmembered rings (24A/25A and 24B/25B). The dependence of reaction
diastereoselectivity (as well as rate) on conformation is known in the epoxidations of related sixꢀmembered
ring substrates. For example, Whitham et al. investigated epoxidation of the diastereoisomers of 5ꢀtertꢀ
butylcyclohexꢀ2ꢀenꢀ1ꢀol (cisꢀ28 and transꢀ29) and found that a pseudoꢀequatorial hydroxyl group was
significantly better than a pseudoꢀaxial one as a directing group:20 for transꢀ29 (pseudoꢀaxial hydroxyl
group) the diastereoselectivity was 84:16 (syn:anti) with a relative rate of reaction on the face syn to the
hydroxyl group of 1.0, whereas for cisꢀ28 (pseudoꢀequatorial hydroxyl group) the diastereoselectivity was
94:6 (syn:anti) with a relative rate of reaction on the face syn to the hydroxyl group of 8.2 (Scheme 5). A
related (albeit much more subtle) effect was noted when we investigated epoxidation of the diastereoisomers
of N,Nꢀdibenzylꢀ5ꢀtertꢀbutylcyclohexꢀ2ꢀenꢀ1ꢀamine (cisꢀ32 and transꢀ33):10 for cisꢀ32 the
diastereoselectivity was >95:5 (syn:anti) with a relative rate of reaction on the face syn to the ammonium
moiety of 1.0 whereas for transꢀ33 the diastereoselectivity was >95:5 (syn:anti) with a relative rate of
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reaction on the face syn to the ammonium moiety of 1.8 (Scheme 6).
SCHEME 4a
NHBn
NHBn
(i)
O
>95:5 dr
OH
OH
cis-24, >99:1 dr
26, >95:5 dr
(ii)
NBn2
NBn2
(i)
>95:5 dr
O
OH
OH
cis-25, >99:1 dr
27, >99:1 dr
59% (from 24)
63% (from 25)
OH
NRBn
NRBn
HO
24A, R = H
25A, R = Bn
24B, R = H
25B, R = Bn
aReagents and Conditions: (i) Cl3CCO2H (10 equiv), mꢀCPBA (5.0 equiv), CH2Cl2, rt, 21 h; (ii) BnBr, iPr2NEt, DMAP, CH2Cl2, rt,
24 h.
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SCHEME 5a
OH
OH
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(i)
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O
O
kobs = 4.8
tBu
tBu
cis-28
OH
30, 96:4 dr
OH
(i)
kobs = 0.67
tBu
trans-29
tBu
31, 84:16 dr
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aReagents and Conditions: (i) PhCO3H, C6H6, 5 °C. k values given in units of 103 dm3 mol−1 s−1.
SCHEME 6a
NBn2
NBn2
(i)
O
O
kobs = 3.3
tBu
tBu
cis-32
NBn2
34, >95:5 dr
NBn2
(i)
kobs = 5.9
tBu
trans-33
tBu
35, >95:5 dr
aReagents and Conditions: (i) Cl3CCO2H, mꢀCPBA, CH2Cl2, rt, 21 h, then K2CO3, MeOH, rt, 16 h. k values given in units of 104
dm3 mol−1 s−1.
As part of our ongoing research program concerning the synthesis of biologically significant
molecules containing an aminotriol moiety, we proposed to investigate the behaviour of the diastereoisomers
of the corresponding Nꢀbenzylꢀ and N,Nꢀdibenzylꢀprotected 4ꢀaminocyclopentꢀ2ꢀenꢀ1ꢀols and 4ꢀ
aminocycloheptꢀ2ꢀenꢀ1ꢀols (i.e., containing fiveꢀ and sevenꢀmembered rings, respectively) under these
epoxidation conditions, and the results of these investigations are reported herein.
Results and Discussion
The requisite fiveꢀmembered ring substrates were prepared from cyclopentadiene 36. The synthesis
began with conversion of 36 into 38 following previously reported procedures:21,22 a [4+2]ꢀcycloaddition of
36 with PhCONO (generated in situ from the oxidation of benzhydroxamic acid by Bu4NIO4) gave bicycle
37 in 75% yield,21 and subsequent N−O bond cleavage upon treatment of 37 with sodium amalgam gave 38
in 85% yield and >99:1 dr.22 Reduction of 38 using LiAlH4 then gave cisꢀ39 in 80% yield and >99:1 dr.
Chemoselective Nꢀbenzylation of cisꢀ39 was achieved using BnBr/iPr2NEt, which gave cisꢀ40 in 83% yield
and >99:1 dr. Unfortunately, attempted Mitsunobu reaction of cisꢀ39 resulted in the formation of a complex
mixture of products from which only an impure sample of transꢀ41 could be isolated in <10% yield.
However, Mitsunobu reaction of cisꢀ40 gave access to transꢀ42 in 60% isolated yield and 98:2 dr (Scheme
7).
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SCHEME 7a
The Journal of Organic Chemistry
NHBz
OH
1
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7
Bz
N
(i)
(ii)
O
37, 75%
38, 85%
>99:1 dr
36
(iii)
8
9
NBn2
NHBn
(iv)
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OH
cis-40, 83%
>99:1 dr
OH
cis-39, 80%
>99:1 dr
(v), (vi)
(v), (vi)
NBn2
NHBn
OH
OH
trans-42, 60%
trans-41, <10%
98:2 dr
impure
aReagents and Conditions: (i) PhCONHOH, Bu4NIO4, MeOH, rt, 1 h; (ii) Na/Hg, Na2HPO4, MeOH, −10 °C then rt, 16 h; (iii)
LiAlH4, THF, reflux, 16 h; (iv) BnBr, iPr2NEt, DMAP, CH2Cl2, rt, 24 h; (v) PPh3, PhCO2H, DEAD, PhMe, 0 °C, 1 h, then rt, 16 h;
(vi) K2CO3, MeOH, rt, 4 h.
With diastereoisomeric N,Nꢀdibenzylꢀprotected cisꢀ40 and transꢀ42 in hand, investigations into the
diastereoselectivities of their epoxidations were undertaken. Our “NMR titration” procedure10 was used to
determine the number of equivalents of Cl3CCO2H required to efficiently protect cisꢀ40 against Nꢀoxidation.
In this experiment, Cl3CCO2H was added in 1.0 equiv portions to a 0.36 M solution of cisꢀ40 in CD2Cl2 and
1
the solution was analysed by H NMR spectroscopy. The resultant differences in chemical shifts (ꢀδ) of
C(1)H, C(2)H and C(3)H (which were easily discernible) versus the free amine were determined. These
differences showed a plateau around 7.0 equiv of Cl3CCO2H. However, in order for a more direct
comparison of the results with those of the corresponding sixꢀmembered substrates transꢀ20 and cisꢀ25 to be
made, it was decided to employ 10 equiv of Cl3CCO2H throughout these investigations. Treatment of cisꢀ40
with 10 equiv of Cl3CCO2H then 1.05 equiv of mꢀCPBA for 3.5 h at rt (i.e., analogous to the optimized
conditions for the ‘parent’ system 8)11 resulted in only 44% conversion to epoxide 43 (in >95:5 dr). Using
2.0 equiv of mꢀCPBA over 16 h, however, gave >95% conversion to 43 (in >95:5 dr), which was isolated in
77% yield and >99:1 dr. Meanwhile, epoxidation of transꢀ42 (98:2 dr) under the same conditions gave >95%
conversion to epoxide 44 in 93:7 dr, with purification giving 44 in 66% yield and >99:1 dr. Both the gross
structure and relative configuration of 44 were unambiguously established by single crystal Xꢀray diffraction
analysis of the corresponding pꢀnitrobenzoate derivative 45.23 Mitsunobu reaction of 44 gave 43, thus
unambiguously establishing both the gross structure and relative configuration of the latter. The effect of Oꢀ
protection on the diastereoselectivities of these epoxidation reactions was also probed in order to assess the
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importance of hydrogenꢀbonding to the hydroxyl group in these transformations; particularly it was hoped
that this might provide some insight into the relative importance of the amino moiety versus the hydroxyl
group in promoting diastereoselective epoxidation of cisꢀ40. The corresponding Oꢀbenzyl ethers cisꢀ46 and
transꢀ47 were duly prepared from cisꢀ40 (>99:1 dr) and transꢀ42 (98:2 dr) upon treatment with NaH and
BnBr. Epoxidation of cisꢀ46 (>99:1 dr) resulted in 84% conversion to epoxide 48 in >95:5 dr, which was
isolated in 71% yield and >99:1 dr. The relative configuration of 48 was unambiguously established by
correlation to 43: treatment of 43 with NaH/BnBr gave 48. Meanwhile, epoxidation of transꢀ47 (>99:1 dr)
resulted in 82% conversion to epoxide 49 in >95:5 dr, which was isolated in 74% yield and >99:1 dr. The
relative configuration of 49 was unambiguously established by correlation to 44: treatment of 44 with
NaH/BnBr gave 49. The formation of epoxides 43, 44, 48 and 49 (rather than formation of ringꢀopened
species) as the major products of all of these reactions is entirely consistent with the behaviour of the
‘parent’ system 8 under analogous conditions which results in formation of the corresponding synꢀepoxide
14 exclusively).11 Epoxidations of cisꢀ40 and cisꢀ46 reveal that epoxidation on the synꢀface of the olefin of
(proximal to both heteroatoms) is favoured even when the oxygen atom is incapable of acting as a hydrogenꢀ
bond donor. Although the increase in diastereoselectivity upon epoxidation of transꢀ47 (>95:5 dr) as
compared to transꢀ40 (93:7 dr) is consistent with formation of the minor diastereoisomeric product being the
result of a hydroxylꢀdirected pathway, steric effects may also contribute (Scheme 8).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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SCHEME 8a
The Journal of Organic Chemistry
NBn2
NBn2
OBn
1
2
3
4
(i)
O
84% conv
>95:5 dr
OBn
cis-46
67%, >99:1 dr
48, >99:1 dr
31% from 43
71% from 46
5
6
7
8
(ii)
(ii)
9
NBn2
NBn2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(i)
O
>95% conv
>95:5 dr
OH
OH
43, >99:1 dr
77% from 40
52% from 44
cis-40, >99:1 dr
(iii)
NBn2
NBn2
(i)
O
>95% conv
93:7 drb
OH
OH
44, 66%, >99:1 dr
trans-42, 98:2 dr
(ii)
(ii)
NBn2
NBn2
(i)
O
82% conv
>95:5 dr
OBn
OBn
trans-47
70%, >99:1 dr
49, >99:1 dr
54% from 44
74% from 47
NO2
Bn2N
O
O
45
O
aReagents and Conditions: (i) Cl3CCO2H (10 equiv), mꢀCPBA (2.0 equiv), CH2Cl2, rt, 16 h; (ii) NaH, THF, 0 °C, 30 min, then
BnBr, Bu4NI, rt, 24 h; (iii) PPh3, PhCO2H, DEAD, PhMe, 0 °C, 1 h, then rt, 16 h. bDiastereoisomeric ratio is for the
diastereoisomeric epoxides derived from epoxidation of transꢀ42; the fate of the 2% of cisꢀ40 in the starting material was not
determined.
The requisite sevenꢀmembered ring substrates 53–56 were prepared from 1,3ꢀcycloheptadiene 50 via
a directly analogous route to that used for the preparation of the corresponding fiveꢀmembered ring
substrates 39–42. Initially, following the previously reported route,24 treatment of 1,3ꢀcycloheptadiene 50
with (in situ generated) PhCONO gave bicycle 51 in quantitative yield,24 and sequential reduction using
sodium amalgam then LiAlH4 gave cisꢀ53 in 68% yield (over two steps from 51).24 The relative
configuration of cisꢀ53 was unambiguously confirmed by single crystal Xꢀray diffraction analysis.23
Chemoselective Nꢀbenzylation of cisꢀ53 delivered cisꢀ54 in 78% yield. Mitsunobu reaction of N,Nꢀdibenzylꢀ
protected cisꢀ54 gave transꢀ56 in 64% yield and >99:1 dr, and although the analogous reaction of Nꢀbenzylꢀ
protected cisꢀ53 proceeded with similar inefficiency to the corresponding reaction of cisꢀ39 in the fiveꢀ
membered ring series, in this case cisꢀ55 was isolated as a pure sample, albeit in only 13% yield (Scheme 9).
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Page 10 of 32
SCHEME 9a
BzHN
HO
1
2
3
4
5
6
Bz
N
(ii)
(i)
O
50
51, quant
52, 85%
>99:1 dr
7
8
(iii)
9
Bn2N
BnHN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(iv)
HO
HO
cis-54, 78%
>99:1 dr
cis-53, 80%
>99:1 dr
(v), (vi)
(v), (vi)
Bn2N
BnHN
HO
HO
trans-56, 64%
>99:1 dr
trans-55, 13%
>99:1 dr
aReagents and Conditions: (i) PhCONHOH, Bu4NIO4, CHCl3, DMF, rt, 3 h; (ii) Na/Hg, Na2HPO4, MeOH, −10 °C then rt, 16 h;
(iii) LiAlH4, THF, reflux, 16 h; (iv) BnBr, Pr2NEt, DMAP, CH2Cl2, rt, 48 h; (v) PPh3, PhCO2H, DEAD, PhMe, 0 °C, 1 h, then rt,
16 h; (vi) K2CO3, MeOH, rt, 4 h.
i
Epoxidation of N,Nꢀdibenzylꢀprotected cisꢀ54 upon treatment of 10 equiv of Cl3CCO2H25 and 1.05
equiv of mꢀCPBA in CH2Cl2 at rt for 3.5 h (i.e., analogous to the optimized conditions for the ‘parent’
system 12)11 gave 69% conversion to an 80:20 mixture of epoxides 59 and 60, respectively. Use of 3.0 equiv
of mꢀCPBA resulted in >95% conversion to the 80:20 mixture of epoxides 59 and 60; chromatography
enabled their partial separation, and 59 and 60 were isolated in 73% total yield. The gross structure and
relative configuration of 59 were unambiguously established by single crystal Xꢀray diffraction analysis of
the corresponding pꢀnitrobenzoate derivative 61.23 The gross structure of 60 was assigned on the basis of
NMR spectroscopic analyses and its relative configuration was thence assigned by reference to that
unambiguously established for 59, i.e., on the basis that 60 is the only alternative diastereoisomer resulting
from the epoxidation of cisꢀ54. Meanwhile, epoxidation of Nꢀbenzylꢀprotected cisꢀ53 under the same
conditions gave >95% conversion to an 18:82 mixture of epoxides 57 and 58, respectively. In order to
facilitate purification, the crude reaction mixture was treated with BnBr/iPr2NEt, which resulted in
chemoselective Nꢀbenzylation to give an 18:82 mixture of the corresponding N,Nꢀdibenzylꢀprotected
epoxides 59 and 60, which were again partially separated by chromatography and isolated in 63% total yield
(over two steps from cisꢀ53). This correlation also unambiguously established the gross structures and
relative configurations of both 57and 58 (Scheme 10).
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SCHEME 10a
The Journal of Organic Chemistry
BnHN
BnHN
BnHN
1
2
3
4
5
6
(i)
>95% conv
+
O
O
18:82 dr
[57:58]
HO
cis-53
>99:1 dr
HO
57
HO
58
(ii)
7
8
18:82 dr
[59:60]
9
Bn2N
Bn2N
Bn2N
(i)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
>95% conv
+
O
O
80:20 dr
[59:60]
HO
cis-54
>99:1 dr
HO
59
HO
60
63% total yield from 53
73% total yield from 54
O
Bn2N
O
NO2
61
O
aReagents and Conditions: (i) Cl3CCO2H (10 equiv), mꢀCPBA (3.0 equiv), CH2Cl2, rt, 3.5 h; (ii) BnBr, Pr2NEt, DMAP, CH2Cl2,
i
rt, 24 h.
Epoxidation of the transꢀdiastereoisomers under the same conditions revealed that epoxidation of
N,Nꢀdibenzylꢀprotected transꢀ56 proceeded to >95% conversion to give a 95:5 mixture of epoxides 64 and
65, respectively. These species proved separable by chromatography, allowing isolation of 64 in 73% yield
and >99:1 dr, although 65 was not isolated in this case. The gross structure and relative configuration of 64
were unambiguously established by single crystal Xꢀray diffraction analysis.23 In order to provide some
insight into the relative importance of the amino moiety versus the hydroxyl group in promoting
diastereoselective epoxidation, the corresponding Oꢀbenzyl ether transꢀ66 was prepared from transꢀ56 upon
treatment with NaH and BnBr. Subsequent epoxidation of transꢀ66 (>99:1 dr) resulted in 86% conversion to
a 94:6 mixture of epoxides 67 and 68, i.e., the same level of diastereoselectivity as transꢀ56, within
experimental error. Meanwhile, epoxidation of Nꢀbenzylꢀprotected transꢀ55 under these conditions resulted
in >95% conversion (within 2 h) to a 44:56 mixture of epoxides 62 and 63, respectively. Chemoselective Nꢀ
benzylation of the crude reaction mixture was performed as before, which gave a 44:56 mixture of epoxides
64 and 65, respectively, from which a sample of diastereoisomerically pure 65 was isolated in 35% yield
(over two steps from transꢀ55) and an 86:14 mixture of 64 and 65 in 16% combined yield (over two steps
from transꢀ55). This allowed the gross structure of 65 to be confirmed by a combination of NMR
spectroscopic analyses and thus, following the same rationale as before, its relative configuration was
assigned from that of 64. The relative configurations of 67 and 68 were unambiguously established by
correlation to the corresponding epoxides 67 and 68 upon their Oꢀbenzylation using NaH/BnBr (Scheme 11).
As with the analogous fiveꢀmembered ring substrates, the formation of epoxides (rather than formation of
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Page 12 of 32
ringꢀopened species) as the major products for all of the sevenꢀmembered ring substrates is entirely
1
2
3
4
consistent with the behaviour of the ‘parent’ systems 11 and 12 under analogous conditions.11
SCHEME 11a
5
6
7
8
BnHN
BnHN
BnHN
(i)
>95% conv
+
O
O
44:56 dr
[62:63]
9
HO
HO
HO
trans-55
>99:1 dr
62
63
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(ii)
44:56 dr
[64:65]
Bn2N
Bn2N
Bn2N
(iii)
>95% conv
+
O
O
95:5 dr
[64:65]
HO
trans-56
>99:1 dr
HO
64, >99:1 dr
73% from 56
HO
65, >99:1 dr
35% from 55
(iv)
(iv)
(iv)
Bn2N
Bn2N
Bn2N
(iii)
86% conv
+
O
O
94:6 dr
[67:68]
BnO
BnO
BnO
trans-66, 89%
>99:1 dr
67, >99:1 dr
55% from 64
48% from 66
68, >99:1 dr
61% from 65
5% from 66
aReagents and Conditions: (i) Cl3CCO2H (10 equiv), mꢀCPBA (3.0 equiv), CH2Cl2, rt, 2 h; (ii) BnBr, Pr2NEt, DMAP, CH2Cl2, rt,
24 h; (iii) Cl3CCO2H (10 equiv), mꢀCPBA (3.0 equiv), CH2Cl2, rt, 3.5 h; (iv) NaH, THF, 0 °C, 30 min, then BnBr, Bu4NI, rt, 24 h.
i
The rates of these epoxidation reactions of the fiveꢀmembered ring substrates 40 and 42, and the
sevenꢀmembered ring substrates 53−56 were next determined using our previously reported procedure,16
with the same condition set (10 equiv of Cl3CCO2H and 1.6 equiv of mꢀCPBA) used for each substrate for
the sake of simplicity (full conversion to the epoxide products not being necessary for determination of
reaction rate). In each case, Cl3CCO2H was added to a 0.36 M solution of the substrate in CD2Cl2 at 298 K.
This resulted in formation of the corresponding ammonium ion which displayed characteristic resonances in
1
the olefinic region of its H NMR spectrum, corresponding to C(2)H and C(3)H, which were distinct from
other resonances in the spectrum and so easy to monitor. The decay in intensity of these signals was
monitored upon addition of mꢀCPBA to the NMR tube. Analysis of the data so generated, by application of
the integrated form of the second order rate law,26 gave the secondꢀorder rate constants (kobs) for the
epoxidation reactions of 40, 42 and 53–56. The rate constants of the epoxidation reactions of sixꢀmembered
ring substrates 19 and 20 have already been determined,18 whilst the rate constants for the (previously
reported) epoxidations of sixꢀmembered ring substrates 24 and 25 were determined here, in an analogous
manner to give a more complete picture of the results across the ring systems (Figure 1).
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
a
n
1
1
1
1
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
X
Y
OH
H
H
H
OH
H
H
H
OH
H
H
H
OH
H
H
H
H
H
OH
OH
Z
H
H
OH
OH
H
dr (A:B)
>95: 5
>95: 5
93: 7
16:84b
>95: 5
95: 5
>95: 5
5:95b
>95: 5
95: 5
25:75
5:95b
kobs
4.9
61
6.0
-
37
360
38
-
0.9
krel
8
100
10
-
10
100
11
-
12
100
37
-
16
100
22
-
30
100
59
-
cis-40
8
trans-42
1
cis-24
9
trans-19
2
cis-25
10
trans-20
2
cis-53
11
trans-55
3
trans-56
12
cis-54
3
NBn2
NBn2
NBn2
H
NHBn
NHBn
NHBn
H
NBn2
NBn2
NBn2
H
NHBn
NHBn
NHBn
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
OH
H
H
7.3
2.7
-
OH
OH
H
82:18
85:15
56:44
39:61b
5:95
28
H
180
39
-
OH
OH
OH
H
H
H
NBn2
NBn2
NBn2
H
6.7
6:94
22
13
-
20:80
61:39b
FIGURE 1. Selected rate constants, relative rate constants and diastereoselectivities for epoxidations of cycloalkꢀ2ꢀenꢀ1ꢀols, Nꢀ
protected cycloalkꢀ2ꢀenꢀ1ꢀamine derivatives and Nꢀprotected 4ꢀaminocycloalkꢀ2ꢀenꢀ1ꢀol derivatives. For ease of comparison,
reactions are grouped into subꢀsets of four: (i) epoxidation of coꢀoperative substrate; (ii) epoxidation of ‘parent’ allylic amine
substrate (i.e., ammoniumꢀdirected reaction); (iii) epoxidation of competitive substrate; (iv) epoxidation of ‘parent’ allylic alcohol
a
substrate (i.e., hydroxylꢀdirected reaction); as such, values for cyclohexꢀ2ꢀenꢀ1ꢀol 2 and cycloheptꢀ2ꢀenꢀ1ꢀol 3 are listed twice.
krel values are listed within each subꢀset of reactions; in each case the relative rate of the ammoniumꢀdirected reaction (i.e.,
epoxidation of 8, 9, 10, 11 or 12) is set at krel = 100. b Result of Teranishi et al. (Ref 5). kobs values given in units of 104 dm3 mol−1
s−1.
As with the sixꢀmembered ring substrates 6ꢀNHBn transꢀ19 and 6ꢀNBn2 transꢀ20, evidence of
competitive ammoniumꢀdirected and hydroxylꢀdirected epoxidation pathways are noted in the fiveꢀ and
sevenꢀmembered ring substrates where the two established, individual directing group preferences would
result in epoxidation being directed to opposite faces of the olefin, depending on which group acts as the
directing group: i.e., the epoxidations of 5ꢀNBn2 transꢀ42, 7ꢀNBn2 cisꢀ54 and 7ꢀNHBn transꢀ55 are less
diastereoselective than those of the corresponding ‘parent’ systems 8 and 11 and 12, possessing only one
potential directing group.27 The diastereoselectivity of epoxidation of 5ꢀNBn2 transꢀ42 suggests that the
order of directing group proficiency in the fiveꢀmembered ring system is: NBn2 > OH. This is in contrast to
the corresponding ranking established (from the diastereoselectivity of the epoxidation of 6ꢀNBn2 transꢀ20)
for the sixꢀmembered ring system: OH > NBn2. As the two possible envelope conformations (42A and 42C)
of 5ꢀNBn2 transꢀ42 place the N,Nꢀdibenzylammonium moiety and hydroxyl group in geometrically nonꢀ
equivalent environments, with only the very high energy conformation 42B with the ring completely planar
placing them in geometrically equivalent environments (Figure 2), it is plausible that the difference in the
observed directing group proficiencies are the result of subtle constraints of geometry, analogous to the
effects already evidenced in sixꢀmembered ring systems.10,20 Furthermore, epoxidation of 5ꢀNBn2 transꢀ42
proceeding from conformation 42A to give 44 (as observed experimentally) proceeds via a favoured boatlike
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transition state with reduction in torsional strain, most significantly between C(3)ꢀproton and the pseudoꢀ
equatorial C(4)ꢀammonium group. In contrast, epoxidation of 5ꢀNBn2 transꢀ42 proceeding from
conformation 42C to give 44 proceeds via a disfavoured chairlike transition state with increase of torsional
strain, most significantly between the C(2)ꢀproton and pseudoꢀequatorial C(1)ꢀhydroxyl group11,14,15 (Figure
3). The combination of conformational differences affecting ability to form a hydrogenꢀbond with the
oxidant, and the drive to minimise torsional strain may therefore be responsible for the apparently higher
directing group proficiency of the N,Nꢀdibenzylammonium moiety versus the hydroxyl group in this case.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
FIGURE 2. Representative conformers of 5ꢀNBn2 transꢀ42.
FIGURE 3. Model to rationalise facial selectivity of epoxidation of 5ꢀNBn2 transꢀ42 proceeding from conformation 42A, based
upon minimisation of torsional strain in transition state.
The diastereoselectivities of the epoxidations of 7ꢀNBn2 cisꢀ54 and 7ꢀNHBn transꢀ55 suggests that
the order of directing group proficiency in the sevenꢀmembered ring system is: NBn2 > NHBn > OH. This is
again in contrast to the ranking established from the diastereoselectivities of the epoxidations of 6ꢀNHBn
transꢀ19 and 6ꢀNBn2 transꢀ20 for the sixꢀmembered ring system: NHBn >> OH > NBn2. The presence of
two relatively nonꢀsterically demanding substituents within 7ꢀNHBn transꢀ55 likely results in a certain
degree of conformational promiscuity (which is known for cycloheptene)17 with several possible reactive
conformations, which satisfy the geometric requirements for efficient hydrogenꢀbonding to either the Nꢀ
benzylammonium moiety or hydroxyl group, being accessible and so allowing the two hydrogenꢀbonding
directed epoxidation processes to compete effectively with each other. The diastereoselectivities of
epoxidation of the ‘parent’ sevenꢀmembered ring substrates 7ꢀNHBn 11 (85:15 dr; syn:anti) and cycloheptꢀ
2ꢀenꢀ1ꢀol 3 (61:39 dr; syn:anti) suggest modest directing proficiencies in this system; if the two are able to
operate largely independently, a mixture of products slightly favouring epoxide 63 (resulting from direction
from the Nꢀbenzylammonium moiety, the superior directing group) may be expected, as observed
experimentally (56:44 dr). Meanwhile, the ‘parent’ system 7ꢀNBn2 12 has been shown to favour a sevenꢀ
membered chair conformation with the bulky N,Nꢀdibenzylammonium moiety occupying a pseudoꢀ
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The Journal of Organic Chemistry
equatorial position in the solid state, with epoxidation of this conformation proceeding on the most sterically
accessible face being assisted by hydrogen bonding and leading to high diastereoselectivity (94:6 dr;
anti:syn).11 It seems likely that 7ꢀNBn2 cisꢀ54 would show a similar conformational preference and favour
54A (Figure 4), with epoxidation of the least sterically encumbered face in this conformation again being
assisted by hydrogenꢀbonding to the ammonium moiety or indeed, given the geometrically similar
environments in this conformation, the hydroxyl group. With the bulky N,Nꢀdibenzylammonium moiety
acting akin to conformational lock, it may be that conformations of 7ꢀNBn2 cisꢀ54 in which the hydroxyl
group is optimally placed to effect hydrogenꢀbonding delivery of the oxidant to the syn face are energetically
disfavoured. A combination of these factors may be responsible for formation of epoxide 59 as the major
product (80:20 dr), and hence the apparent enhancement of the directing group proficiency of the N,Nꢀ
dibenzylammonium moiety in this case.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
FIGURE 4. Representative conformers of 7ꢀNBn2 cisꢀ54.
In the substrates where the two established, individual directing group preferences would result in
epoxidation being directed to the same face of the olefin, regardless of which group acts as the directing
group (i.e., 5ꢀNBn2 cisꢀ40, 6ꢀNHBn cisꢀ24, 6ꢀNBn2 cisꢀ25, 7ꢀNHBn cisꢀ53 and 7ꢀNBn2 transꢀ56), the
observed diastereoselectivities are higher than those of the respective ‘parent’ allylic alcohol 1−3 and
ostensibly the same as those of the respective ‘parent’ allylic amine 8–12. Although in most cases the
diastereoselectivities of the latter epoxidation process is at or beyond the limit of detection, the
diastereoselectivity of epoxidation of 7ꢀNHBn 11 (85:15 dr), resulting from direction by the ammonium
moiety alone25 and falling well within the limits of detection, is not enhanced by the presence of the
hydroxyl group within 7ꢀNHBn cisꢀ53 (82:18 dr) and in this instance at least, the effect is unlikely due to a
lack of conformational freedom given that sevenꢀmembered rings with nonꢀsterically demanding substituents
are involved.17 It may be that it is simply not feasible for both directing groups to form hydrogenꢀbonds to
the peracid oxidant simultaneously. The observation that 5ꢀNBn2 cisꢀ40 and 7ꢀNBn2 transꢀ56 undergo
epoxidation with the same levels of diastereoselectivity as the corresponding Oꢀbenzyl ethers 5ꢀNBn2 cisꢀ46
and 7ꢀNBn2 transꢀ56 demonstrates that hydrogenꢀbonding to the hydroxyl group is not prerequisite for the
high diastereoselectivity observed in these instances. The reaction rates of all of these systems are lower than
those of the corresponding ‘parent’ allylic amine 8–12 (and, in fact, are also lower than for the
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diastereoisomeric substrates 5ꢀNBn2 transꢀ42, 6ꢀNHBn transꢀ19, 6ꢀNBn2 transꢀ20, 7ꢀNHBn transꢀ55 and 7ꢀ
NBn2 cisꢀ54,28 which may be due to steric/electrostatic repulsive effects, geometrical restrictions imposed on
hydrogenꢀbonding, or indeed both). It is apparent, however, that the incorporation of a second, allylic
heteroatom into the substrate retards the epoxidation reaction for all of the fiveꢀ, sixꢀ and sevenꢀmembered
ring substrates examined in this study when compared to the corresponding ‘parent’ system. The
diminishment of the nucleophilicity of the olefin by introduction of the second inductively electronꢀ
withdrawing heteroatom is clearly the dominant factor here, and any assistance to the epoxidation reaction
by the potential ability to form hydrogenꢀbonds to two directing groups rather than one is clearly unable to
overwhelm it.
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Conclusion
In conclusion, in the epoxidations of a range of diastereoisomeric, Nꢀprotected 4ꢀaminocycloalkꢀ2ꢀ
enꢀ1ꢀols containing fiveꢀ, sixꢀ and sevenꢀmembered rings, evidence of competitive epoxidation pathways,
promoted by hydrogenꢀbonding to either the in situ formed ammonium moiety or the hydroxyl group, are
observed in those systems within which the two potential directing groups can promote epoxidation on the
opposite faces of the olefin, depending upon which acts as the directing group. In the fiveꢀ and sevenꢀ
membered ring substrates, an N,Nꢀdibenzylammonium moiety appears more efficacious than a hydroxyl
group at promoting a diastereoselective reaction in comparison to the corresponding sixꢀmembered ring
substrate. In the fiveꢀmembered ring, this was proposed to be the result of reduction of torsional strain in the
transition state being coupled with assistance from hydrogenꢀbonding with a pseudoꢀequatorial ammonium
moiety. Meanwhile in the sevenꢀmembered ring it was proposed that the N,Nꢀdibenzylammonium moiety,
being able to mimic the effects of a conformational lock, enforces a wellꢀdefined conformational preference
on the otherwise mobile sevenꢀmembered ring, disfavouring conformations within which the hydroxyl group
is optimally placed to promote hydrogenꢀbonded delivery of the oxidant to the syn face. In a system within
which the two potential directing groups can promote epoxidation on the same face of the ring scaffold, an
enhancement of epoxidation diastereoselectivity was not observed. The introduction of a second, allylic
heteroatom to the substrate results in diminishment of the rate of epoxidation in all cases, indicating that the
diminishment of the nucleophilicity of the olefin by inductive electronꢀwithdrawing effect of the second
heteroatom is the dominant factor, and any assistance to the epoxidation reaction by the potential to form
hydrogenꢀbonds to two directing groups rather than one is clearly unable to overwhelm it. It is hoped that the
results from these studies will be instructive for the future design of syntheses of aminopolyols of biological
interest.
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Experimental Section
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General Experimental Details. Reactions involving moistureꢀsensitive reagents were carried out
under a nitrogen atmosphere using standard vacuum line techniques and glassware that was flameꢀdried and
cooled under nitrogen before use. Solvents were dried according to the procedure outlined by Grubbs and
coꢀworkers.29 Organic layers were dried over Na2SO4. Flash column chromatography was performed on
Kieselgel 60 silica.
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Melting points are uncorrected. IR spectra were recorded as a thin film on NaCl plates (film), as a
KBr disc (KBr), or using an ATR module (ATR). Selected characteristic peaks are reported in cm–1. NMR
spectra were recorded in the deuterated solvent stated. The field was locked by external referencing to the
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relevant deuteron resonance. H–1H COSY and H–13C HMQC analyses were used to establish atom
connectivity. Accurate mass measurements were run on a MicroTOF instrument internally calibrated with
polyalanine.
X-ray Crystal Structure Determination.23 Data were collected using either graphite
monochromated CuꢀKα radiation (for 53) or graphite monochromated MoꢀKα radiation (for 45, 61 and 64)
via standard procedures at 150 K. The structure was solved by direct methods (SIR92); all nonꢀhydrogen
atoms were refined with anisotropic thermal parameters. Hydrogen atoms were added at idealised positions.
The structure was refined using CRYSTALS.30
(1RS,4SR)-4-(N-Benzylamino)cyclopent-2-en-1-ol 39. A solution of 3822 (5.34 g, 26.3 mmol, >99:1
dr) in THF (270 mL) at rt was added via cannula to a stirred solution of powdered LiAlH4 (4.89 g, 129
mmol) in THF (170 mL) at rt. The resultant solution was heated at reflux for 16 h, then allowed to cool to rt
and then further cooled to 0 °C. Crushed ice (~20 g) was then added portionwise, followed by addition of
satd. aq. sodium potassium tartrate (200 mL). The resultant mixture was stirred vigorously at rt for 2 h, then
filtered through Celite (eluent Et2O). The organic layer was washed with brine (500 mL), dried and
concentrated in vacuo to give 39 as a yellow solid (3.98 g, 80%, >99:1 dr); mp 43ꢀ45 °C; νmax (film) 3285,
3060, 3028, 1642, 1598; δH (400 MHz, CDCl3) 1.46ꢀ1.52 (1H, m, C(5)HA), 2.54ꢀ2.61 (1H, m, C(5)HB),
3.69ꢀ3.71 (1H, m, C(4)H), 3.81ꢀ3.83 (2H, m, NCH2Ph), 4.67ꢀ4.68 (1H, m, C(1)H), 5.94ꢀ5.99 (2H, m, C(2)H,
C(3)H), 7.25ꢀ7.33 (5H, m, Ph); δC (100 MHz, CDCl3) 39.8 (C(5)), 41.3 (NCH2Ph), 61.7 (C(1)), 75.5 (C(4)),
127.1, 128.3, 128.5 (o,m,pꢀPh), 135.5, 136.0 (C(2), C(3)), 139.8 (iꢀPh); m/z (ESI+) 190 ([M+H]+, 96%), 172
([M−OH]+, 100%); HRMS (ESI+) C12H16NO+ ([M+H]+) requires 190.1226; found 190.1234.
i
(1RS,4SR)-4-(N,N-Dibenzylamino)cyclopent-2-en-1-ol 40. BnBr (1.78 mL, 15.0 mmol), Pr2NEt
(2.61 mL, 15.0 mmol) and DMAP (122 mg, 1.00 mmol) were added sequentially to a stirred solution of 39
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(1.89 g, 10.0 mmol, >99:1 dr) in CH2Cl2 (100 mL) at rt and the resultant mixture was stirred at rt for 24 h,
then washed with H2O (2 × 100 mL). The combined aqueous washings were extracted with CH2Cl2 (200
mL) and the combined organic extracts were washed with brine (300 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O, 1:1) gave 40 as a yellow
solid (2.32 g, 83%, >99:1 dr); mp 52ꢀ54 °C; νmax (film) 3385, 1642, 1598, 1494, 1453; δH (400 MHz,
CDCl3) 0.87ꢀ0.91 (1H, m, C(5)HA), 2.41ꢀ2.49 (1H, m, C(5)HB), 3.46ꢀ3.49 (2H, d, J 14.0, N(CHAHBPh)2),
3.72 (2H, d, J 14.0, N(CHAHBPh)2), 3.83ꢀ3.92 (1H, m, C(4)H), 4.69ꢀ4.72 (1H, m, C(1)H), 5.88ꢀ5.90 (1H, m,
CH=CH), 5.95ꢀ5.98 (1H, m, CH=CH), 7.21ꢀ7.40 (10H, m, Ph); δC (100 MHz, CDCl3) 34.3 (C(5)), 54.6
(N(CH2Ph)2), 54.6 (C(4)), 64.0 (C(1)), 126.8, 128.2, 128.7, (o,m,pꢀPh), 135.0, 136.4 (C(2), C(3)), 140.1 (iꢀ
Ph); m/z (ESI+) (ESI+) 280 ([M+H]+, 100%); HRMS (ESI+) C19H22NO+ ([M+H]+) requires 280.1696; found
280.1705.
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(1RS,4RS)-4-(N,N-Dibenzylamino)cyclopent-2-en-1-ol 42. DEAD (40% wt solution in PhMe, 7.74
mL, 17.0 mmol) was added dropwise via syringe pump over 1 h to a stirred solution of 40 (2.79 g, 10.0
mmol, >99:1 dr), PPh3 (5.25 g, 20.0 mmol) and benzoic acid (1.83 g, 15.0 mmol) in PhMe (100 mL) at 0 °C.
The resultant solution was allowed warm to rt and stirred at rt for a further 16 h, then concentrated in vacuo.
The residue was dissolved in Et2O (100 mL) and the resultant solution was washed sequentially with satd aq
Na2CO3 (3 × 100 mL) and brine (100 mL), then dried and concentrated in vacuo. The residue was dissolved
in MeOH (100 mL) and K2CO3 (6.91 g, 50.0 mmol) was added. The resultant suspension was stirred at rt for
4 h, then filtered and concentrated in vacuo. The residue was dissolved in Et2O (100 mL) and the resultant
solution was washed sequentially with H2O (3 × 100 mL) and brine (100 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 1:1) gave 42 as a pale
yellow oil (1.67 g, 60%, 98:2 dr); νmax (film) 3300, 2982, 2935, 1602; δH (400 MHz, CDCl3) 1.57ꢀ1.68 (1H,
m, OH), 1.77 (1H, ddd, J 14.3, 7.9, 2.7, C(5)HA), 2.24 (1H, ddd, J 14.3, 7.5, 4.5, C(5)HB), 3.43 (2H, d, J
13.9, N(CHAHBPh)2), 3.63 (2H, d, J 13.9, N(CHAHBPh)2), 4.27ꢀ4.31 (1H, m, C(4)H), 4.94ꢀ4.96 (1H, m,
C(1)H), 5.95ꢀ5.97 (1H, m, CH=CH), 6.01ꢀ6.03 (1H, m, CH=CH), 7.19ꢀ7.40 (10H, m, Ph); δC (100 MHz,
CDCl3) 34.4 C(5), 54.4 (N(CH2Ph)2), 65.1 (C(4)), 76.6 (C(1)), 127.0, 128.2, 128.6 (o,m,pꢀPh), 135.4, 137.1
(C(2), C(3)), 140.0 (iꢀPh); m/z (ESI+) 280 ([M+H]+, 100%); HRMS (ESI+) C19H22NO+ ([M+H]+) requires
280.1696; found 280.1701.
(1RS,2RS,3SR,4SR)-2,3-Epoxy-4-(N,N-dibenzylamino)cyclopent-1-ol 43. Cl3CCO2H (2.36 g, 14.4
mmol) was added to a stirred solution of 40 (401 mg, 1.44 mmol, >99:1 dr) in CH2Cl2 (4.0 mL, 0.36 M w.r.t.
40) at rt and the resultant solution was stirred at rt for 5 min. mꢀCPBA (72% by wt, 690 mg, 2.88 mmol) was
added and the resultant suspension was stirred at rt for 16 h. Na2SO3 (726 mg, 5.76 mmol) was added and
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the resultant suspension was stirred until it solidified (~5 min). The resultant mixture was diluted with
CH2Cl2 (20 mL) and washed with 10% aq NaOH (3 × 20 mL). The combined aqueous washings were
extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were washed with brine (100 mL), dried
and concentrated in vacuo to give >95% conversion to 43 in >95:5 dr. Purification via flash column
chromatography (eluent 30ꢀ40 °C petrol/Et2O, 1:1) gave 43 as a white solid (347 mg, 77%, >99:1 dr); mp
74ꢀ76 °C; νmax (film) 3406, 3028, 2947, 2804, 1603, 1494, 1453, 1256; δH (400 MHz, CDCl3) 1.41 (1H, ddd,
J 12.3, 10.1, 8.2, C(5)HA), 1.77 (1H, br s, OH), 1.98 (1H, ddd, J 12.3, 7.5, 7.3, C(5)HB), 3.19 (1H, ddd, J
10.1, 7.3, 1.0, C(4)H), 3.41 (1H, dd, J 3.0, 1.5, C(2)H), 3.52ꢀ3.53 (1H, d, J 3.0, 1.0, C(3)H), 3.66 (2H, d, J
14.5, N(CHAHBPh)2), 3.88 (2H, d, J 14.5, N(CHAHBPh)2), 4.03ꢀ4.07 (1H, m, C(1)H), 7.23ꢀ7.27 (2H, m, Ph),
7.33 (4H, app t, 7.4, Ph), 7.40 (4H, d, 7.4, Ph); δC (100 MHz, CDCl3) 26.4 (C(5)), 55.2 (N(CH2Ph)2), 55.9
(C(2)), 56.7 (C(3)), 58.3 (C(4)), 71.1 (C(1)), 126.9 (pꢀPh), 128.3, 128.5 (o,mꢀPh), 139.9 (iꢀPh); m/z (ESI+)
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296 ([M+H]+, 100%); HRMS (ESI+) C19H21NNaO2 ([M+Na]+) requires 318.1465; found 318.1470.
(1RS,2SR,3RS,4RS)-2,3-Epoxy-4-(N,N-dibenzylamino)cyclopent-1-ol 44. Cl3CCO2H (585 mg,
3.58 mmol) was added to a stirred solution of 42 (100 mg, 0.358 mmol, 98:2 dr) in CH2Cl2 (1.0 mL, 0.36 M
w.r.t. 42) at rt and the resultant solution was stirred at rt for 5 min. mꢀCPBA (72% by wt, 172 mg, 0.72
mmol) was added and the resultant suspension was stirred at rt for 16 h. Na2SO3 (180 mg, 1.43 mmol) was
added and the resultant suspension was stirred until it solidified (~5 min). The resultant mixture was diluted
with CH2Cl2 (5 mL) and washed with 10% aq NaOH (3 × 5 mL). The combined aqueous washings were
extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were washed with brine (25 mL), dried
and concentrated in vacuo to give >95% conversion to 44 in 93:7 dr. Purification via flash column
chromatography (eluent 30ꢀ40 °C petrol/Et2O, 1:1) gave 44 as a white solid (41 mg, 66%, >99:1 dr); mp 83ꢀ
85 °C; νmax (film) 3406, 3028, 2947, 2804, 1602, 1494, 1453, 1251; δH (400 MHz, CDCl3) 1.52 (1H, br s,
OH), 1.62 (1H, dd, J 13.8, 7.7, C(5)HA), 1.74ꢀ1.81 (1H, m, C(5)HB), 3.31 (1H, app d, J 2.6, C(2)H), 3.53
(1H, app d, J 2.6 C(3)H), 3.60ꢀ3.64 (1H, m, C(4)H), 3.69ꢀ3.72 (2H, m, N(CHAHBPh)2), 3.79ꢀ3.82 (2H, m,
N(CHAHBPh)2), 4.38 (1H, app d, J 5.5, C(1)H), 7.22ꢀ7.25 (2H, m, Ph), 7.34 (4H, app t, J 7.3 Ph) 7.40ꢀ7.41
(4H, m, Ph); δC (100 MHz, CDCl3) 29.6 (C(5)), 55.5 (C(2)), 55.5 (N(CH2Ph)2), 55.9 (C(3)), 59.4 (C(4)),
70.5 (C(1)), 126.9 (pꢀPh), 128.2, 128.5 (o,mꢀPh), 140.0 (iꢀPh); m/z (ESI+) 296 ([M+H]+, 100%); HRMS
+
(ESI+) C19H22NO2 ([M+H]+) requires 296.1645; found 296.1644.
(1RS,2SR,3RS,4RS)-1-(p-Nitrobenzoyloxy)-2,3-epoxy-4-(N,N-dibenzylamino)cyclopentane 45.
pꢀNitrobenzoyl chloride (67 mg, 0.37 mmol) and DMAP (3 mg, 0.02 mmol) were added sequentially to a
stirred solution of 44 (60 mg, 0.20 mmol, >99:1 dr) in pyridine (1 mL) at rt. The resultant solution was
stirred at rt for 16 h then diluted with CH2Cl2 (5 mL). The resultant solution was washed sequentially with
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sat. aq. NaHCO3 (5 mL), sat. aq. citric acid (2 × 5 mL) and brine (2 × 5 mL), dried and concentrated in
vacuo to give 45 as a pale yellow solid (60 mg, 67%, >99:1 dr); mp 98ꢀ102 °C; νmax (ATR) 3029, 2803,
1726, 1527, 1270; δH (400 MHz, CDCl3) 1.79 (1H, dd, J 7.8, 14.3, C(5)HA), 1.91 (1H, ddd, J 5.7, 9.9, 14.5,
C(5)HB), 3.46 (1H, d, J 2.6, C(2)H), 3.52 (1H, d, J 1.8, C(3)H), 3.59 (1H, t, J 9.3, C(4)H), 3.64 (2H, d, J
14.0, N(CHAHBPh)2), 3.77 (2H, d, J 14.0, N(CHAHBPh)2), 5.44 (1H, d, J 5.6, C(1)H), 7.13ꢀ7.39 (10H, m,
Ph), 7.99ꢀ8.04 (2H, m, Ar), 8.17ꢀ8.21 (2H, m, Ar); δC (100 MHz, CDCl3) 26.7 (C(5)), 53.1 (C(2)), 55.4
(NCH2Ph), 56.1 (C(3)), 59.7 (C(4)), 74.5 (C(1)), 123.5 (Ar), 127.0 (pꢀPh), 128.3, 128.5 (o,mꢀPh), 130.8 (Ar),
135.1, 139.7 (iꢀPh, Ar), 150.6 (Ar), 164.0 (C=O); m/z (ESI+) 445 ([M+H]+, 100%); HRMS (ESI+)
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C26H25N2O5 ([M+H]+) requires 445.1758; found 445.1746.
(1RS,4SR)-1-Benzyloxy-4-(N,N-dibenzylamino)cyclopent-2-ene 46. NaH (60% dispersion in
mineral oil, 84 mg, 2.1 mmol) was stirred at rt for 20 min in pentane (5 mL). The pentane was then decanted
under a stream of argon, and THF (5 mL) was added. The resultant suspension was cooled to 0 °C and a
solution of 40 (300 mg, 1.07 mmol, >99:1 dr) in THF (5 mL) was added dropwise. The resultant suspension
was stirred at 0 °C for 30 min, after which time BnBr (0.26 mL, 2.1 mmol) and Bu4NI (12 mg, 0.10 mmol)
were added sequentially. The resultant mixture was allowed to warm to rt and stirred at rt for 24 h, then
quenched with H2O (5 mL). The resultant mixture was extracted with CHCl3 (5 × 20 mL) and the combined
organic extracts were washed with brine (2 × 50 mL), then dried and concentrated in vacuo. Purification via
flash column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 9:1) gave 46 as a colourless oil (263 mg, 67%,
>99:1 dr); νmax (film) 3061, 3028, 2919, 2850, 1733, 1603, 1494, 1454; δH (400 MHz, CDCl3) 1.81 (1H, dt, J
13.6, 5.5, C(5)HA), 2.38 (1H, dt, J 13.6, 7.7 C(5)HB), 3.50 (2H, d, J 14.2, N(CHAHBPh)2), 3.78 (2H, d, J
14.2, N(CHAHBPh)2), 3.90 (1H, t, J 6.8, C(4)H), 4.46 (1H, dd, J 7.5, 5.2, (C(1)H), 4.58 (1H, d, J 11.9,
OCHAHBPh), 4.60 (1H, d, J 11.9, OCHAHBPh), 5.96ꢀ6.00 (2H, m, C(2)H, C(3)H), 7.21ꢀ7.41 (15H, m, Ph);
δC (100 MHz, CDCl3) 31.2 (C(5)), 54.6 (N(CH2Ph)2), 63.7 (C(4)), 70.9 (OCH2Ph), 82.1 (C(1)), 126.7, 127.5,
127.8, 128.2, 128.4, 128.6 (o,m,pꢀPh), 132.8, 136.4 (C(2), C(3)), 138.7, 140.3 (iꢀPh); m/z (ESI+) 370
([M+H]+, 100%); HRMS (ESI+) C26H28NO+ ([M+H]+) requires 370.2165; found 370.2161.
(1RS,4RS)-1-Benzyloxy-4-(N,N-dibenzylamino)cyclopent-2-ene 47. NaH (60% dispersion in
mineral oil, 80 mg, 2.0 mmol) was stirred at rt for 20 min in pentane (5 mL). The pentane was then decanted
under a stream of argon, and THF (5 mL) was added. The resultant suspension was cooled to 0 °C and a
solution of 42 (279 mg, 1.00 mmol, >99:1 dr) in THF (5 mL) was added dropwise. The resultant suspension
was stirred at 0 °C for 30 min, after which time BnBr (0.24 mL, 2.0 mmol) and Bu4NI (12 mg, 0.10 mmol)
were added sequentially. The resultant mixture was allowed to warm to rt and stirred at rt for 24 h, then
quenched with H2O (5 mL). The resultant mixture was extracted with CHCl3 (5 × 20 mL) and the combined
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organic extracts were washed with brine (2 × 50 mL), then dried and concentrated in vacuo. Purification via
flash column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 9:1) gave 47 as a colourless oil (258 mg, 70%,
>99:1 dr); C26H27NO requires C, 84.5; H, 7.4; N, 3.8%; found C, 84.4; H, 7.3; N, 3.8%; νmax (film) 3061,
3028, 2932, 2833, 2799, 1746, 1603, 1494, 1453; δH (400 MHz, CDCl3) 1.91ꢀ1.97 (1H, m, C(5)HA), 2.12ꢀ
2.19 (1H, m, C(5)HB), 3.44 (2H, d, J 13.9, N(CHAHBPh)2), 3.63 (2H, d, J 13.9, N(CHAHBPh)2), 4.28ꢀ4.32
(1H, m, C(4)H), 4.48ꢀ4.57 (2H, m, OCH2Ph), 4.74ꢀ4.77 (1H, m, C(1)H), 6.03ꢀ6.08 (2H, m, C(2)H, C(3)H),
7.22ꢀ7.39 (15H, m, Ph); δC (100 MHz, CDCl3) 31.1 (C(5)), 54.4 (N(CH2Ph)2), 65.2 (C(4)), 70.8 (OCH2Ph),
83.5 (C(1)), 126.8, 127.5, 127.7, 128.2, 128.4, 128.6 (o,m,pꢀPh), 133.1, 137.7 (C(2), C(3)), 138.6, 140.0 (iꢀ
Ph); m/z (ESI+) 370 ([M+H]+, 100%); HRMS (ESI+) C26H28NO+ ([M+H]+) requires 370.2165; found
370.2165.
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(1RS,2RS,3RS,4RS)-1-Benzyloxy-2,3-epoxy-4-(N,N-dibenzylamino)cyclopentane 48. Method A.
O-Benzylation of 43. NaH (60% dispersion in mineral oil, 4 mg, 0.1 mmol) was stirred at rt for 20 min in
pentane (0.5 mL). The pentane was then decanted under a stream of argon, and THF (0.5 mL) was added.
The resultant suspension was cooled to 0 °C and a solution of 43 (32 mg, 0.11 mmol, >99:1 dr) in THF (0.5
mL) was added dropwise. The resultant suspension was stirred at 0 °C for 30 min, after which time BnBr (20
ꢁL, 0.20 mmol) and Bu4NI (1 mg, 0.01 mmol) were added sequentially. The resultant mixture was allowed
to warm to rt and stirred at rt for 24 h, then quenched with H2O (0.5 mL). The resultant mixture was
extracted with CHCl3 (5 × 2 mL) and the combined organic extracts were washed with brine (2 × 5 mL),
then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30ꢀ40 °C
petrol/Et2O, 4:1) gave 48 as a colourless oil (13 mg, 31%, >99:1 dr); νmax (film) 3029, 2918, 2850, 1604,
1494, 1257; δH (400 MHz, CDCl3) 1.64 (1H, ddd, J 11.9, 10.2, 8.5, C(5)HA), 1.91 (1H, dt, J 11.9, 7.3,
C(5)HB), 3.18 (1H, app dd, J 10.1, 7.3, C(4)H), 3.44 (1H, dd, J 2.9, 1.0, C(2)H), 3.51 (1H, d, J 2.9, C(3)H),
3.71 (2H, d, J 14.2, N(CHAHBPh)2), 3.82ꢀ3.86 (1H, m, C(1)H), 3.92 (2H, d, J 14.2, N(CHAHBPh)2), 4.61ꢀ
4.68 (2H, m, OCH2Ph), 7.24ꢀ7.44 (15H, m, Ph); δC (100 MHz, CDCl3) 23.0 (C(5)), 53.4 (C(2)), 55.2
(N(CH2Ph)2), 55.6 (C(3)), 57.9 (C(4)), 71.3 (OCH2Ph), 76.8 (C(1)), 126.9, 127.7, 127.8, 128.3, 128.5, 128.5
+
(o,m,pꢀPh), 138.1, 140.0 (iꢀPh); m/z (ESI+) 386 ([M+H]+, 100%); HRMS (ESI+) C26H28NO2 ([M+H]+)
requires 386.2115; found 386.2115.
Method B. Epoxidation of 46. Cl3CCO2H (359 mg, 2.19 mmol) was added to a stirred solution of 46
(81 mg, 0.22 mmol, >99:1 dr) in CH2Cl2 (0.61 mL, 0.36 M w.r.t. 46) at rt and the resultant solution was
stirred at rt for 5 min. mꢀCPBA (75% by wt, 103 mg, 0.44 mmol) was added and the resultant suspension
was stirred at rt for 16 h. Na2SO3 (111 mg, 0.88 mmol) was added and the resultant suspension was stirred
until it solidified (~5 min). The resultant mixture was diluted with CH2Cl2 (5 mL) and washed with 10% aq
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NaOH (3 × 5 mL). The combined aqueous washings were extracted with CH2Cl2 (2 × 5 mL). The combined
organic extracts were washed with brine (25 mL), dried and concentrated in vacuo to give 82% conversion
to 48 in >95:5 dr. Purification via flash column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 4:1) gave 48
as a colourless oil (60 mg, 71%, >99:1 dr).
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(1RS,2SR,3RS,4RS)-1-Benzyloxy-2,3-epoxy-4-(N,N-dibenzylamino)cyclopentane 49. Method A.
O-Benzylation of 44. NaH (60% dispersion in mineral oil, 8 mg, 0.2 mmol) was stirred at rt for 20 min in
pentane (0.5 mL). The pentane was then decanted under a stream of argon, and THF (0.5 mL) was added.
The resultant suspension was cooled to 0 °C and a solution of 44 (30 mg, 0.10 mmol, >99:1 dr) in THF (0.5
mL) was added dropwise. The resultant suspension was stirred at 0 °C for 30 min, after which time BnBr (24
ꢁL, 0.20 mmol) and Bu4NI (1 mg, 0.01 mmol) were added sequentially. The resultant mixture was allowed
to warm to rt and stirred at rt for 24 h, then quenched with H2O (0.5 mL). The resultant mixture was
extracted with CHCl3 (5 × 2 mL) and the combined organic extracts were washed with brine (2 × 5 mL),
then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30ꢀ40 °C
petrol/Et2O, 6:1) gave 49 as a colourless oil (21 mg, 54%, >99:1 dr); νmax (film) 3062, 3028, 2890, 2803,
1602, 1494, 1453, 1256; δH (400 MHz, CDCl3) 1.62ꢀ1.70 (1H, m, C(5)HA), 1.79ꢀ1.85 (1H, m, C(5)HB), 3.39
(1H, app d, J 2.4, C(2)H), 3.53 (1H, app d, J 2.4, C(3)H), 3.63ꢀ3.67 (1H, m, C(4)H), 3.70ꢀ3.73 (2H, m,
N(CHAHBPh)2), 3.81ꢀ3.84 (2H, m, N(CHAHBPh)2), 4.13 (1H, app d, J 5.6, C(1)H), 4.48ꢀ4.51 (1H, m,
OCHAHBPh), 4.56ꢀ4.58 (1H, m, OCHAHBPh), 7.23ꢀ7.43 (15H, m, Ph); δC (100 MHz, CDCl3) 26.4 (C(5)),
54.2 (C(2)), 54.2 (N(CH2Ph)2), 56.3 (C(3)), 59.8 (C(4)), 71.6 (OCH2Ph), 77.6 (C(1)), 126.8, 127.7, 127.8,
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128.2, 128.5 (o,m,pꢀPh), 138.0, 140.1 (iꢀPh); m/z (ESI+) 386 ([M+H]+, 100%); HRMS (ESI+) C26H28NO2
([M+H]+) requires 386.2115; found 386.2111.
Method B. Epoxidation of 47. Cl3CCO2H (340 mg, 2.08 mmol) was added to a stirred solution of 47
(77 mg, 0.21 mmol, >99:1 dr) in CH2Cl2 (0.60 mL, 0.36 M w.r.t. 47) at rt and the resultant solution was
stirred at rt for 5 min. mꢀCPBA (75% by wt, 101 mg, 0.42 mmol) was added and the resultant suspension
was stirred at rt for 16 h. Na2SO3 (106 mg, 0.84 mmol) was added and the resultant suspension was stirred
until it solidified (~5 min). The resultant mixture was diluted with CH2Cl2 (5 mL) and washed with 10% aq
NaOH (3 × 5 mL). The combined aqueous washings were extracted with CH2Cl2 (2 × 5 mL). The combined
organic extracts were washed with brine (25 mL), dried and concentrated in vacuo to give 82% conversion
to 49 in >95:5 dr. Purification via flash column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 6:1) gave 49
as a colourless oil (59 mg, 74%, >99:1 dr).
(1RS,4SR)-4-(N-Benzylamino)cyclohept-2-en-1-ol 53. A solution of 5224 (427 mg, 1.73 mmol,
>99:1 dr) in THF (37 mL) at rt was added via cannula to a stirred solution of powdered LiAlH4 (319 mg,
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The Journal of Organic Chemistry
8.40 mmol) in THF (18 mL) at rt. The resultant solution was heated at reflux for 16 h, then allowed to cool
to rt and then further cooled to 0 °C. Crushed ice (~2 g) was then added portionwise, followed by addition of
satd. aq. sodium potassium tartrate (40 mL). The resultant mixture was stirred vigorously at rt for 2 h, then
filtered through Celite (eluent Et2O). The organic layer was washed with brine (100 mL), dried and
concentrated in vacuo. Purification via flash column chromatography (eluent EtOAc) gave 53 as a white
solid (322 mg, 80%, >99:1 dr);23 mp 107ꢀ109 °C; δH (400 MHz, CDCl3) 1.58ꢀ2.36 (6H, m, C(5)H2, C(6)H2,
C(7)H2), 3.31 (1H, td, J 6.6, 1.9, C(4)H), 3.70ꢀ3.82 (2H, m, NCH2Ph), 4.22 (1H, td, J 6.6, 1.7, C(1)H), 5.92
(1H, dd, J 11.3, 6.6, CH=CH), 6.22 (1H, dd, J 11.3, 6.6, CH=CH), 7.25ꢀ7.36 (5H, m, Ph).
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(1RS,4SR)-4-(N,N-Dibenzylamino)cyclohept-2-en-1-ol 54. BnBr (410 ꢁL, 3.45 mmol), Pr2NEt
(601 ꢁL, 3.45 mmol) and DMAP (28 mg, 0.23 mmol) were added sequentially to a stirred solution of 53
(500 mg, 2.30 mmol, >99:1 dr) in CH2Cl2 (23 mL) at rt and the resultant solution was stirred at rt for 24 h,
then washed with H2O (2 × 25 mL). The combined aqueous washings were extracted with CH2Cl2 (50 mL)
and the combined organic extracts were washed with brine (75 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 4:1) gave 54 as a yellow solid
(550 mg, 78%, >99:1 dr); mp 48ꢀ50 °C; νmax (film) 3387, 3028, 2927, 1603, 1493, 1453; δH (400 MHz,
CDCl3) 1.45ꢀ2.07 (7H, m, C(5)H2, C(6)H2, C(7)H2, OH), 3.21ꢀ3.22 (1H, m, C(4)H), 3.57ꢀ3.61 (2H, m,
N(CHAHBPh)2), 3.69ꢀ3.72 (2H, m, N(CHAHBPh)2), 4.20ꢀ4.21 (1H, m, C(1)H), 5.80ꢀ5.83 (1H, m, CH=CH),
5.94ꢀ5.97 (1H, m, CH=CH), 7.27ꢀ7.38 (10H, m, Ph); δC (100 MHz, CDCl3) 25.0, 29.1, 36.4, (C(5), C(6),
C(7)), 53.8 (N(CH2Ph)2), 58.9 (C(4)), 71.9 (C(1)), 126.8 (pꢀPh), 128.2, 128.6 (o,mꢀPh), 133.4, 137.1 (C(2),
C(3)), 139.9 (iꢀPh); m/z (ESI+) 308 ([M+H]+, 100%); HRMS (ESI+) C21H26NO+ ([M+H]+) requires
308.2009; found 308.2006.
(1RS,4RS)-4-(N-Benzylamino)cyclohept-2-en-1-ol 55. DEAD (40% wt solution in PhMe, 1.79 mL,
3.93 mmol) was added dropwise via syringe pump over 1 h to a stirred solution of 53 (502 mg, 2.31 mmol,
>99:1 dr), PPh3 (1.21 g, 4.62 mmol) and benzoic acid (423 mg, 3.47 mmol) in PhMe (18 mL) at 0 °C. The
resultant solution was allowed warm to rt and stirred at rt for a further 16 h, then concentrated in vacuo. The
residue was dissolved in Et2O (20 mL) and the resultant solution was washed sequentially with satd aq
Na2CO3 (3 × 20 mL) and brine (20 mL), then dried and concentrated in vacuo. The residue was dissolved in
MeOH (6 mL) and K2CO3 (1.60 g, 11.6 mmol) was added. The resultant suspension was stirred at rt for 4 h,
then filtered and concentrated in vacuo. The residue was dissolved in Et2O (20 mL) and the resultant
solution was washed sequentially with H2O (3 × 20 mL) and brine (20 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent EtOAc) gave 55 as a colourless oil (65 mg,
13%, >99:1 dr); νmax (film) 3355, 3025, 2930, 2858, 1651, 1603, 1495, 1453; δH (400 MHz, CDCl3) 1.61ꢀ
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1.87 (6H, m, C(5)H2, C(6)H2, C(7)H2), 3.42ꢀ3.44 (1H, m, C(4)H), 3.76ꢀ3.83 (2H, m, NCH2Ph), 4.47ꢀ4.50
(1H, m, C(1)H), 5.75ꢀ5.82 (2H, m, C(2)H, C(3)H), 7.24ꢀ7.34 (5H, m, Ph); δC (100 MHz, CDCl3) 20.8, 32.4,
35.3 (C(5), C(6), C(7)), 51.4 (NCH2Ph), 55.6 (C(4)), 69.9 (C(1)), 127.0 (pꢀPh), 128.2, 128.4 (o,mꢀPh),
134.8, 135.9 (C(2), C(3)), 140.4 (iꢀPh); m/z (ESI+) 497 (100%), 218 ([M+H]+, 80%); HRMS (ESI+)
C14H20NO+ ([M+H]+) requires 218.1539; found 218.1537.
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(1RS,4RS)-4-(N,N-Dibenzylamino)cyclohept-2-en-1-ol 56. DEAD (40% wt solution in PhMe, 1.23
mL, 2.69 mmol) was added dropwise over 1 h to a stirred solution of 54 (487 mg, 1.58 mmol, >99:1 dr),
PPh3 (831 mg, 3.17 mmol) and benzoic acid (290 mg, 2.38 mmol) in PhMe (12 mL) at 0 °C. The resultant
solution was allowed warm to rt and stirred at rt for a further 16 h, then concentrated in vacuo. The residue
was dissolved in Et2O (20 mL) and washed sequentially with sat. aq. Na2SO3 (3 × 20 mL) and brine (20
mL), dried and concentrated in vacuo. The residue was dissolved in MeOH (5 mL) and K2CO3 (1.09 g, 7.92
mmol) was added. The resultant suspension was stirred at rt for 4 h, then filtered and concentrated in vacuo.
The residue was dissolved in Et2O (20 mL) and washed sequentially with H2O (3 × 20 mL) and brine (20
mL), dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30ꢀ40 °C
petrol/Et2O, 4:1) gave 56 as a white solid (312 mg, 64%, >99:1 dr); mp 56ꢀ58 °C; νmax (film) 3356, 3026,
2934, 1646, 1602, 1493, 1454; δH (400 MHz, CDCl3) 1.44 (1H, d, J 3.79, OH), 1.54ꢀ1.61 (2H, m, C(5)HA,
C(7)HA), 1.70ꢀ1.82 (3H, m, C(6)H2, C(7)HB), 2.02ꢀ2.09 (2H, m, C(5)HB), 3.36 (1H, ddd, J 8.1, 5.2, 2.4,
C(4)H), 3.5 (2H, d, J 14.0, N(CHAHBPh)2), 3.74 (2H, d, J 14.0, N(CHAHBPh)2), 4.39ꢀ4.41 (1H, m, C(1)H),
5.77ꢀ5.82 (1H, m, C(3)H), 5.89ꢀ5.92 (1H, m, C(2)H), 7.21ꢀ7.40 (5H, m, Ph); δC (100 MHz, CDCl3) 20.9
(C(6)), 26.6 (C(5)), 35.0 (C(7)), 53.8 (N(CH2Ph)2), 56.9 (C(4)), 69.1 (C(1)), 126.8 (pꢀPh), 128.2, 128.5 (o,mꢀ
Ph), 135.5, 136.0 (C(2), C(3)), 140.3 (iꢀPh); m/z (ESI+) 308 ([M+H]+, 100%); HRMS (ESI+) C21H26NO+
([M+H]+) requires 308.2009; found 308.2006.
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(1RS,2SR,3RS,4SR)- and (1RS,2RS,3SR,4SR)-2,3-Epoxy-4-(N,N-dibenzylamino)cyclohept-1-ol
59 and 60. Method A. via Epoxidation of 53. Step 1. Cl3CCO2H (376 mg, 2.30 mmol) was added to a stirred
solution of 53 (50 mg, 0.23 mmol, >99:1 dr) in CH2Cl2 (0.64 mL, 0.36 M w.r.t 53) at rt and the resultant
solution was stirred at rt for 5 min. mꢀCPBA (69% by wt, 173 mg, 0.69 mmol) was added and the resultant
suspension was stirred at rt for 3.5 h. Na2SO3 (174 mg, 1.38 mmol) was added and the resultant suspension
was stirred until it solidified (~5 min). The resultant mixture was diluted with CH2Cl2 (5 mL) and washed
with 10% aq. NaOH (3 × 5 mL). The combined aqueous washings were extracted with CH2Cl2 (2 × 5 mL).
The combined organic extracts were washed with brine (10 mL), dried and concentrated in vacuo to give an
18:82 mixture of 57 and 58 (62 mg).
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Step 2. BnBr (41 µL, 0.35 mmol), Pr2NEt (60 µL, 0.35 mmol) and DMAP (2 mg, 0.02 mmol) were
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added sequentially to a stirred solution of the residue from the previous step (62 mg) in CH2Cl2 (2.3 mL) at
rt and the resultant solution was stirred at rt for 24 h, then washed with H2O (2 × 5 mL). The combined
aqueous washings were extracted with CH2Cl2 (10 mL) and the combined organic extracts were washed with
brine (20 mL), dried and concentrated in vacuo to give an 18:82 mixture of 59 and 60. Purification via flash
column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 3:2) gave 60 as a colourless oil (44 mg, 53%, >99:1
dr); νmax (film) 3384, 2932, 2851, 1603, 1494, 1453, 1264; δH (500 MHz, CDCl3) 0.73ꢀ0.83 (1H, m,
C(6)HA), 1.51ꢀ1.59 (2H, m, C(5)HA, C(7)HA), 1.74ꢀ1.78 (2H, m, C(6)HB, C(7)HB), 1.84ꢀ1.89 (1H, m,
C(5)HB) 2.85ꢀ2.88 (1H, m, C(4)H), 3.20 (1H, app d, J 5.1, C(2)H), 3.89 (1H, dd, J 5.1, 1.0, C(3)H), 3.58
(2H, d, J 14.0, N(CHAHBPh)2), 3.82ꢀ3.89 (3H, m, C(1)H, N(CHAHBPh)2), 7.22ꢀ7.26 (2H, m, Ph), 7.30ꢀ7.33
(4H, m, Ph), 7.38 (4H, m, Ph); δC (125 MHz, CDCl3) 23.0 (C(6)), 23.7 (C(5)), 33.9 (C(7)), 54.1
(N(CH2Ph)2), 57.9 (C(4)), 58.5 (C(2)), 58.5 (C(3)), 72.0 (C(1)), 126.8 (pꢀPh), 128.2, 128.5 (o,mꢀPh), 140.0,
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(iꢀPh); m/z (ESI+) 346 ([M+Na]+, 100%); HRMS (ESI+) C21H25NNaO2 ([M+Na]+) requires 346.1778; found
346.1773. Further elution gave a 53:47 mixture of 59 and 60 as a colourless oil (8 mg, 10%).
Method B. Epoxidation of 54. Cl3CCO2H (2.66 g, 16.3 mmol) was added to a stirred solution of 54
(500 mg, 1.63 mmol, >99:1 dr) in CH2Cl2 (4.5 mL, 0.36 M w.r.t 54) at rt and the resultant solution was
stirred at rt for 5 min. mꢀCPBA (69% by wt, 1.22 g, 4.89 mmol) was added and the resultant suspension was
stirred at rt for 3.5 h. Na2SO3 (1.23 g, 9.77 mmol) was added and the resultant suspension was stirred until it
solidified (~5 min). The resultant mixture was diluted with CH2Cl2 (5 mL) and washed 10% aq. NaOH (3 ×
5 mL). The combined aqueous washings were extracted with CH2Cl2 (2 × 15 mL). The combined organic
extracts were washed with brine (50 mL), dried and concentrated in vacuo to give an 80:20 mixture of 59
and 60. Purification via flash column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 3:2) gave a 23:77
mixture of 59 and 60 as a colourless oil (89 mg, 17%). Further elution gave an 82:18 mixture of 59 and 60 as
a colourless oil (275 mg, 52%). Further elution gave 59 as a colourless oil (20 mg, 4%, 95:5 dr); νmax (film)
3406, 3062, 2929, 2854, 1602, 1494, 1453, 1260; δH (400 MHz, CDCl3) 1.27ꢀ1.33 (1H, m, C(6)HA), 1.52ꢀ
1.88 (5H, m, C(5)H2, C(6)HB, C(7)H2), 2.47 (1H, app dd, J 10.6, 7.5, C(4)H), 3.04 (1H, t, J 5.5, C(2)H), 3.32
(1H, dd, J 7.5, 5.5, C(3)H), 3.39ꢀ3.44 (1H, m, C(1)H), 3.70ꢀ3.73 (2H, m, N(CHAHBPh)2), 3.78ꢀ3.81 (2H, m,
N(CHAHBPh)2), 7.21ꢀ7.41 (10H, m, Ph); δC (100 MHz, CDCl3) 25.5, 29.8, 33.9 (C(5), C(6), C(7)), 54.0
(C(3)), 54.3 (N(CH2Ph)2), 58.5 (C(2)), 60.9 (C(4)), 73.4 (C(1)), 126.9 (pꢀPh), 128.2, 128.8 (o,mꢀPh), 139.6,
+
(iꢀPh); m/z (ESI+) 346 ([M+Na]+, 100%); HRMS (ESI+) C21H25NNaO2 ([M+Na]+) requires 346.1778; found
346.1778.
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(1RS,2SR,3RS,4SR)-1-(p-Nitrobenzoyloxy)-2,3-epoxy-4-(N,N-dibenzylamino)cycloheptane 61.
pꢀNitrobenzoyl chloride (246 mg, 1.33 mmol) and DMAP (9 mg, 0.07 mmol) were added sequentially to a
stirred solution of 59 (215 mg, 0.66 mmol, 82:18 dr) in pyridine (2.6 mL) at rt. The resultant solution was
stirred at rt for 16 h then diluted with CH2Cl2 (10 mL). The resultant solution was washed sequentially with
sat. aq. NaHCO3 (10 mL), sat. aq. citric acid (2 × 10 mL) and brine (2 × 10 mL), dried and concentrated in
vacuo to give 61 in 82:18 dr. Purification via flash column chromatography (eluent PhMe/Et2O, 15:1) gave
61 as a white solid (248 mg, 79%, 93:7 dr). Recrystallisation gave an analytical sample of 61 (>99:1 dr); mp
154ꢀ156 °C; νmax (film) 3029, 2930, 2856, 1725, 1607, 1494, 1454, 1271; δH (500 MHz, CDCl3) 1.43ꢀ1.51
(1H, m, C(6)HA), 1.58ꢀ1.66 (1H, m, C(5)HA), 1.68ꢀ1.76 (1H, m, C(7)HA), 1.91ꢀ1.97 (3H, m, C(5)HB,
C(6)HB, C(7)HB), 2.56 (1H, dd, J 11.0, 7.6, C(4)H), 3.30ꢀ3.32 (1H, m, C(2)H), 3.40 (1H, dd, J 7.6, 5.3,
C(3)H), 3.73ꢀ3.76 (2H, m, N(CHAHBPh)2), 3.82ꢀ3.85 (2H, m, N(CHAHBPh)2), 4.64 (1H, ddd, J 11.9, 6.2,
1.7, C(1)H), 7.23ꢀ7.42 (10H, m, Ph), 8.21ꢀ8.23 (2H, m, Ar), 8.29ꢀ8.31 (2H, m, Ar); δC (125 MHz, CDCl3)
25.5 (C(6)), 30.0 (C(5)), 31.5 (C(7)), 53.8 (C(3)), 54.5 (NCH2Ph), 55.4 (C(2)), 61.5 (C(4)), 77.8 (C(1)),
123.5 (Ar), 127.0 (pꢀPh), 128.2, 128.7 (o,mꢀPh), 130.8 (Ar), 135.5, 139.5 (iꢀPh, Ar), 150.6 (Ar), 163.7
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+
(C=O); m/z (ESI+) 473 ([M+H]+, 100%); HRMS (ESI+) C28H29N2O5 ([M+H]+) requires 473.2071; found
473.2065.
(1RS,2RS,3SR,4RS)- and (1RS,2SR,3RS,4RS)-2,3-Epoxy-4-(N,N-dibenzylamino)cyclohept-1-ol
64 and 65. Method A. via Epoxidation of 55. Step 1. Cl3CCO2H (376 mg, 2.30 mmol) was added to a stirred
solution of 55 (50 mg, 0.23 mmol, >99:1 dr) in CH2Cl2 (0.64 mL, 0.36 M w.r.t 55) at rt and the resultant
solution was stirred at rt for 5 min. mꢀCPBA (69% by wt, 173 mg, 0.69 mmol) was added and the resultant
suspension was stirred at rt for 3.5 h. Na2SO3 (174 mg, 1.38 mmol) was added and the resultant suspension
was stirred until it solidified (~5 min). The resultant mixture was diluted with CH2Cl2 (5 mL) and washed
with 10% aq. NaOH (3 × 5 mL). The combined aqueous washings were extracted with CH2Cl2 (2 × 5 mL).
The combined organic extracts were washed with brine (10 mL), dried and concentrated in vacuo to give a
44:56 mixture of 62 and 63 (60 mg).
i
Step 2. BnBr (41 µL, 0.35 mmol), Pr2NEt (60 µL, 0.35 mmol) and DMAP (2 mg, 0.02 mmol) were
added sequentially to a stirred solution of the residue from the previous step (60 mg) in CH2Cl2 (2.3 mL) at
rt and the resultant solution was stirred at rt for 24 h, then washed with H2O (2 × 5 mL). The combined
aqueous washings were extracted with CH2Cl2 (10 mL) and the combined organic extracts were washed with
brine (20 mL), dried and concentrated in vacuo to give a 44:56 mixture of 64 and 65. Purification via flash
column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 4:1) gave 65 as a colourless oil (29 mg, 35%, >99:1
dr); νmax (film) 3357, 3030, 2927, 2854, 1496, 1454; δH (400 MHz, CDCl3) 1.08ꢀ1.90 (6H, m, C(5)H2,
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C(6)H2, C(7)H2), 3.04 (1H, dd, J 11.8, 2.6, C(4)H), 3.09 (1H, m, C(2)H), 3.41 (1H, d, J 3.4, C(3)H), 3.59
(2H, d, J 14.2, N(CHAHBPh)2), 3.87 (2H, d, J 14.2, N(CHAHBPh)2), 4.51ꢀ4.44 (1H, m, C(1)H), 7.21ꢀ7.40
(10H, m, Ph); δC (125 MHz, CDCl3) 18.7 (C(6)), 23.3 (C(5)), 32.5 (C(7)), 54.3 (N(CH2Ph)2), 54.9 (C(2)),
57.9 (C(4)), 60.6 (C(3)), 69.8 (C(1)), 126.8 (pꢀPh), 128.2, 128.5 (o,mꢀPh), 140.1, (iꢀPh); m/z (ESI+) 346
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([M+Na]+, 100%); HRMS (ESI+) C21H25NNaO2 ([M+Na]+) requires 346.1778; found 346.1777.
+
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Method B. Epoxidation of 56. Cl3CCO2H (2.66 g, 16.3 mmol) was added to a stirred solution of 56
(500 mg, 1.63 mmol, >99:1 dr) in CH2Cl2 (4.5 mL, 0.36 M w.r.t 56) at rt and the resultant solution was
stirred at rt for 5 min. mꢀCPBA (69% by wt, 1.22 g, 4.89 mmol) was added and the resultant suspension was
stirred at rt for 3.5 h. Na2SO3 (1.23 g, 9.77 mmol) was added and the resultant suspension was stirred until it
solidified (~5 min). The resultant mixture was diluted with CH2Cl2 (5 mL) and washed 10% aq. NaOH (3 ×
5 mL). The combined aqueous washings were extracted with CH2Cl2 (2 × 15 mL). The combined organic
extracts were washed with brine (50 mL), dried and concentrated in vacuo to give a 95:5 mixture of 64 and
65. Purification via flash column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 4:1) gave 64 as a white solid
(48 mg, 73%, >99:1 dr); mp 92ꢀ94 °C; νmax (film) 3443, 1494, 1453, 1260; δH (400 MHz, CDCl3) 1.36ꢀ1.44
(1H, m, C(6)HA), 1.53ꢀ1.66, 1.75ꢀ1.82 (4H, m, C(5)H2, C(6)HB, C(7)HA), 1.90ꢀ1.98 (1H, m, C(7)HB), 2.93
(1H, m, C(4)H), 3.06 (1H, t, J 4.7, C(2)H), 3.35ꢀ3.37 (1H, m, C(3)H) 3.68ꢀ3.71 (2H, m, N(CHAHBPh)2),
3.76ꢀ3.80 (2H, m, N(CHAHBPh)2), 4.25ꢀ4.28 (1H, m, C(1)H), 7.22ꢀ7.45 (10H, m, Ph); δC (100 MHz, CDCl3)
21.0 (C(6)), 30.0, 30.2 (C(7), (C(5)), 54.4 (C(2)), 54.6 (N(CH2Ph)2), 56.9 (C(3)), 58.8 (C(4)), 65.1 (C(1)),
126.9 (pꢀPh), 128.2, 128.7 (o,mꢀPh), 139.8 (iꢀPh); m/z (ESI+) 324 ([M+H]+, 100%); HRMS (ESI+)
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C21H26NO2 ([M+H]+) requires 324.1958; found 324.1955.
(1RS,4RS)-1-Benzyloxy-4–(N,N-dibenzylamino)cyclohept-2-ene 66. NaH (60% dispersion in
mineral oil, 20 mg, 0.50 mmol) was stirred at rt for 20 min in pentane (1 mL). The pentane was then
decanted under a stream of argon, and THF (1 mL) was added. The resultant suspension was cooled to 0 °C
and a solution of 56 (76 mg, 0.25 mmol, >99:1 dr) in THF (1 mL) was added dropwise. The resultant
suspension was stirred at 0 °C for 30 min, after which time BnBr (60 ꢁL, 0.50 mmol) and Bu4NI (1 mg, 0.01
mmol) were added sequentially. The resultant mixture was allowed to warm to rt and stirred at rt for 24 h,
then quenched with H2O (1 mL). The resultant mixture was extracted with CHCl3 (5 × 5 mL) and the
combined organic extracts were washed with brine (2 × 10 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 24:1) gave 66 as a colourless oil
(88 mg, 89%, 99:1 dr); νmax (film) 3027, 2933, 2859, 1649, 1603, 1494, 1454; δH (400 MHz, CDCl3) 1.52ꢀ
1.68 (2H, m, C(5)HA, C(6)HA), 1.74ꢀ1.88 (3H, m, C(6)HB, C(7)H2), 2.01ꢀ2.05 (1H, m, C(5)HB), 3.46ꢀ3.49
(1H, m, C(4)H), 3.53 (2H, d, J 14.2, N(CHAHBPh)2), 3.72 (2H, d, J 14.2, N(CHAHBPh)2), 4.11ꢀ4.12 (1H, m,
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(C(1)H), 4.44ꢀ4.53 (2H, m, OCH2Ph), 5.87ꢀ5.91 (1H, m, C(2)H), 5.98ꢀ6.02 (1H, m, C(3)H), 7.21ꢀ7.40 (15H,
m, Ph); δC (100 MHz, CDCl3) 21.4 (C(6)), 26.9 (C(5)), 31.4 (C(7)), 53.8 (N(CH2Ph)2), 57.4 (C(4)), 70.1
(OCH2Ph), 75.2 (C(1)), 126.7, 127.4, 127.6, 128.2, 128.3, 128.5 (o,m,pꢀPh), 133.2 (C(3)), 136.7 (C(2)),
138.8, 140.4 (iꢀPh); m/z (ESI+) 398 ([M+H]+, 100%); HRMS (ESI+) C28H32NO+ ([M+H]+) requires
398.2478; found 398.2478.
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(1RS,2RS,3SR,4RS)-
and
(1RS,2SR,3RS,4RS)-1-Benzyloxy-2,3-epoxy-4-(N,N-
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dibenzylamino)cycloheptane 67 and 68. Method A. O-Benzylation of 64. NaH (60% dispersion in mineral
oil, 6.8 mg, 0.17 mmol) was stirred at rt for 20 min in pentane (1 mL). The pentane was then decanted under
a stream of argon, and THF (1 mL) was added. The resultant suspension was cooled to 0 °C and a solution of
64 (27 mg, 0.083 mmol, >99:1 dr) in THF (0.5 mL) was added dropwise. The resultant suspension was
stirred at 0 °C for 30 min, after which time BnBr (20 ꢁL, 0.17 mmol) and Bu4NI (1 mg, 0.01 mmol) were
added sequentially. The resultant mixture was allowed to warm to rt and stirred at rt for 24 h, then quenched
with H2O (0.5 mL). The resultant mixture was extracted with CHCl3 (5 × 2 mL) and the combined organic
extracts were washed with brine (2 × 5 mL), then dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30ꢀ40 °C petrol/Et2O, 9:1) gave 67 as a colourless oil (17 mg, 55%, >99:1
dr); νmax (film) 3029, 2929, 2851, 1602, 1494, 1453; δH (400 MHz, CDCl3) 1.44ꢀ1.67 (4H, m, C(5)HA,
C(6)H2, C(7)HA), 1.77ꢀ1.88 (2H, m, C(5)HB, C(7)HB), 3.02 (1H, dd, J 4.6, 3.4, C(2)H), 3.17ꢀ3.22 (1H, m,
C(4)H), 3.28 (1H, dd, J 6.1, 4.6, C(3)H), 3. 75 (4H, s, N(CH2Ph)2), 3.95 (1H, ddd, J 7.9, 3.4, 1.4, C(1)H),
4.43 (1H, d, J 12.1, OCHAHBPh), 4.63 (1H, d, J 12.1, OCHAHBPh), 7.16ꢀ7.21, 7.25ꢀ7.30, 7.40ꢀ7.42 (10H, m,
Ph); δC (100 MHz, CDCl3) 21.2 (C(5)), 28.8 (C(7), 29.7 (C(6)), 54.7 (N(CH2Ph)2), 54.8 (C(2)), 55.6 (C(3)),
58.4 (C(4)), 71.3 (OCH2Ph), 73.4 (C(1)), 126.8, 127.1, 127.2, 128.1, 128.2, 128.7 (o,m,pꢀPh), 138.8, 140.0
+
(iꢀPh); m/z (ESI+) 415 (100%), 414 ([M+H]+, 95%); HRMS (ESI+) C28H32NO2 ([M+H]+) requires
414.2428; found 414.2429.
Method B. O-Benzylation of 65. NaH (60% dispersion in mineral oil, 3.7 mg, 0.092 mmol) was
stirred at rt for 20 min in pentane (0.5 mL). The pentane was then decanted under a stream of argon, and
THF (0.5 mL) was added. The resultant suspension was cooled to 0 °C and a solution of 65 (15 mg, 0.046
mmol, >99:1 dr) in THF (0.5 mL) was added dropwise. The resultant suspension was stirred at 0 °C for 30
min, after which time BnBr (11 ꢁL, 0.092 mmol) and Bu4NI (0.5 mg, 0.001 mmol) were added sequentially.
The resultant mixture was allowed to warm to rt and stirred at rt for 24 h, then quenched with H2O (0.5 mL).
The resultant mixture was extracted with CHCl3 (5 × 2 mL) and the combined organic extracts were washed
with brine (2 × 5 mL), then dried and concentrated in vacuo. Purification via flash column chromatography
(eluent 30ꢀ40 °C petroleum ether/Et2O, 9:1) gave 68 as a colourless oil (12 mg, 61%, >99:1 dr); νmax (film)
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3030, 2962, 2919, 1603, 1494, 1454; δH (500 MHz, CDCl3) 1.14ꢀ1.27 (1H, m, C(6)HA), 1.41ꢀ1.52 (3H, m,
C(5)HA, C(6)HB, C(7)HA), 1.84ꢀ1.97 (2H, m, C(5)HB, C(7)HB), 3.12ꢀ3.13 (1H, m, C(4)H), 3.14ꢀ3.15 (1H, m,
C(2)H), 3.39 (1H, d, J 4.4, C(3)H), 3.59 (2H, d, J 14.0, N(CHAHBPh)2), 3.87 (2H, app d, J 14.0,
N(CHAHBPh)2), 4.19 (1H, t, J 5.1, (C(1)H), 4.40 (1H, d, J 12.0, OCHAHBPh), 4.58 (1H, d, J 12.0,
OCHAHBPh), 7.19ꢀ7.23, 7.25ꢀ7.33, 7.38ꢀ7.40 (10H, m, Ph); δC (125 MHz, CDCl3) 19.1 (C(6)), 23.1 (C(5)),
28.1 (C(7)), 54.0 (C(4)), 54.3 (N(CH2Ph)2), 57.5 (C(2)), 60.7 (C(3)), 70.8 (OCH2Ph), 76.4 (C(1)), 126.7,
127.4, 127.6, 128.2, 128.4, 128.6 (o,m,pꢀPh), 138.3, 140.2 (iꢀPh); m/z (ESI+) 436 ([M+Na]+, 100%); HRMS
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(ESI+) C28H31NNaO2 ([M+Na]+) requires 436.2247; found 436.2251.
Method C. Epoxidation of 66. Cl3CCO2H (376 mg, 2.30 mmol) was added to a stirred solution of 66
(71 mg, 0.23 mmol, >99:1 dr) in CH2Cl2 (0.64 mL, 0.36 M w.r.t 66) at rt and the resultant solution was
stirred at rt for 5 min. mꢀCPBA (69% by wt, 173 mg, 0.69 mmol) was added and the resultant suspension
was stirred at rt for 3.5 h. Na2SO3 (174 mg, 1.38 mmol) was added and the resultant suspension was stirred
until it solidified (~5 min). The resultant mixture was diluted with CH2Cl2 (5 mL) and washed with 10% aq.
NaOH (3 × 5 mL). The combined aqueous washings were extracted with CH2Cl2 (2 × 5 mL). The combined
organic extracts were washed with brine (10 mL), dried and concentrated in vacuo to give 86% conversion
to a 94:6 mixture of 67 and 68, respectively. Purification via flash column chromatography (eluent 30ꢀ40 °C
petrol/Et2O, 9:1) gave 68 as a colourless oil (4 mg, 5%, >99:1 dr). Further elution gave 67 as a colourless oil
(36 mg, 48%, >99:1 dr).
Kinetics Experiments. Cl3CCO2H (10 equiv) was added to a solution of the requisite substrate (1.0
equiv, 1.0 mmol) in CD2Cl2 (0.36 M w.r.t. substrate). After five minutes, mꢀCPBA (1.6 equiv) was quickly
1
added to the solution and the H NMR spectrum (16 scans) of an aliquot of the resultant solution was
recorded immediately and then at regular intervals, without removal of the sample from the NMR
spectrometer.
1
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Supporting Information Available: Copies of H and C NMR spectra, and crystallographic information
file (for structures CCDC 1562293–1562296). This material is available free of charge via the Internet at
http://pubs.acs.org.
† Deceased.
References and Notes
1 Bard, A. J.; Whitesides, G. M.; Zare, R. N.; McLafferty, F. W. Acc. Chem. Res. 1995, 28, 91.
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