Diastereoselective synthesis of substituted tetrahydropyrans by copper(II)-bisphosphine-catalyzed olefin migration and prins cyclization

Article abstract of DOI:10.1055/s-0032-1317495

We developed a copper(II) triflate-bisphosphine complex catalyzed olefin migration and Prins cyclization which lead to the synthesis of substituted tetrahydropyran derivatives. The protocol is convenient and a variety of substituted tetrahydropyrans were obtained in good to excellent yields with excellent diastereoselectivities. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317495

FEATURE ARTICLE
▌3579
feature article
Diastereoselective Synthesis of Substituted Tetrahydropyrans by Copper(II)–
Bisphosphine-Catalyzed Olefin Migration and Prins Cyclization
Diastereoselective Synthesis of Substituted Tetrahydropyrans
Arun K. Ghosh,* Jorden Kass, Daniel R. Nicponski, Chad Keyes
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA
Fax +1(765)4961612; E-mail: akghosh@purdue.edu
Received: 06.07.2012; Accepted after revision: 30.09.2012
Electron-poor aromatic aldehydes 4-fluorobenzaldehyde
Abstract: We developed a copper(II) triflate–bisphosphine com-
(4), 4-nitrobenzaldehyde (6), and 4-cyanobenzaldehyde
plex catalyzed olefin migration and Prins cyclization which lead to
(8) also resulted in good yields (75–85%) of the trans
products trans-5, trans-7, and trans-9, respectively, along
the synthesis of substituted tetrahydropyran derivatives. The proto-
col is convenient and a variety of substituted tetrahydropyrans were
obtained in good to excellent yields with excellent diastereoselec- with some (7–17%) cis product (entries 2–4). However,
tivities.
reaction with electron-rich p-anisaldehyde (10) gave a
complex mixture with <37% yield of the desired trans
product trans-11 (entry 5). Reaction with aliphatic alde-
hydes, octanal (12) and cyclohexanecarbaldehyde (14)
gave slightly lower yields 65% and 59% in comparison to
electron-poor aromatic aldehydes, but better diastereose-
lectivity with no detectable cis isomers (entries 6 and 7).
Key words: tetrahydropyrans, olefin migration, Prins cyclization,
diastereoselective, metal-ligand catalyzed
Substituted tetrahydropyran structural motifs are ubiqui-
tous in numerous bioactive natural products.1 The impor-
tance of this heterocycle is also well recognized in
medicinal chemistry.2 Compounds containing this ring
system are widely utilized as pharmaceutical agents and
molecular probes.3 Recently, in the context of our nonpep-
tide ligand design and synthesis work, we have demon-
strated that the tetrahydropyran ring oxygen can be used
to mimic the carbonyl oxygen of a peptide bond.4 Over the
years, a lot of effort has been devoted to the synthesis of
stereochemically defined and substituted tetrahydropyran
derivatives.5 Among these, hetero-Diels–Alder reactions,6
Prins cyclizations,7 oxy-Michael reactions,8 Petasis–
Ferrier rearrangements,9 and Maitland–Japp reactions10
are widely used for the synthesis of functionalized tetra-
hydropyrans containing multiple stereocenters. We re-
cently reported a highly diastereoselective synthesis of di-
and trisubstituted tetrahydropyrans via a tandem olefin
migration and Prins cyclization process.11 For example,
the reaction of 5-methylhex-5-en-1-ol with a variety of al-
iphatic, electron-rich, and electron-poor aromatic alde-
hydes proceeded efficiently in the presence of a catalytic
amount of copper(II) triflate–bisphosphine complex. This
protocol is an improvement over previously reported plat-
inum(II) triflate catalyzed cyclizations12 in both lowering
reaction temperature and broadening substrate scope.
Table 1 Earlier Work by Hosomi et al.12
OH
O
R
O
R
PtCl2 (0.5 mol%)
AgOTf (1 mol%)
O
+
+
PhMe, 100 °C
R
trans
1
cis
Entry Aldehyde
R
Product Yield (%) dr
1
2
3
4
5
6
7
2
4
Ph
3
5
77
75
9:1
4.4:1
11:1
4-FC6H4
4-O2NC6H4
4-NCC6H4
4-MeOC6H4
(CH2)6Me
Cy
6
7
77
8
9
85
11:1
a
10
12
14
11
13
15
<37
65
–
>20:1
>20:1
59
a Not determined.
As shown in Table 2, synthesis of trisubstituted tetrahy-
dropyrans was also explored with the platinum(II) chlo-
ride/silver(I) triflate catalyst system.12 Reactions with 1-,
2-, and 3-methylalkenols 16, 20, and 24 gave 6-, 5-, and
4-methyltetrahydropyrans, respectively. Use of 6-methyl-
hept-6-en-2-ol (16) under the standard reaction conditions
gave 17–19 in excellent yields (>84%) and diastereoselec-
tivities (>15:1 dr) (entries 1–3). Reactions with 2,5-di-
methylhex-5-en-1-ol (20) under standard conditions lead
to Prins cyclization giving 21–23 in excellent yields
(>80%), but result in lower diastereoselectivities (from
99:1 to 4:1 dr, entries 4–6). However, reactions with 3,5-
dimethylhex-5-en-1-ol (24) resulted in substituted tetra-
hydropyrans 25–27 with excellent diastereoselectivity
In an earlier paper, Hosomi et al. utilized a combination of
platinum(II) chloride (0.5 mol%) and silver(I) triflate (1
mol%) catalyst system at 100 °C with 5-methylhex-5-en-
1-ol (1) and a number of aldehydes to affect cyclization
resulting in 2,3-disubstituted tetrahydropyrans.12 As
shown in Table 1, reaction with benzaldehyde (2) gave
trans product trans-3 in 77% yield along with the cis-dia-
stereomer cis-3 and other unidentified products (entry 1).
SYNTHESIS 2012, 44, 3579–3589
Advanced online publication: 06.11.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317495; Art ID: SS-2012-Z0569-FA
© Georg Thieme Verlag Stuttgart · New York

3580
A. K. Ghosh et al.
FEATURE ARTICLE
(19:1), but lower yields than the unsubstituted analogues
(entries 7–9).
OH
PtCl2 (0.5 mol%)
AgOTf (1 mol%)
O
Ph
O
Ph
O
+
+
PhMe, 100 °C
Ph
In an effort to probe the reaction mechanism, reactions of
5-methylhex-4-en-1-ol (28) and benzaldehyde (2) were
used (Scheme 1). This reaction afforded major product
trans-3 in high yield (79%) and a small amount (12%) of
the cis-3 product. This result has provided some evidence
that the reaction with either substrate likely involved sim-
ilar intermediates or transition states.
28
2
trans-3
cis-3
79%
12%
Scheme 1 Earlier work by Hosomi et al.12
As shown in Table 3, similar reactions were reported pre-
viously by Loh et al. wherein 6-methylhept-5-en-2-ol (29)
Biographical Sketches█
Arun K. Ghosh was born J. Corey at Harvard Univer- ment of Medicinal Chemis-
and raised in Calcutta, India. sity (1985–1988). He was a try and Molecular
He received his B.S. in research fellow at Merck Pharmacology. He became
chemistry (1979) and M.S. Research Laboratories and the Ian P. Rothwell Distin-
in chemistry (1981) from in 1994, he joined Universi- guished Professor in 2009.
the University of Calcutta ty of Illinois, Chicago as As- His research interests in-
and Indian Institute of Tech- sistant Professor, eventually clude diverse areas of or-
nology, Kanpur respective- becoming Professor of ganic, bioorganic, and
ly. He received his Ph.D. in chemistry in 1998. In 2005, medicinal chemistry with
organic chemistry in 1985 at he moved to Purdue Univer- particular emphasis on or-
the University of Pittsburgh. sity, with a joint appoint- ganic synthesis and protein-
He then pursued postdoctor- ment in the Department of structure-based drug design.
al research with Professor E. Chemistry and the Depart-
Jorden Kass was born in versity. Subsequently, he (2009–2011). His thesis
Toledo, Ohio (USA) in joined Professor Ghosh’s work has focused on the de-
1984. He received his B.S. research group for his thesis velopment of asymmetric
in chemistry in 2006 from work. He was awarded the multicomponent reactions
Eastern Kentucky Universi- Fredrick N. Andrews Fel- and total synthesis. He plans
ty. He taught at Lehman lowship from 2007–2009 to defend his thesis work in
College (spring 2007). In followed by a Purdue Re- fall 2012.
fall 2007, he began his grad- search Foundation Fellow-
uate studies at Purdue Uni- ship at Purdue University
Daniel R. Nicponski was York. He is presently study- metric carbon–carbon bond
born in 1984 in Medina, ing for his Ph.D. degree in forming reactions, and on
New York (USA). He re- organic chemistry at Purdue the synthesis of reaction-
ceived his B.S. in chemistry University. His research tailored, phosphine-based
in 2006 from the University work has focused on the de- ligands.
at Buffalo in Buffalo, New velopment of novel, asym-
Chad Keyes was born in Upon completion of his ed the Ross Fellowship in
West Lafayette, Indiana B.S., he moved to Purdue 2008 at Purdue University.
(USA). He received his BS University in the spring of Currently, his thesis work is
in chemistry from Ball State 2010 to further pursue his focused on asymmetric ca-
University. Chad was an in- graduate studies in organic talysis and synthesis of nat-
tern during the summer of chemistry with Professor ural products.
2008 at Dow Agrosciences. Arun Ghosh. He was award-
Synthesis 2012, 44, 3579–3589
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Diastereoselective Synthesis of Substituted Tetrahydropyrans
3581
Table 2 Earlier Work by Hosomi et al. with Substituted Alkenols12
R1
R2
OH
R3
R1
R2
O
R4
PtCl2 (0.5 mol%)
AgOTf (1 mol%)
O
+
PhMe, 100 °C
R4
R3
Entry
Alkenol
R1
R2
R3
Aldehyde
R4
Product
Yield (%) dr
1
2
3
4
5
6
7
8
9
16
16
16
20
20
20
24
24
24
Me
Me
Me
H
H
H
2
8
Ph
17
18
19
21
22
23
25
26
27
85
90
84
82
84
80
56
68
65
19:1
16:1
24:1
4:1
H
H
4-NCC6H4
(CH2)6Me
Ph
H
H
12
2
Me
Me
Me
H
H
H
H
8
4-NCC6H4
(CH2)6Me
Ph
20:1
4:1
H
H
12
2
H
Me
Me
Me
20:1
20:1
19:1
H
H
8
4-NCC6H4
(CH2)6Me
H
H
12
and an appropriate aldehyde in the presence of indium(III) ously reported as a synthetic method for the synthesis of
triflate afforded substituted tetrahydropyrans.13 It was tetrahydropyrans and tetrahydrofurans.15
proposed that the reaction proceeded through a (3,5)
oxonium-ene-type cyclization. However, there is evi-
As shown in Scheme 3, reaction of 5-methylhex-5-en-1-ol
(1) with benzaldehyde (2) utilizing the same platinum(II)
chloride and silver(I) triflate catalyst at room temperature
afforded acetal 35 exclusively albeit in low yield (14%).
dence that the reaction proceeds in a stepwise manner via
an intermediate carbocation.14
It was found that reaction of this acetal 35 under the typi-
cal reaction conditions with an elevated temperature gave
the expected cyclized product 3.
Table 3 Earlier Work by Loh et al.13
O
R
OH
In(OTf)3
(10 mol%)
O
+
CH2Cl2, 0 °C
R
29
PtCl2
(0.5 mol%)
AgOTf
PtCl2
(0.5 mol%)
AgOTf
(1 mol%)
Entry
Aldehyde R
Product Yield (%) dr
Ph
O
HO
O
Ph
(1 mol%)
1
2
3
4
2
Ph
17
18
31
33
77
86
89
87
12:1
13:1
9:1
O
1
+
PhMe, 23 °C
PhMe, 60 °C
35
8
4-NCC6H4
3
Ph
O
~60%
14% isolated
2
30
32
(E)-CH=CHPh
(CH2)7Me
Scheme 3 Reaction involving an acetal12
20:1
While this reaction did proceed well for electron-poor ar-
omatic or aliphatic aldehydes, improvement was needed
both in reaction temperature and substrate scope. Also,
platinum(II) was implicated in the olefin migration pro-
cess. In light of this precedence, we planned to explore
this transformation with relatively inexpensive metal–
ligand complexes. Towards this objective, we examined a
variety of Lewis acids and Lewis acid–ligand complexes
to catalyze these reactions. For initial studies, we utilized
5-methylhex-5-en-1-ol (1) with benzyloxyacetaldehyde
(47) and bisphosphine ligands shown in Figure 1. First,
we examined various metal triflates typically used for
Prins-type cyclizations16 at 100 °C. This led to the identi-
fication of copper(II) triflate as the best ligand-free Lewis
acid. However, copper(II) triflate by itself turned out to be
Further studies on the olefin isomerization from 1 and 28
without the presence of an aldehyde were carried out. As
shown in Scheme 2, the reaction of 5-methylhex-5-en-1-
ol (1) in the presence of platinum(II) chloride/silver(I) tri-
flate catalytic system provided a cyclized product 2,2-di-
methyltetrahydro-2H-pyran (34). It was found that 34 was
often a byproduct of the reaction, lowering the yield of the
desired tetrahydropyran. In fact, this reaction was previ-
OH
O
PtCl2 (0.25 mol%)
AgOTf (1 mol%)
PhMe, 100 °C
1
34
Scheme 2 Side product found by Hosomi et al.12
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3579–3589

3582
A. K. Ghosh et al.
FEATURE ARTICLE
unsatisfactory at lower temperatures. Subsequently, we L1 and L2 gave pyran 48 with good yield and excellent
examined copper(II) triflate–bisphosphine complex cata- diastereoselectivity (>20:1). Similarly, while tosyloxy-
lyzed reactions and found that 1,2-bis(diphenylphosphi- acetaldehyde 49 also afforded good yield of 50, the diaste-
no)ethylene (L1) and 1,2-bis(diphenylphosphino)benzene reomeric ratio was reduced with L1 (dr 16:1) and L2 (dr
(L2) were effective ligands at 40 °C.11a Further explora- 13:1, entries 25–28).
tion led to the development of 1-(diphenylphosphino)-2-
Table 4 Copper(II) Triflate–L1–L3 Catalyzed Reactions with Alde-
hydes
[(diphenylphosphino)methyl]benzene (L3) which al-
lowed the reaction to proceed at room temperature.11b Re-
actions with benzaldehyde (2) and electron-poor aromatic
OH
O
R
aldehydes gave good yields and excellent diastereoselec-
tivity with ligands L1 and L2, however electron-rich aro-
matic aldehydes resulted in much lower yields. This
prompted us to explore the development of the phosphine
ligand L3 with a varied bite angle that also possesses a σ-
donor ability through an electron-neutral triarylphos-
phine.17
O
Cu(OTf)2-L
CH2Cl2
+
R
1
trans
Entry Aldehyde
R
Product Liganda Yield dr
(%)
L1
1
2
2
6
Ph
3
7
92
52
>20:1
>20:1
L2
3
4
5
4-O2NC6H4
4-MeOC6H4
2-MeOC6H4
L1
L2
L3
80
62
63
>20:1
>20:1
11:1
PPh2
Ph2P
PPh2
Ph2P
PPh2
PPh2
L1
L2
L3
6
7
8
10
36
38
30
11
37
L1
L2
L3
42
20
69
>20:1
>20:1
>20:1
Figure 1 Ligands found to be effective with copper(II) triflate
9
10
11
L1
L2
L3
22
27
34
>20:1
>20:1
>20:1
As shown in Table 4, the use of benzaldehyde (2) and 5-
methylhex-5-en-1-ol (1) provided an excellent yield of
trans-tetrahydropyran 3 (92% with L1) and high diastereo-
selectivity. While the copper(II) triflate–L3-catalyzed
reaction with electron-poor 4-nitrobenzaldehyde (6)
showed similar results as those with ligand L2, the reac-
tion yield was significantly better with ligand L1 (entries
3–5). As can be seen, the reaction of 1 with electron-rich
p-anisaldehyde (10) in the presence of copper(II) triflate–
L3 complex proceeded at 23 °C to provide 11 in 69%
yield with excellent diastereoselectivity (dr >20:1); the
corresponding reactions with ligands L1 and L2 were less
satisfactory and were very slow at room temperature.
These reactions were all carried out at 40 °C for two hours
(entries 6–8). Reaction of electron-rich o-anisaldehyde
(36) with copper(II) triflate–L3 complex provided tetra-
hydropyran 37 in 34% yield at 23 °C for 24 hours. The
corresponding reaction with L1 and L2 provided lower
yields of 37 (entries 9–11). Reaction of piperonal (38) us-
ing copper(II) triflate–L3 complex provided tetrahydro-
pyran 39 in 46% yield and the corresponding reaction
using L1 or L2 ligands afforded 39 in lower yields (entries
12–14). The copper(II) triflate–L3 catalyzed reaction with
trans-cinnamaldehyde (30) proceeded with improved
yield and excellent diastereoselectivitity, providing tetra-
hydropyran 40 in 74% yield and dr >20:1. In the case of
anthracene-9-carbaldehyde (41), good yield and good di-
astereoselectivity were observed with L1 and L2. Thio-
phene-2-carbaldehyde (43) is also a suitable substrate for
this reaction, providing excellent yields and diastereose-
lectivities (entries 20, 21). The reaction with isovaleralde-
hyde (45) utilizing L3 also provided improved yields over
L1 and L2 with comparable diastereoselectivity (entries
22–24). Reactions of benzyloxyacetaldehyde (47) with
12
13
14
3,4-(OCH2O)C6H3 39
L1
L2
L3
36
29
46
>20:1
>20:1
>20:1
15
16
17
(E)-CH=CHPh
40
L1
L2
L3
59
53
74
>20:1
>20:1
>20:1
L1
L2
L1
L2
18
19
41
43
45
9-anthryl
2-thienyl
i-Bu
42
44
46
59
50
16:1
24:1
20
21
84
82
>20:1
>20:1
22
23
24
L1
L2
L3
59
62
70
>20:1
>20:1
16:1
L1
L2
L1
L2
25
26
47
49
CH2OBn
CH2OTs
48
50
67
57
>20:1
>20:1
27
28
67
67
16:1
13:1
a Reaction temperature: 40 °C for L1 and L2, 23 °C for L3.
We then examined reactions with 1-substituted 5-methyl-
hex-5-en-1-ols. As shown in Table 5, substituted alkenols
provided the expected 2,3,6-trisubstituted tetrahydropy-
rans, however product yields were lower. Reactions with
trans-cinnamaldehyde (30) utilizing either copper(II) tri-
flate–L1 or copper(II) triflate–L3 resulted in good yields
and excellent diastereoselectivity. Reaction of methyl-
substituted alkenol 16 with trans-cinnamaldehyde (30)
catalyzed by copper(II) triflate–L1 led to the desired tet-
rahydropyran 31 in 64% yield and excellent diastereose-
Synthesis 2012, 44, 3579–3589
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Diastereoselective Synthesis of Substituted Tetrahydropyrans
3583
Table 5 Reactions with Substituted Alkenols
R1
OH
Cu(OTf)2 (15 mol%) R1
ligand (15 mol%)
O
R2
O
+
CH2Cl2, 40 °C for L1
and 23 °C for L3
R2
Entry
Alkenol
R1
Aldehyde
R2
Ligand
Product
Yield (%)
dr
19:1
1
2
16
51
53
53
55
57
59
16
51
55
57
Me
30
30
30
30
30
30
30
10
10
10
10
(E)-CH=CHPh
(E)-CH=CHPh
(E)-CH=CHPh
(E)-CH=CHPh
(E)-CH=CHPh
(E)-CH=CHPh
(E)-CH=CHPh
4-MeOC6H4
L1
L3
L1
L3
L3
L3
L3
L3
L3
L3
L3
31
52
54
54
56
58
60
61
62
63
64
64
56
28
48
34
34
48
56
59
46
61
i-Pr
t-Bu
t-Bu
allyl
Bn
>20:1
13:1
3
4
>20:1
18:1
5
6
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
7
Ph
8
Me
9
i-Pr
allyl
Bn
4-MeOC6H4
10
11
4-MeOC6H4
4-MeOC6H4
lectivity [19:1 dr (1H NMR), entry 1]. The use of the tertiary carbocation 68, followed by elimination. The for-
bulkier isopropyl-substituted alkenol 51 catalyzed by cop- mation of eight-membered ring was observed as a minor
per(II) triflate–L3 gave the desired trisubstituted tetrahy- product for reactions with benzyloxyacetaldehyde (47) or
dropyran 52 with good yield and excellent tosyloxyacetaldehyde (49) with all alkenol substrates
diastereoselectivity (entry 2). The copper(II) triflate–L3 shown in Table 5. Further studies on this interesting ring
catalyzed reaction between tert-butyl-substituted alkenol formation are currently being explored.
53 with trans-cinnamaldehyde (30) was a significant im-
provement over the similar copper(II) triflate–L1 cata-
OH
lyzed system (48% vs 28% yield, entries 3 and 4). Phenyl-
OBn
substituted alkenol 59 also reacted with trans-cinnamal-
O
O
OBn
dehyde (30) to give the tetrahydropyran 60 in moderate
yield (entry 7). While both allyl 55 and benzyl 57 substi-
tutions were tolerated, their reactions with trans-cinnam-
aldehyde (30) proceeded with slightly lower yields
(entries 5, 6). Reaction of the methyl-substituted alkenol
16 with p-anisaldehyde (10) maintained the high yield and
diastereoselectivity previously observed with an unsubsti-
tuted alkenol. Use of isopropyl-substituted alkenol 51
with p-anisaldehyde (10) catalyzed by copper(II) triflate–
L3 led to the desired product 62 in 59% yield with excel-
lent diastereoselectivity (entry 9). Unlike with trans-
cinnamaldehyde, reactions with allyl- 55 and benzyl-sub-
stituted alkenols 57 with p-anisaldehyde (10) maintained
good yield and diastereoselectivity (entries 10, 11).
16
Cu(OTf)2-L1
+
O
+
CH2Cl2
OBn
65
55%
66
47
11%
H
H
O
O
OBn
O
Bn
O
O
66
Bn
68
67
Scheme 4 Formation of an oxocin byproduct
Reaction of methyl-substituted alkenol 16 with benzyl-
oxyacetaldehyde (47) utilizing reaction conditions with
either L1 or L3 ligand and copper(II) triflate led to a mix-
ture of expected tetrahydropyran 65 along with a small
amount of the eight-member cyclic ether 66 (3,4,7,8-tetra-
hydro-2H-oxocin) (Scheme 4). Presumably, this was
formed by a direct nucleophilic attack by the olefin onto
the oxocarbenium ion 67 leading to the oxygen-stabilized
As shown in Table 6, reactions with 2,5-dimethylhex-5-
en-1-ol (20) and 3,5-dimethylhex-5-en-1-ol (24) with our
standard conditions using copper(II) triflate and L3 result-
ed in lower yields. The reaction of methyl alkenol 20 and
p-anisaldehyde (10) provided the desired trisubstituted
tetrahydropyran 69 in 49% yield, but with lower diaste-
reoselectivity (methyl diastereomer 6:1). Similar results
were obtained by Hosomi et al.12 Similar results were also
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3579–3589

3584
A. K. Ghosh et al.
FEATURE ARTICLE
Table 6 Reactions with Dimethylhex-5-en-1-ols
OH
R3
Cu(OTf)2 (15 mol%)
O
O
L3 (15 mol%)
R1
+
R3
R1
CH2Cl2
R2
R2
Entry
Alkenol
R1
R2
Aldehyde
R3
Product
Yield (%)
dr
6:1
1
2
3
4
5
20
20
20
24
24
Me
Me
Me
H
H
10
30
6
4-MeOC6H4
(E)-CH=CHPh
4-O2NC6H4
69
70
71
72
73
49
43
29
12
13
H
4:1
6:1
H
Me
Me
10
30
4-MeOC6H4
(E)-CH=CHPh
20:1
20:1
H
observed when trans-cinnamaldehyde (30) was used to oxocarbenium ion 74.19 Subsequent olefin migration fol-
give tetrahydropyran 70. Again, there was a drop in yield lowed by cyclization may proceed through either favored
when methyl alkenol 20 was reacted with 4-nitrobenzal- transition state 76 or disfavored transition state 75. Proton
dehyde (6) as previously shown in Table 4. When 3,5-di- abstraction β to the carbocation would give rise to trans-
methylhex-5-en-1-ol (24) was used as the substrate, the 2,3- and cis-2,3-tetrahydropyrans 78 and 77, respective-
drop in reaction yield was even more dramatic. Reaction ly.20,21 The transition state 76 is favored due to the lack of
with either p-anisaldehyde (10) or trans-cinnamaldehyde developing pseudo-1,3-diaxial interactions, as is seen in
(30) resulted in formation of tetrahydropyrans 72 and 73, 75. Consistent with the primary alkenol cyclizations, the
respectively, in less than 20% yield. In all of these reac- secondary alkenol cyclization also provided a 2,3,6-
tions, along with formation of the desired tetrahydropy- trans,trans-tetrahydropyran 78 as the major isomer. Ste-
rans, cyclization of the alkenol also resulted in substituted reochemistry of the trisubstituted tetrahydropyran prod-
2,2-dimethyltetrahydropyran as shown in Scheme 2. Un- ucts shown in Table 6 can similarly be explained via the
reacted aldehyde was also recovered. Reaction yield same Zimmerman–Traxler transition-state model. This
based on recovered aldehyde (limiting reagent) is typical- also accounts for the lower diastereoselectivity in reac-
ly >85%.
tions with 2,5-dimethylhex-5-en-1-ol (20).
The stereochemical outcome of the olefin migration and Interestingly, the addition of water or the attempted elim-
Prins cyclization reactions which lead to trans-2,3-disub- ination of water (CaCl2, MgSO4, and 4 Å MS) resulted in
stituted tetrahydropyran derivatives can be rationalized the cessation of this reaction.22 However, the reaction did
based upon the Zimmerman–Traxler18 transition-state proceed once a catalytic amount of triflic acid was added.
models (Scheme 5). The copper(II) triflate based Lewis Thus, it appears that a protic acid is possibly required for
acid catalyzed reaction could lead to the formation of an the olefin rearrangement step.23
Stereochemical models for reactions of 2,5-dimethylhex-
5-en-1-ol (20) and 3,5-dimethylhex-5-en-1-ol (24) with
R1
OH
R1
O
R2
Cu(L)(OTf)2
– OH
various aldehydes are shown in Scheme 6. As can be seen,
for reactions with 2,5-dimethylhex-5-en-1-ol (20), the
major product 83 would form through transition state 81,
which shows all equatorial substituents. The minor diaste-
reomer 82 would form through transition state 80, which
shows unfavorable 1,3-diaxial interaction between sub-
stituents. Similarly, for reactions with 3,5-dimethylhex-5-
en-1-ol (24), transition state 86 would be favored over 85,
providing product 88 as the major diastereomer.
O
+
R2
74
δ+
H
R2
R2
δ+
H
δ+
H
O
O
δ+
R1
H
R1
H
H
H
76 favored
75 disfavored
In an effort to further gain insight, reaction of 5-methyl-
hex-5-en-1-ol (1) with salicylaldehyde was explored. As
shown in Scheme 7, under standard conditions utilizing
the copper(II) triflate–L2 at 40 °C gave bicyclic product
R1
O
R2
R1
O
R2
1
91 in 55% yield as a single diastereomer (by H NMR).
Presumably, the product 91 resulted from the nucleophilic
attack of salicylaldehyde phenol to the tertiary carboca-
tion intermediate formed by olefin migration. The forma-
77
78
Scheme 5 Zimmerman–Traxler transition states
Synthesis 2012, 44, 3579–3589
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Diastereoselective Synthesis of Substituted Tetrahydropyrans
3585
separable diastereomers 50a (trans-major) and 50b (cis-
minor). The stereochemical assignment of these com-
pounds was carried out by 1H NMR NOESY experiments
(Figure 2). The observed NOESY between Ha–Hd, Hb–Hc,
Hc–Hf, and Hd–He for compound 50a is consistent with the
assigned trans stereochemistry. Similarly, the observed
NOESY between Hb–Hc, Hc–Hd, Hc–Hf, and Hd–Hf sup-
ported the assigned cis stereochemistry for compound
50b.
OH
O
R2
Cu(L)(OTf)2
– OH
O
R1
R1
R2
+
79
H
H
δ+
δ+
R2
O
R2
O
R1
R1
H
δ+
H
H
H
δ+
81 favored
80 disfavored
He
He
Hd
Hf
R2
O
O
R2
Ha
Ha
O
O
OTs
OTs
R1
R1
Hd
Hb
Hb
Hf
83
82
Hc
Hc
OH
O
R2
trans-50a major
cis-50b minor
Cu(L)(OTf)2
– OH
O
Figure 2 NOE of tetrahydropyran 50
R2
+
R1
R1
H
84
Rychnovski and co-workers have shown that the conden-
sation of alcohols with aldehydes in attempted 6-(2,5)-
Prins reactions undergoes partial or complete racemiza-
tion via an oxonia-Cope process.25 To examine whether
our catalytic system can undergo such stereoisomeriza-
tion or not, we have carried out olefin migration and Prins
cyclization using enantioenriched alcohol 92. This was
prepared by Corey–Bakshi–Shibata reduction26 of the cor-
responding ketone in 89% ee. As shown in Scheme 8, re-
action of alcohol 92 with benzyloxyacetaldehyde (47)
provided 93, with good diastereoselectively (dr >20:1)
and 59% yield. The trans-isomer 93 was obtained in 89%
ee, which indicated that the cyclization resulted in no loss
of optical activity.11a This indicates that the present cycli-
zation pathway does not involve a [3,3]-sigmatropic rear-
rangement.
δ+
R2
R2
δ+
δ+
H
O
O
H
R1
δ+
R1
H
H
H
86 favored
85 disfavored
R2
O
R2
O
R1
R1
87
88
Scheme 6 Stereochemical models for alkenols 20 and 24
OH
H
H
O
OH
O
Cu(OTf)2-L2
+
OH
CH2Cl2
1
89
O
OH
OBn
+
90
92
47
H
89% ee
O
H
Cu(OTf)2-L1
(15 mol%)
O
91
Scheme 7 Reaction of alkenol 1 with salicylaldehyde
O
O
OBn
OBn
+
tion of tricyclic product 91 was previously observed by
Inoue and co-workers.24
trans-93
cis-93
89% ee
As shown, the trans-isomer was the major product and of-
ten the only isomer observable by NMR analysis. The
reaction of 5-methylhex-5-en-1-ol (1) with tosyloxyacet-
aldehyde (49) was found to provide chromatographically
59% yield (>20:1 dr)
Scheme 8 Experiment with optically enriched alkenol
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3579–3589

3586
A. K. Ghosh et al.
FEATURE ARTICLE
pletion the reaction was diluted with CH2Cl2 (10 mL) and washed
with aq NaHCO3 (10 mL) and brine (10 mL). The organic layer was
dried (Na2SO4) and concentrated. The crude product was purified
by column chromatography (10% EtOAc–hexanes) to provide tet-
rahydropyran 69 (76 mg, 49%); dr ~7:1 (1H NMR).
1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 8.6 Hz, 2 H), 6.83 (d,
J = 8.8 Hz, 2 H), 4.62 (d, J = 10.2 Hz, 2 H), 4.07 (d, J = 10.0 Hz, 1
H), 3.99 (ddd, J = 11.1, 4.3, 2.4 Hz, 1 H), 3.78 (s, 3 H), 3.16 (t, J =
11.0 Hz, 1 H), 2.63–2.55 (m, ~0.14 H, methyl diastereomer), 2.38
(ddd, J = 12.0, 10.0, 3.3 Hz, 1 H), 1.91 (m, 2 H), 1.45 (s, 3 H), 1.35
(q, J = 12.2 Hz, 1 H), 1.26 (d, J = 7.0 Hz, ~0.42 H methyl diastereo-
mer), 0.87 (d, J = 6.4 Hz, 3 H).
In conclusion, we have developed a mild copper(II) tri-
flate–bisphosphine-catalyzed reaction involving an ap-
propriate alkenol and an aldehyde to provide a variety of
substituted tetrahydropyrans. Both electron-rich and elec-
tron-deficient aromatic aldehydes were tolerated under
our reaction conditions. The reaction proceeded via a tan-
dem olefin migration and Prins cyclization to provide tet-
rahydropyran derivatives in good to excellent yields and
excellent trans diastereoselectivity. This copper(II) tri-
flate and bisphosphine ligand combination has not been
previously employed in such synthesis of substituted tet-
rahydropyrans. Mechanistic explorations and further ap-
plications are in progress in our laboratory.
13C NMR (100 MHz, CDCl3): δ = 158.93, 146.20, 133.18, 128.39
(2 C), 113.35 (2 C), 111.82, 83.44, 74.99, 55.07, 53.33, 50.30,
39.12, 31.18, 21.28, 17.00.
MS (EI): m/z = 121, 161, 246 [M+].
Chemicals and reagents were purchased from commercial suppliers
and used without further purification. L3 was prepared as report-
ed.11b Anhydrous CH2Cl2 was distilled from CaH2. All other sol-
vents were reagent grade. All moisture-sensitive reactions were
carried out in oven-dried glassware under argon. All new com-
MS (CI): m/z = 121, 139, 247 [M + H].
trans-3-Isopropenyl-2-(2-methoxyphenyl)tetrahydro-2H-py-
ran (37)
Following the typical procedure using 5-methylhex-5-en-1-ol (1;
143 mg, 1.25 mmol) and 2-anisaldehyde (36; 136 mg, 1 mmol) with
L3 gave 37 (79 mg, 34%).
1H NMR (500 MHz, CDCl3): δ = 7.42 (dd, J = 7.5, 1.8 Hz, 1 H),
7.25 (td, J = 8.3, 1.8 Hz, 1 H), 6.98 (t, J = 7.4 Hz, 1 H), 6.86 (d, J =
8.2 Hz, 1 H), 4.84 (d, J = 10.2 Hz, 1 H), 4.54 (d, J = 7.9 Hz, 2 H),
4.16–4.08 (m, 1 H), 3.83 (s, 3 H), 3.65 (td, J = 11.8, 2.2 Hz, 1 H),
2.52 (td, J = 10.7, 3.5 Hz, 1 H), 1.97–1.67 (m, 4 H), 1.59 (s, 3 H).
pounds were isolated as colorless oils except 71. 1H NMR and 13
C
NMR spectra were recorded on a Bruker Avance ARX-400, a Bruker
DRX-500, or a Bruker Avance III-800 spectrometer. Chemical
shifts are given in ppm and are referenced against the diluting sol-
1
vent. For chloroform-d: 13C triplet = 77.00 and H singlet = 7.26
1
ppm. For methanol-d4: 13C septuplet = 49.05 and H quintuplet =
3.31 ppm.
13C (125 MHz, CDCl3): δ = 156.72, 146.22, 129.58, 128.51, 127.89,
120.66, 111.64, 110.50, 68.97, 55.33, 50.22, 30.31, 26.43, 20.42.
MS (EI): m/z = 124, 232 [M+].
(2S*,3S*,6R*)-3-Isopropenyl-6-methyl-2-[(E)-styryl]tetra-
hydro-2H-pyran (31); Typical Procedure Using Ligands L1 and
L2
To a suspension of Cu(OTf)2 (33 mg, 0.092 mmol, 15 mol%) in
CH2Cl2 (4 mL) was added bis(diphenylphosphino)ethylene (L1; 36
mg, 0.092 mmol, 15 mol%) under an argon atmosphere. This was
stirred at r.t. for 1 h to form completely the L1–Cu(OTf)2 complex.
To this was added a soln of 6-methylhept-6-en-2-ol (16; 98 mg,
0.766 mmol, 1.25 equiv) and trans-cinnamaldehyde (30; 77 μL,
0.613 mmol, 1 equiv) in CH2Cl2 (4 mL) via cannula. The flask was
fitted with a reflux condenser and heated to 40 °C for 2 h. Upon
cooling the reaction was diluted with CH2Cl2 (10 mL) and washed
with aq NaHCO3 (10 mL) and brine (10 mL). The organic layer was
dried (Na2SO4) and concentrated. The crude product was purified
by column chromatography (10% EtOAc–hexanes) to provide tet-
rahydropyran 31 (95 mg, 64%).
1H NMR (500 MHz, CDCl3): δ = 7.42–7.38 (m, 2 H), 7.35–7.30 (m,
2 H), 7.27–7.21 (m, 1 H), 6.64 (d, J = 15.9 Hz, 1 H), 6.21 (dd, J =
16.0, 6.7 Hz, 1 H), 4.80 (s, 2 H), 3.96 (ddd, J = 10.0, 6.7, 1.2 Hz, 1
H), 3.62 (ddd, J = 11.4, 6.3, 2.0 Hz, 1 H), 2.11 (ddd, J = 11.8, 10.1,
3.8 Hz, 1 H), 1.95–1.81 (m, 1 H), 1.79–1.65 (m, 5 H), 1.50–1.36 (m,
1 H), 1.29 (d, J = 6.1 Hz, 3 H).
MS (CI): m/z = 125, 233 [M + H].
trans-3-Isopropenyl-2-[3,4-(methylenedioxy)phenyl]tetra-
hydro-2H-pyran (39)
Following the typical procedure using 5-methylhex-5-en-1-ol (1;
143 mg, 1.25 mmol) and piperonal (38; 150 mg, 1 mmol) with L3
gave 39 (111 mg, 46%).
1H NMR (500 MHz, CDCl3): δ = 6.87 (s, 1 H), 6.84–6.56 (m, 2 H),
5.94 (d, J = 3.4 Hz, 2 H), 4.67 (d, J = 15.2 Hz, 2 H), 4.12 (d, J = 9.9
Hz, 2 H), 3.60 (td, J = 11.8, 2.1 Hz, 1 H), 2.32 (ddd, J = 11.6, 9.6,
3.7 Hz, 1 H), 2.01–1.62 (m, 4 H), 1.51 (s, 3 H).
13C (125 MHz, CDCl3): δ = 147.37, 146.88, 146.27, 135.24, 120.96,
112.05, 107.76, 107.62, 100.83, 84.18, 68.85, 50.56, 30.25, 26.29,
21.42.
MS (EI): m/z = 124, 246 [M+].
MS (CI): m/z = 125, 247 [M + H].
(2S*,3S*,6S*)-3-Isopropenyl-6-isopropyl-2-[(E)-styryl]tetra-
hydro-2H-pyran (52)
Following the typical procedure using 2,7-dimethyloct-7-en-3-ol
(51; 112 mg, 0.725 mmol, 1.25 equiv) and trans-cinnamaldehyde
(30; 73 μL, 0.58 mmol, 1 equiv) with L3 gave 52 (88 mg, 56%).
13C NMR (125 MHz, CDCl3): δ = 146.29, 137.14, 131.24, 129.07,
128.35, 127.33, 126.54, 112.13, 80.94, 77.25, 77.00, 76.93, 76.75,
73.67, 49.71, 33.37, 29.98, 22.05, 20.88.
MS (EI): m/z = 131, 227, 242 [M+].
1H NMR (500 MHz, CDCl3): δ = 7.41 (dd, J = 7.7, 1.6 Hz, 2 H),
7.33 (t, J = 7.6 Hz, 2 H), 7.24 (t, J = 7.3 Hz, 1 H), 6.66 (d, J = 15.9
Hz, 1 H), 6.25 (dd, J = 15.9, 5.9 Hz, 1 H), 4.81 (s, 2 H), 3.94 (ddd,
J = 10.1, 5.9, 1.5 Hz, 1 H), 3.16 (ddd, J = 11.2, 6.5, 2.1 Hz, 1 H),
2.08 (ddd, J = 12.3, 10.1, 3.8 Hz, 1 H), 1.89 (dd, J = 13.2, 3.5 Hz, 1
H), 1.84–1.76 (m, 2 H), 1.74 (s, 3 H), 1.68 (dd, J = 12.5, 3.9 Hz, 1
H), 1.38 (tdd, J = 12.8, 11.1, 3.9 Hz, 1 H), 1.04 (d, J = 6.8 Hz, 3 H),
0.97 (d, J = 6.9 Hz, 3 H).
MS (CI): m/z = 133, 138, 225, 243 [M + H].
(2S*,3R*,5R*)-3-Isopropenyl-2-(4-methoxyphenyl)-5-methyl-
tetrahydro-2H-pyran (69); Typical Procedure for Ligand L3
To a suspension of Cu(OTf)2 (34 mg, 0.094 mmol, 15 mol%) in
CH2Cl2 (5 mL) was added 1-(diphenylphosphino)-2-[(diphe-
nylphosphino)methyl]benzene (L3; 43 mg, 0.094 mmol, 15 mol%)
under an argon atmosphere. This was stirred at r.t. for 1 h to form
completely the L3–Cu(OTf)2 complex. To this was added a soln of
2,5-dimethylhex-5-en-1-ol (20; 100 mg, 0.78 mmol, 1.25 equiv)
and p-anisaldehyde (10; 76 μL, 0.62 mmol, 1 equiv) in CH2Cl2 (5
mL) via cannula. The reaction was stirred at r.t. for 18 h. Upon com-
13C NMR (125 MHz, CDCl3): δ = 146.50, 137.39, 130.24, 129.45,
128.38, 127.20, 126.48, 112.02, 82.66, 80.47, 50.16, 33.17, 30.17,
27.93, 20.90, 18.96, 18.38.
Synthesis 2012, 44, 3579–3589
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Diastereoselective Synthesis of Substituted Tetrahydropyrans
3587
(2S*,3S*,6S*)-6-tert-Butyl-3-(prop-1-en-2-yl)-2-styryltetra-
hydro-2H-pyran (54)
Following the typical procedure using 2,2,7-trimethyloct-7-en-3-ol
(53; 113 mg, 0.667 mmol, 1.25 equiv) and trans-cinnamaldehyde
(30; 66 μL, 0.533 mmol, 1 equiv) with L3 gave 54 (72 mg, 48%).
13C NMR (101 MHz, CDCl3): δ = 146.11, 142.97, 137.17, 130.87,
128.93, 128.36, 128.24, 127.29, 126.49, 125.97, 125.88, 112.33,
81.10, 79.57, 49.76, 33.86, 30.37, 20.94.
MS (EI): m/z = 104, 133, 286, 304 [M+].
MS (CI): m/z = 133, 173, 227, 287, 305 [M + H].
1H NMR (400 MHz, CDCl3): δ = 7.43–7.36 (m, 2 H), 7.33–7.29 (t,
J = 8.5, 6.8 Hz, 8 H), 7.23 (m, J = 7.3 Hz, 3 H), 6.68–6.63 (dd, J =
16.0, 1.5 Hz, 1 H), 6.28–6.23 (dd, J = 15.9, 5.2 Hz, 1 H), 4.81 (d,
J = 6.1 Hz, 2 H), 3.95–3.91 (ddd, J = 10.1, 5.2, 1.6 Hz, 1 H), 3.08–
3.04 (dd, J = 11.2, 1.8 Hz, 1 H), 2.04–1.96 (m, 1 H), 1.93–1.83 (m,
1 H), 1.74 (s, 3 H), 1.73–1.62 (m, 2 H), 1.41 (m, 1 H), 0.97 (s, 9 H).
(2R*,3S*,6R*)-3-Isopropenyl-2-(4-methoxyphenyl)-6-methyl-
tetrahydro-2H-pyran (61)
Following the typical procedure using 6-methylhept-6-en-2-ol (16;
54 mg, 0.49 mmol, 1.25 equiv) and p-anisaldehyde (10; 41 μL, 0.34
mmol, 1 equiv) with L3 gave 61 (47 mg, 56%).
13C NMR (101 MHz, CDCl3): δ = 146.55, 137.48, 129.73, 129.28,
128.33, 127.03, 126.36, 111.87, 85.15, 80.08, 50.17, 34.17, 30.38,
26.14, 25.34, 20.90.
1H NMR (500 MHz, CDCl3): δ = 7.27 (d, J = 8.7 Hz, 2 H), 6.86 (d,
J = 8.7 Hz, 2 H), 4.65 (d, J = 13.3 Hz, 2 H), 4.23 (d, J = 10.0 Hz, 1
H), 3.81 (s, 3 H), 3.67 (dtt, J = 12.3, 6.1, 3.1 Hz, 1 H), 2.29 (ddd, J =
11.9, 9.9, 3.8 Hz, 1 H), 1.97–1.88 (m, 1 H), 1.84–1.71 (m, 2 H),
1.52–1.43 (m, 1 H), 1.48 (s, 3 H), 1.27 (d, J = 6.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 158.94, 146.57, 133.78, 128.56,
113.44, 111.82, 83.67, 74.31, 55.17, 50.13, 33.65, 30.50, 22.18,
21.44.
MS (EI): m/z = 96, 133, 154, 269, 284 [M+].
MS (CI): m/z = 133, 267, 285 [M + H].
(2S*,3S*,6S*)-6-Allyl-3-(prop-1-en-2-yl)-2-styryltetrahydro-
2H-pyran (56)
Following the typical procedure using 8-methylnona-1,8-dien-4-ol
(55; 68 mg, 0.44 mmol, 1.25 equiv) and trans-cinnamaldehyde (30;
44 μL, 0.35 mmol, 1 equiv) with L3 gave 56 (32 mg, 34%).
MS (EI): m/z = 136, 246 [M+].
MS (CI): m/z = 139, 247 [M + H].
1H NMR (500 MHz, CDCl3): δ = 7.41 (d, J = 7.3 Hz, 2 H), 7.33 (t,
J = 7.6 Hz, 2 H), 7.25 (t, J = 7.3 Hz, 1 H), 6.66 (d, J = 15.9 Hz, 1
H), 6.23 (dd, J = 15.9, 6.3 Hz, 1 H), 5.93 (ddt, J = 17.1, 10.3, 7.0
Hz, 1 H), 5.21–5.04 (m, 2 H), 4.82 (s, 2 H), 3.97 (ddd, J = 9.9, 6.3,
1.4 Hz, 1 H), 3.52 (dtd, J = 11.1, 6.4, 2.1 Hz, 1 H), 2.53–2.42 (m, 1
H), 2.36–2.25 (m, 1 H), 2.12 (ddd, J = 12.1, 10.2, 3.7 Hz, 1 H),
1.94–1.83 (m, 1 H), 1.83–1.76 (m, 1 H), 1.74 (s, 3 H), 1.69 (td, J =
13.0, 4.1 Hz, 1 H), 1.41 (tdd, J = 12.9, 11.1, 4.0 Hz, 1 H).
(2R*,3S*,6S*)-3-Isopropenyl-6-isopropyl-2-(4-methoxyphe-
nyl)tetrahydro-2H-pyran (62)
Following the typical procedure using 2,7-dimethyloct-7-en-3-ol
(51; 65 mg, 0.419 mmol, 1.25 equiv) and p-anisaldehyde (10; 41
μL, 0.335 mmol, 1 equiv) with L3 gave 62 (54 mg, 59%).
1H NMR (400 MHz, CDCl3): δ = 7.25–7.23 (d, J = 2.0 Hz, 2 H),
6.84–6.82 (d, J = 2.0 Hz, 2 H), 4.64–4.60 (d, J = 17.3 Hz, 2 H),
4.19–4.16 (d, J = 9.9 Hz, 1 H), 3.79 (s, 3 H), 3.25–3.12 (dd, J = 11.3,
5.8 Hz, 1 H), 2.22–2.16 (t, J = 10.7 Hz, 1 H), 1.95–1.89 (m, 1 H),
1.77–1.70 (m, 4 H), 1.45 (s, 3 H), 0.94 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 158.67, 146.69, 134.23, 128.33,
113.15, 111.61, 83.39, 82.82, 55.05, 50.72, 32.83, 30.43, 27.37,
21.47, 18.69, 17.96.
13C NMR (126 MHz, CDCl3): δ = 146.26, 137.20, 134.95, 130.90,
129.04, 128.38, 127.32, 126.53, 116.69, 112.18, 109.73, 80.77,
77.13, 49.92, 40.81, 30.98, 29.91, 20.89.
MS (EI): m/z = 105, 131, 284 [M+].
MS (CI): m/z = 123, 197, 269 [M + H].
MS (EI): m/z = 137, 274 [M+].
(2S*,3S*,6S*)-6-Benzyl-3-(prop-1-en-2-yl)-2-styryltetrahydro-
2H-pyran (58)
MS (CI): m/z = 137, 167, 275 [M + H].
Following the typical procedure using 6-methyl-1-phenylhept-6-
en-2-ol (57; 100 mg, 0.49 mmol, 1.25 equiv) and trans-cinnamalde-
hyde (30; 49 μL, 0.39 mmol, 1 equiv) with L3 gave 58 (42 mg,
34%).
1H NMR (500 MHz, CDCl3): δ = 7.44 (d, J = 7.5 Hz, 2 H), 7.40–
7.23 (m, 6 H), 6.71 (d, J = 15.9 Hz, 1 H), 6.28 (dd, J = 16.0, 6.0 Hz,
1 H), 4.84 (s, 2 H), 4.01 (dd, J = 9.8, 6.0 Hz, 1 H), 3.71 (dt, J = 10.5,
5.5 Hz, 1 H), 3.13 (dd, J = 13.4, 5.9 Hz, 1 H), 2.79 (dd, J = 13.4, 7.1
Hz, 1 H), 2.16 (ddd, J = 12.1, 10.3, 3.8 Hz, 1 H), 1.92–1.77 (m, 1
H), 1.75 (s, 3 H), 1.68–1.40 (m, 4 H), 1.16 (qd, J = 12.8, 5.0 Hz, 1 H).
(2R*,3S*,6S*)-6-Allyl-2-(4-methoxyphenyl)-3-(prop-1-en-2-
yl)tetrahydro-2H-pyran (63)
Following the typical procedure using 8-methylnona-1,8-dien-4-ol
(55; 100 mg, 0.65 mmol, 1.25 equiv) and p-anisaldehyde (10; 63
μL, 0.52 mmol, 1 equiv) with L3 gave 63 (65 mg, 46%).
1H NMR (400 MHz, CDCl3): δ = 7.26–7.24 (d, J = 8.6 Hz, 2 H),
6.86–6.84 (d, J = 8.6 Hz, 2 H), 5.97–5.85 (m, 1 H), 5.15–4.99 (m, 2
H), 4.65–4.61 (d, J = 14.2 Hz, 2 H), 4.22–4.19 (d, J = 10.4, 3.4 Hz,
1 H), 3.79 (s, 3 H), 3.57–3.52 (m, 1 H), 2.43–2.38 (m, 1 H), 2.31–
2.23 (m, 2 H), 1.92–1.89 (m, 1 H), 1.82–1.70 (m, 2 H), 1.46 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.83, 146.45, 134.93, 133.71,
128.43, 116.53, 113.28, 111.80, 83.58, 77.57, 55.07, 50.32, 40.76,
30.93, 30.27, 21.42.
13C NMR (126 MHz, CDCl3): δ = 146.24, 138.72, 137.27, 130.84,
129.57 (2 C), 129.03, 128.44 (2 C), 128.22 (2 C), 127.36, 126.54 (2
C), 126.16, 112.25, 80.65, 78.55, 71.54, 49.93, 42.96, 30.85, 20.91.
MS (EI): m/z = 91, 117, 131, 188, 303, 318 [M+].
(2R*,3S*,6S*)-6-Benzyl-2-(4-methoxyphenyl)-3-(prop-1-en-2-
yl)tetrahydro-2H-pyran (64)
MS (CI): m/z = 107, 117, 301, 319 [M + H].
Following the typical procedure using 6-methyl-1-phenylhept-6-
en-2-ol (57; 100 mg, 0.49 mmol, 1.25 equiv) and p-anisaldehyde
(10; 47 μL, 0.39 mmol, 1 equiv) with L3 gave 64 (76 mg, 61%).
1H NMR (500 MHz, CDCl3): δ = 7.41–7.18 (m, 7 H), 6.88 (d, J =
8.6 Hz, 2 H), 4.65 (d, J = 21.2 Hz, 2 H), 4.26 (d, J = 10.0 Hz, 1 H),
3.83 (s, 3 H), 3.74 (m, 1 H), 3.07 (dd, J = 13.5, 5.1 Hz, 1 H), 2.76
(dd, J = 13.4, 7.7 Hz, 1 H), 2.34–2.20 (m, 1 H), 1.90 (m, 2 H), 1.83–
1.50 (m, 3 H), 1.47 (s, 3 H).
(2S*,3S*,6S*)-6-Phenyl-3-(prop-1-en-2-yl)-2-styryltetrahydro-
2H-pyran (60)
Following the typical procedure using 5-methyl-1-phenylhex-5-en-
1-ol (59; 138 mg, 0.735 mmol, 1.25 equiv) and trans-cinnamalde-
hyde (30; 74 μL, 0.588 mmol, 1 equiv) with L3 gave 60 (85 mg,
48%).
1H NMR (400 MHz, CDCl3): δ = 7.52–7.20 (m, 10 H), 6.74–6.71
(dd, J = 15.9 Hz, 1 H), 6.34–6.28 (dd, J = 15.9, 6.2 Hz, 1 H), 4.88
(s, 2 H), 4.57–4.54 (dd, J = 11.4, 2.1 Hz, 1 H), 4.17 (dd, J = 9.6, 6.4
Hz, 1 H), 2.29–2.20 (ddd, J = 13.6, 10.0, 3.7 Hz, 1 H), 2.00 (m, 2
H), 1.95–1.84 (m, 1 H), 1.80 (s, 3 H), 1.78–1.66 (m, 1 H).
13C NMR (126 MHz, CDCl3): δ = 158.91, 146.48, 138.67, 133.81,
129.60 (2 C), 128.48 (2 C), 128.13 (2 C), 126.05, 113.35 (2 C),
111.85, 83.70, 78.99, 55.14, 50.41, 42.93, 30.74, 30.27, 21.47.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3579–3589

3588
A. K. Ghosh et al.
FEATURE ARTICLE
MS (EI): m/z = 91, 117, 136, 188, 231, 322 [M+].
MS (CI): m/z = 121, 137, 215, 305, 323 [M + H].
H), 1.90–1.74 (m, 2 H), 1.71 (s, 3 H), 1.29 (q, J = 12.1 Hz, 1 H),
0.86 (d, J = 6.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 145.98, 137.04, 131.06, 128.72,
128.33 (2 C), 127.30, 126.40 (2 C), 112.10, 80.35, 74.33, 50.14,
38.65, 30.98, 20.76, 16.98.
(2R*,3S*,6R*)-2-(Benzyloxymethyl)-3-isopropenyl-6-methyl-
tetrahydro-2H-pyran (65) and 8-(Benzyloxymethyl)-2,6-di-
methyl-3,4,7,8-tetrahydro-2H-oxocin (66)
Following the typical procedure using 6-methylhept-6-en-2-ol (16;
105 mg, 0.82 mmol, 1.25 equiv) and benzyloxyacetaldehyde (47; 92
µL, 0.66 mmol, 1 equiv) with L1 gave 65 (94 mg, 55%) and less-
polar oxocin 66 (19 mg, 11%).
MS (EI): m/z = 68, 95, 112, 131, 227, 242 [M+].
MS (CI): m/z = 139, 243 [M + H].
(2R*,3S*,5S*)-5-Methyl-2-(4-nitrophenyl)-3-(prop-1-en-2-
yl)tetrahydro-2H-pyran (71)
Following the typical procedure using 2,5-dimethylhex-5-en-1-ol
(20; 100 mg, 0.78 mmol, 1.25 equiv) and 4-nitrobenzaldehyde (6;
94 mg, 0.62 mmol, 1 equiv) with L3 gave 71 (48 mg, 29%). Color-
less solid; mp 58–60 °C.
1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 8.6 Hz, 2 H), 7.46 (d,
J = 8.6 Hz, 2 H), 4.65 (s, 1 H), 4.55 (s, 1 H), 4.21 (d, J = 10.0 Hz, 1
H), 4.02 (ddd, J = 11.3, 4.3, 2.4 Hz, 1 H), 3.17 (t, J = 11.0 Hz, 1 H),
2.26 (ddd, J = 12.1, 10.1, 3.2 Hz, 1 H), 1.97–1.88 (m, 2 H), 1.45 (s,
3 H), 1.43–1.30 (m, 1 H), 1.26 (d, J = 6.9 Hz, ~0.5 H, methyl dia-
stereomer), 0.89 (d, J = 6.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 148.44, 147.23, 144.81, 127.95
(2 C), 123.12 (2 C), 112.89, 82.70, 74.74, 51.19, 38.63, 30.98,
21.34, 16.89.
Tetrahydropyran 65
1H NMR (500 MHz, CDCl3): δ = 7.42–7.28 (m, 5 H), 4.79–4.73 (m,
2 H), 4.60 (dd, J = 15.35, 12.35 Hz, 2 H), 3.63–3.56 (m, 2 H), 3.53
(ddd, J = 11.1, 6.2, 2.0 Hz, 1 H), 3.47 (dd, J = 11.1, 6.9 Hz, 1 H),
2.11 (ddd, J = 11.9, 10.0, 3.9 Hz, 1 H), 1.81–1.77 (m, 1 H), 1.69 (s,
3 H), 1.68–1.57 (m, 2 H), 1.42–1.31 (m, 1 H), 1.27 (d, J = 6.2 Hz, 3
H).
13C NMR (126 MHz, CDCl3): δ = 146.61, 138.60, 128.21 (2 C),
127.68 (2 C), 127.36, 111.92, 79.56, 73.73, 73.34, 71.86, 45.66,
33.27, 30.12, 22.05, 20.13.
MS (EI): m/z = 91, 107, 139, 260 [M+].
MS (CI): m/z = 91, 111, 261 [M + H].
Oxocin 66
MS (EI): m/z = 68, 95, 112, 246, 262 [M+].
1H NMR (500 MHz, CDCl3): δ = 7.42–7.29 (m, 5 H), 5.49–5.42 (m,
1 H), 4.62 (q, J = 12.0 Hz, 2 H), 3.62–3.50 (m, 3 H), 3.49–3.40 (m,
1 H), 2.53–2.41 (m, 2 H), 2.00 (dd, J = 13.9, 1.4 Hz, 1 H), 1.98–1.91
(m, 1 H), 1.81 (s, 3 H), 1.70–1.59 (m, 1 H), 1.53 (dddd, J = 13.7,
12.5, 4.8, 3.5 Hz, 1 H), 1.17 (d, J = 6.3 Hz, 3 H).
MS (CI): m/z = 112, 262 [M + H].
(2R*,3S*,4S*)-2-(4-Methoxyphenyl)-4-methyl-3-(prop-1-en-2-
yl)tetrahydro-2H-pyran (72)
Following the typical procedure using 3,5-dimethylhex-5-en-1-ol
(24; 118 mg, 0.918 mmol, 1.25 equiv) and p-anisaldehyde (10; 89
μL, 0.734 mmol, 1 equiv) with L3 gave 72 (22 mg, 12%).
1H NMR (400 MHz, CDCl3): δ = 7.23–7.18 (d, J = 8 Hz, 2 H), 6.83–
6.79 (d, J = 8 Hz, 2 H), 4.66 (s, 1 H), 4.56 (s, 1 H), 4.14–4.04 (m, 2
H), 3.78 (s, 3 H), 3.66–3.57 (td, J = 12.1, 2.3 Hz, 1 H), 1.92–1.89 (t,
J = 10.3 Hz, 1 H), 1.79 (m, 1 H), 1.73–1.59 (m, 2 H), 1.56–1.46 (m,
1 H), 1.43 (s, 3 H), 0.91 (d, J = 6.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.83, 144.00, 133.46, 128.33,
113.90, 113.26, 83.42, 77.14, 68.37, 58.10, 55.07, 34.46, 33.89,
19.81.
13C NMR (125 MHz, CDCl3): δ = 138.55, 135.30, 128.30 (2 C),
127.59 (2 C), 127.47, 124.99, 79.18, 75.52, 74.03, 73.28, 38.11,
36.99, 25.37, 24.27, 22.21.
MS (EI): m/z = 91, 107, 139, 260 [M+].
MS (CI): m/z = 91, 111, 153, 261 [M + H].
(2R*,3S*,5S*)-2-(4-Methoxyphenyl)-5-methyl-3-(prop-1-en-2-
yl)tetrahydro-2H-pyran (69)
Following the typical procedure using 2,5-dimethylhex-5-en-1-ol
(20; 100 mg, 0.78 mmol, 1.25 equiv) and p-anisaldehyde (10; 76
μL, 0.62 mmol, 1 equiv) with L3 gave 69 (76 mg, 49%).
1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 8.6 Hz, 2 H), 6.83 (d,
J = 8.8 Hz, 2 H), 4.62 (d, J = 10.2 Hz, 2 H), 4.07 (d, J = 10.0 Hz, 1
H), 3.99 (ddd, J = 11.1, 4.3, 2.4 Hz, 1 H), 3.78 (s, 3 H), 3.16 (t, J =
11.0 Hz, 1 H), 2.63–2.55 (m, ~0.14 H, methyl diastereomer), 2.38
(ddd, J = 12.0, 10.0, 3.3 Hz, 1 H), 1.91 (m, 2 H), 1.45 (s, 3 H), 1.35
(q, J = 12.2 Hz, 1 H), 1.26 (d, J = 7.0 Hz, ~0.42 H methyl diastereo-
mer), 0.87 (d, J = 6.4 Hz, 3 H); dr ~7:1.
13C NMR (101 MHz, CDCl3): δ = 158.93, 146.20, 133.18, 128.39
(2 C), 113.35 (2 C), 111.82, 83.44, 74.99, 55.07, 53.33, 50.30,
39.12, 31.18, 21.28, 17.00.
MS (EI): m/z = 85, 112, 135, 161, 246 [M+].
MS (CI): m/z = 121, 139, 247 [M + H].
(2S*,3S*,4S*)-4-Methyl-3-(prop-1-en-2-yl)-2-styryltetrahydro-
2H-pyran (73)
Following the typical procedure using 3,5-dimethylhex-5-en-1-ol
(24; 122 mg, 0.950 mmol, 1.25 equiv) and trans-cinnamaldehyde
(30; 95 μL, 0.757 mmol, 1 equiv) with L3 gave 62 (24 mg, 13%).
1H NMR (400 MHz, CDCl3): δ = 7.41–7.19 (m, 5 H), 6.62–6.52 (dd,
J = 15.9 Hz, 1 H), 6.20–6.13 (dd, J = 16.0, 6.3 Hz, 1 H), 4.84–4.78
(d, J = 24.0 Hz, 2 H), 4.10–4.06 (dd, J = 11.4, 4.4 Hz, 1 H), 3.86–
3.81 (m, 1 H), 3.64–3.55 (m, 1 H), 1.76–1.69 (m, 2 H), 1.69–1.59
(m, 5 H), 1.41 (m, 1 H), 0.89 (d, J = 5.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 143.76, 137.11, 130.73, 128.98,
128.33, 127.26, 126.40, 126.17, 80.25, 77.14, 67.87, 57.72, 34.29,
33.10, 19.66.
MS (EI): m/z = 68, 95, 112, 121, 135, 161, 246 [M+].
MS (CI): m/z = 121, 139, 247 [M + H].
(2S*,3S*,5S*)-5-Methyl-3-(prop-1-en-2-yl)-2-styryltetrahydro-
2H-pyran (70)
Following the typical procedure using 2,5-dimethylhex-5-en-1-ol
(20; 100 mg, 0.78 mmol, 1.25 equiv) and trans-cinnamaldehyde
(30; 79 μL, 0.62 mmol, 1 equiv) with L3 gave 70 (65 mg, 43%).
MS (EI): m/z = 67, 82, 112, 131, 227, 242 [M+].
MS (CI): m/z = 139, 225, 243 [M + H].
1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J = 7.2 Hz, 2 H), 7.29 (t,
J = 7.4 Hz, 2 H), 7.21 (t, J = 7.2 Hz, 1 H), 6.62 (d, J = 16.1 Hz, 1
H), 6.18 (dd, J = 16.0, 6.3 Hz, 1 H), 4.79 (d, J = 1.5 Hz, 2 H), 3.98
(ddd, J = 11.2, 4.2, 2.3 Hz, 1 H), 3.82 (ddd, J = 10.3, 6.4, 1.3 Hz, 1
H), 3.11 (t, J = 11.1 Hz, 1 H), 2.17 (ddd, J = 12.3, 10.0, 3.3 Hz, 1
Acknowledgment
Financial support by the National Institutes of Health is gratefully
acknowledged.
Synthesis 2012, 44, 3579–3589
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
References
Diastereoselective Synthesis of Substituted Tetrahydropyrans
3589
(10) Clarke, P. A.; Martin, W. H. C.; Hargreaves, J. M.; Wilson,
C.; Blake, A. J. Org. Biomol. Chem. 2005, 3, 3551.
(11) (a) Ghosh, A. K.; Nicponski, D. R. Org. Lett. 2011, 13,
4328. (b) Ghosh, A. K.; Nicponski, D. R.; Kass, J.
Tetrahedron Lett. 2012, 53, 3699.
(12) Miura, K.; Horiike, M.; Inoue, G.; Ichikawa, J.; Hosomi, A.
Chem. Lett. 2008, 37, 270.
(13) Loh, T.-P.; Hu, Q.-Y.; Tan, K.-T.; Cheng, H.-S. Org. Lett.
2001, 3, 2669.
(14) For examples of Lewis acid catalyzed ene reactions, see:
Snider, B. B.; Rodini, D. J.; Kirk, T. C.; Cordova, R. J. Am.
Chem. Soc. 1982, 104, 555.
(15) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc.
2004, 126, 9536.
(16) Clarke, M. L.; France, M. B. Tetrahedron 2008, 64, 9003.
(17) Tolman, C. A. Chem. Rev. 1977, 77, 313.
(18) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957,
79, 1920.
(1) (a) Reymond, S.; Ferrie, L.; Guerinot, A.; Capdevielle, P.;
Cossy, J. Pure Appl. Chem. 2008, 80, 1683. (b) Sanz, M. A.;
Voigt, T.; Waldmann, H. Adv. Synth. Catal. 2006, 348, 1511.
(c) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301.
(d) Nakata, T. Chem. Rev. 2005, 105, 4314. (e) Gademann,
K.; Portmann, C. Curr. Org. Chem. 2008, 12, 326.
(2) (a) Carrillo, R.; Leon, L. G.; Martın, T.; Martın, V. S.;
Padron, J. M. Bioorg. Med. Chem. Lett. 2006, 16, 6135.
(b) Singh, P.; Bhardwaj, A. J. Med. Chem. 2010, 53, 3707.
(c) Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthesis 2001,
2203. (d) List, B.; Castello, C. Synlett 2001, 1687.
(3) (a) Ghosh, A. K.; Anderson, D. D. Future Med. Chem. 2011,
3, 1181. (b) Wender, P. A.; Baryza, J. L.; Brenner, S. E.;
Clarke, M. O.; Gamber, C. G.; Horan, J. C.; Jessop, T. C.;
Kan, C.; Pattabiraman, K.; Williams, T. J. Pure Appl. Chem.
2003, 75, 143.
(4) (a) Ghosh, A. K.; Chapsal, B. D.; Baldridge, A.; Steffey, M.
P.; Walters, D. E.; Koh, Y.; Amano, M.; Mitsuya, H. J. Med.
Chem. 2011, 54, 622. (b) Ide, K.; Aoki, M.; Amano, M.;
Koh, Y.; Yedidi, R. S.; Das, D.; Leschenko, S.; Chapsal, B.;
Ghosh, A. K.; Mitsuya, H. Antimicrob. Agents Chemother.
2011, 55, 1717.
(5) Tietze, L. F.; Kettschau, G.; Gewer, J. A.; Schuffenhauer, A.
Curr. Org. Chem. 1998, 2, 19.
(6) Pellissier, H. Tetrahedron 2009, 65, 2839.
(7) Yadav, J. S.; Purnima, K. V.; Reddy, B. V. S.; Nagaih, K.;
Ghamdi, A. K. Tetrahedron Lett. 2011, 52, 6709.
(8) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2008, 1218.
(9) Smith, A. B. III; Fox, R. J.; Razler, T. M. Acc. Chem. Res.
2008, 41, 675.
(19) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021.
(20) Kocovsky, P.; Ahmed, G.; Srogl, J.; Malkov, A. V.; Steele,
J. J. Org. Chem. 1999, 64, 2765.
(21) Gesinski, M. R.; Van Orden, L. J.; Rychnovsky, S. D. Synlett
2008, 363.
(22) Tadpetch, K.; Rychnovsky, S. D. Org. Lett. 2008, 10, 4839.
(23) Cloninger, M. J.; Overman, L. E. J. Am. Chem. Soc. 1999,
121, 1092.
(24) Inoue, S.; Asami, M.; Honda, K.; Miyazaki, H. Chem. Lett.
1996, 10, 889.
(25) Rychnovski, S. D.; Jasti, R. J. Am. Chem. Soc. 2006, 128,
13640.
(26) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3579–3589